Caffeic Acid Phenethyl Ester Induces N-myc Downstream Regulated Gene 1 to Inhibit Cell Proliferation and Invasion of Human Nasopharyngeal Cancer Cells.
Caffeic acid phenethyl ester (CAPE), a bioactive component extracted from propolis, is widely studied due to its anti-cancer effect. Nasopharyngeal carcinoma (NPC) is distinct from other head and neck carcinomas and has a high risk of distant metastases. N-myc downstream regulated gene 1 (NDRG1) is demonstrated as a tumor suppressor gene in several cancers. Our result showed that CAPE treatment could repress NPC cell growth, through induction of S phase cell cycle arrest, and invasion. CAPE treatment stimulated NDRG1 expression in NPC cells. NDRG1 knockdown increased NPC cell proliferation and invasion and rendered NPC cells less responsive to CAPE growth-inhibiting effect, indicating CAPE repressed NPC cell growth partly through NDRG1indcution. CAPE treatment increased phosphorylation of ERK, JNK, and p38 in a dose- and time-dependent manner. Pre-treatments by inhibitors of ERK (PD0325901), JNK (SP600125), or p38 (SB201290), respectively, all could partly inhibit the CAPE effect on NDRG1 induction in NPC cells. Further, STAT3 activity was also repressed by CAPE in NPC cells. In summary, CAPE attenuates NPC cell proliferation and invasion by upregulating NDRG1 expression via MAPK pathway and by inhibiting phosphorylation of STAT3. Considering the poor prognosis of NPC patients with metastasis, CAPE could be a promising agent against NPC.


Let's Move Together.
Due to shared health behaviors and disease risk, families may be more effective targets for health promotion. This study assessed whether providing family health history (FHH)-based risk information for heart disease and diabetes affected encouragement to engage in physical activity (PA) and healthy weight (HW) maintenance and co-engagement in physical activity among 320 Mexican-origin parents and their 1,081 children. At baseline and 10 months, parents indicated who they encouraged and who encouraged them to engage in PA/HW, and with whom they co-engaged in PA. Households were randomized to receive FHH-based assessments either by one or all adult household members. Primary analyses consisted of regression analyses using generalized estimating equations. At baseline, parents reported encouraging their child for both PA and HW in 37.6% of parent-child dyads and reported receiving children's encouragement for both in 12.1% of dyads. These increased to 56.8% and 17.5% at 10 months ( p < .001). Co-engagement in PA increased from 11.4% to 15.7% ( p < .001), with younger children (30.4%) and mother-daughter dyads (26.8%) most likely to co-engage at 10 months. Providing FHH-based risk information to all adult household members (vs. one) was associated with increased parent-to-child encouragement of PA/HW ( p = .011) at 10 months but not child-to-parent encouragement. New encouragement from parent-to-child ( p = .048) and from child-to-parent ( p = .003) predicted new 10-month PA co-engagement. Providing FHH information on a household level can promote parental encouragement for PA/HW, which can promote greater parent-child co-engagement in PA. In this high-risk population with a cultural emphasis on family ties, using FHH-based risk information for all adult household members may be a promising avenue to promote PA.


Spatial turnover in host-plant availability drives host-associated divergence in a South African leafhopper (Cephalelus uncinatus).
The evolution of reproductive isolation between herbivorous insect populations is often initiated by shifts to novel host-plants, a process that underlies some of the best examples of ecological speciation. However, it is not well understood why host-shifts occur. Arguably the most common hypothesis is that host-shifts occur in response to competition, while a less frequently invoked hypothesis is that herbivores adapt locally to geographic differences in potential host-plant communities. Here we investigate whether geographic variation in host-plant availability is likely to have driven host-shifts in restio leafhoppers. We studied local adaptation of a camouflaged restio leafhopper species, Cephalelus uncinatus, to host-plants in the Restionaceae (restios); a family of plants with exceptional diversity in the anomalously species-rich Cape Floristic Region (CFR). To determine whether C. uncinatus experiences heterogeneous host communities across its range, we first quantified the degree of geographic overlap between C. uncinatus and each of its associated host-plant species. Then we quantified trait divergence (host preference, body size and colour) for three pairs of C. uncinatus populations found on different host-plant species differing in their degree of spatial overlap. Spectral reflectance was modelled in bird visual space to investigate whether body colour divergence in C. uncinatus corresponds to leaf sheath colour differences between restio species as perceived by potential predators. We demonstrate that C. uncinatus is forced to use different restio species in different regions because of turnover in available host species across its range. Comparisons between geographically separated populations were consistent with local adaptation: restio leafhoppers had preferences for local host-plants over alternative host-plants and matched local plants better in terms of size and colour. Spatial turnover in host-plant availability has likely facilitated host-shifts in C. uncinatus. Spatial turnover in host-plant availability may be an important driver of insect diversification in the CFR and globally.


On the origin of Mycobacterium ulcerans, the causative agent of Buruli ulcer.
Mycobacterium ulcerans is an unusual bacterial pathogen with elusive origins. While closely related to the aquatic dwelling M. marinum, M. ulcerans has evolved the ability to produce the immunosuppressive polyketide toxin mycolactone and cause the neglected tropical disease Buruli ulcer. Other mycolactone-producing mycobacteria (MPM) have been identified in fish and frogs and given distinct species designations (M. pseudoshottsii, M. shinshuense, M. liflandii and M. marinum), however the evolution of M. ulcerans and its relationship to other MPM has not been defined. Here we report the comparative analysis of whole genome sequences from 30 MPM and five M. marinum. A high-resolution phylogeny based on genome-wide single nucleotide polymorphisms (SNPs) showed that M. ulcerans and all other MPM represent a single clonal group that evolved from a common M. marinum progenitor. The emergence of the MPM was driven by the acquisition of the pMUM plasmid encoding genes for the biosynthesis of mycolactones. This change was accompanied by the loss of at least 185 genes, with a significant overrepresentation of genes associated with cell wall functions. Cell wall associated genes also showed evidence of substantial adaptive selection, suggesting cell wall remodeling has been critical for the survival of MPM. Fine-grain analysis of the MPM complex revealed at least three distinct lineages, one of which comprised a highly clonal group, responsible for Buruli ulcer in Africa and Australia. This indicates relatively recent transfer of M. ulcerans between these continents, which represent the vast majority of the global Buruli ulcer burden. Our data provide SNPs and gene sequences that can differentiate M. ulcerans lineages, suitable for use in the diagnosis and surveillance of Buruli ulcer. M. ulcerans and all mycolactone-producing mycobacteria are specialized variants of a common Mycobacterium marinum progenitor that have adapted to live in restricted environments. Examination of genes lost or retained and now under selective pressure suggests these environments might be aerobic, and extracellular, where slow growth, production of an immune suppressor, cell wall remodeling, loss or modification of cell wall antigens, and biofilm-forming ability provide a survival advantage. These insights will guide our efforts to find the elusive reservoir(s) of M. ulcerans and to understand transmission of Buruli ulcer.


Identification of osteoclast-specific monoclonal antibodies.
Studies on the origin, identification, and characterization of osteoclasts have been difficult. This is in part due to a lack of definitive osteoclast markers and the similarity of these cells in form and function to cells of the mononuclear phagocyte system. To solve this problem, we inoculated isolated chick osteoclasts into mice to generate osteoclast-specific monoclonal antibodies. Supernatants from growth-positive hybridomas were screened by indirect immunofluorescent methods against cultured osteoclasts, monocyte-derived multinucleated giant cells, cultured monocytes, fibroblasts, and limb mesenchyme. Select hybridomas were cloned to produce 375 clones, which were analyzed as described above. Antibody from select clones was also reacted with paraffin sections of bone. In addition, two clones have been analyzed by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Antibody binding from an osteoclast-specific clone and a clone reactive with osteoclasts, giant cells, and cultured monocytes (as determined by immunohistochemical assay) was confirmed by antibody-binding and titration curves quantitated by ELISA. The above studies demonstrate that osteoclast specific antigens exist, and that osteoclasts, giant cells, and cultured monocytes share common determinants not found on other cells screened.


Adolescent outpatient treatment and continuing care: main findings from a randomized clinical trial.
This study evaluated the effectiveness and cost-effectiveness of two types of outpatient treatment with and without Assertive Continuing Care (ACC) for 320 adolescents with substance use disorders. Study participants were randomly assigned to one of four conditions: (a) Chestnut's Bloomington Outpatient Treatment (CBOP) without ACC; (b) CBOP with ACC; (c) Motivational Enhancement Therapy/Cognitive Behavior Therapy-7 session model (MET/CBT7) without ACC; and (d) MET/CBT7 with ACC. All study conditions attained high rates of participant engagement and retention. Follow-up interviews were completed with over 90% of the adolescents at three, six, nine, and 12 months after treatment admission. There was a significant time by condition effect over 12 months, with CBOP having a slight advantage for average percentage of days abstinent. Unlike previous findings that ACC provided incremental effectiveness following residential treatment, there were no statistically significant findings with regard to the incremental effectiveness of ACC following outpatient treatment. Analysis of the costs of each intervention combined with its outcomes revealed that the most cost-effective condition was MET/CBT7 without ACC.


rahu is a mutant allele of Dnmt3c, encoding a DNA methyltransferase homolog required for meiosis and transposon repression in the mouse male germline.
Transcriptional silencing by heritable cytosine-5 methylation is an ancient strategy to repress transposable elements. It was previously thought that mammals possess four DNA methyltransferase paralogs-Dnmt1, Dnmt3a, Dnmt3b and Dnmt3l-that establish and maintain cytosine-5 methylation. Here we identify a fifth paralog, Dnmt3c, that is essential for retrotransposon methylation and repression in the mouse male germline. From a phenotype-based forward genetics screen, we isolated a mutant mouse called 'rahu', which displays severe defects in double-strand-break repair and homologous chromosome synapsis during male meiosis, resulting in sterility. rahu is an allele of a transcription unit (Gm14490, renamed Dnmt3c) that was previously mis-annotated as a Dnmt3-family pseudogene. Dnmt3c encodes a cytosine methyltransferase homolog, and Dnmt3crahu mutants harbor a non-synonymous mutation of a conserved residue within one of its cytosine methyltransferase motifs, similar to a mutation in human DNMT3B observed in patients with immunodeficiency, centromeric instability and facial anomalies syndrome. The rahu mutation lies at a potential dimerization interface and near the potential DNA binding interface, suggesting that it compromises protein-protein and/or protein-DNA interactions required for normal DNMT3C function. Dnmt3crahu mutant males fail to establish normal methylation within LINE and LTR retrotransposon sequences in the germline and accumulate higher levels of transposon-derived transcripts and proteins, particularly from distinct L1 and ERVK retrotransposon families. Phylogenetic analysis indicates that Dnmt3c arose during rodent evolution by tandem duplication of Dnmt3b, after the divergence of the Dipodoidea and Muroidea superfamilies. These findings provide insight into the evolutionary dynamics and functional specialization of the transposon suppression machinery critical for mammalian sexual reproduction and epigenetic regulation.


The Serum Oxidative/Anti-oxidative Stress Balance Becomes Dysregulated in Patients with Non-alcoholic Steatohepatitis Associated with Hepatocellular Carcinoma.
Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44). Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated. Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging. Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function.


Transformation of endocrine disrupting chemicals, pharmaceutical and personal care products during drinking water disinfection.
Pharmaceuticals and personal care products (PPCPs) and endocrine disrupting compounds (EDCs) are frequently detected in drinking water sources. This raises concerns about the formation of potentially more toxic transformation products (TPs) after drinking water disinfection. This study applied a combination of computational and experimental methods to investigate the biological activity of eight EDCs and PPCPs commonly detected in source waters (acetaminophen, bisphenol A, carbamazepine, estrone, 17α-ethinylestradiol, gemfibrozil, naproxen and triclosan) before and after disinfection. Using a Stepped Forced Molecular Dynamics (SFMD) method, we detected 911 unique TPs, 36% of which have been previously reported in the scientific literature. We calculated the likelihood that TPs would cause damage to biomolecules or DNA relative to the parent compound based on lipophilicity and the occurrence of structural alerts, and applied two Quantitative Structure-Activity Relationship (QSAR) tools to predict toxicity via receptor-mediated effects. In parallel, batch experiments were performed with three disinfectants, chlorine, chlorine dioxide and chloramine. After solid-phase extraction, the resulting TP mixtures were analyzed by chemical analysis and a battery of eleven in vitro bioassays covering a variety of endpoints. The laboratory results were in good agreement with the predictions. Overall, the combination of computational and experimental chemistry and toxicity methods used in this study suggest that disinfection of the studied EDCs and PPCPs will produce a large number of TPs, which are unlikely to increase specific toxicity (e.g., endocrine activity), but may result in increased reactive and non-specific toxicity.


Expression of an expansin is associated with endosperm weakening during tomato seed germination.
Expansins are extracellular proteins that facilitate cell wall extension, possibly by disrupting hydrogen bonding between hemicellulosic wall components and cellulose microfibrils. In addition, some expansins are expressed in non-growing tissues such as ripening fruits, where they may contribute to cell wall disassembly associated with tissue softening. We have identified at least three expansin genes that are expressed in tomato (Lycopersicon esculentum Mill.) seeds during germination. Among these, LeEXP4 mRNA is specifically localized to the micropylar endosperm cap region, suggesting that the protein might contribute to tissue weakening that is required for radicle emergence. In gibberellin (GA)-deficient (gib-1) mutant seeds, which germinate only in the presence of exogenous GA, GA induces the expression of LeEXP4 within 12 hours of imbibition. When gib-1 seeds were imbibed in GA solution combined with 100 microM abscisic acid, the expression of LeEXP4 was not reduced, although radicle emergence was inhibited. In wild-type seeds, LeEXP4 mRNA accumulation was blocked by far-red light and decreased by low water potential but was not affected by abscisic acid. The presence of LeEXP4 mRNA during seed germination parallels endosperm cap weakening determined by puncture force analysis. We hypothesize that LeEXP4 is involved in the regulation of seed germination by contributing to cell wall disassembly associated with endosperm cap weakening.


Long-term dietary treatment with increased amounts of fiber-rich low-glycemic index natural foods improves blood glucose control and reduces the number of hypoglycemic events in type 1 diabetic patients.
To evaluate in type 1 diabetic patients 1) the long-term feasibility of a high-fiber (HF) diet composed exclusively of natural foodstuffs and 2) the efficacy of this diet in relation to blood glucose control and incidence of hypoglycemic episodes. The study was randomized with parallel groups. Participants were part of a larger multicenter study on the effects of acarbose on glucose control in diabetes. A total of 63 type 1 diabetic patients, age 28 +/- 9 years, BMI 24 +/- 0.6 kg/m2, after a 4-week run-in period on their habitual diet, were randomized to either an HF (n = 32) or a low-fiber (LF) diet (n = 31) for 24 weeks. The two diets, composed exclusively of natural foodstuffs, were weight-maintaining and, aside from their fiber content, were similar for all nutrients. At the end of the run-in period and the dietary treatment, fasting blood samples for the measurement of plasma cholesterol, HDL cholesterol, triglyceride, and HbA(1c) were collected. A daily glycemic profile was performed on a day in which the participants had consumed a standard menu representative of their treatment diet (HF or LF). Of the 63 study subjects, 29 in the HF group (91%) and 25 in the LF group (81%) completed the study Compared with the LF diet, the HF diet after 24 weeks decreased both mean daily blood glucose concentrations (P < 0.05) and number of hypoglycemic events (P < 0.01). When compliance to diet was taken into account, 83% of the subjects on the HF diet and 88% on the LF diet were compliant. In this subgroup, compared with the LF diet, the HF diet significantly reduced mean daily blood glucose concentrations (P < 0.001), HbA(1c) (P < 0.05), and number of hypoglycemic events (P < 0.01). In type 1 diabetic patients, an HF diet is feasible in the long term and, compared with an LF diet, improves glycemic control and reduces the number of hypoglycemic events.


Substance use and sexual intercourse onsets in adolescence: a genetically informative discordant twin design.
Using a genetically informed, discordant twin analysis, the objective of this study was to examine whether earlier onset of drinking and smoking behaviors predicted early sexual intercourse onset. Over 3,400 adult same-sex twins from the Australian Twin Registry completed a structured interview that included retrospective reports on onsets of smoking, drinking, intoxication, and sexual intercourse and conduct disorder symptoms. A two-level frailty model estimated within-twin-pair and between-twin-pair comparisons. Onsets of smoking, drinking, drunkenness, and conduct disorder symptoms were estimated as sexual intercourse onset predictors. After controlling for conduct disorder, smoking and drinking onset did not predict sexual intercourse onset for either within-twin-pair or between-twin-pair comparisons. Drunkenness onset had a significant effect on sexual intercourse onset, such that twins who first experienced alcohol intoxication at a younger age than their co-twins were also more likely to have sex earlier than their co-twins. Relationships between substance use and sexual intercourse onsets may be due mostly to shared underlying factors; there was only a small relation between intoxication onset and sexual intercourse onset, and no direct relation between smoking and drinking onset and sexual intercourse onset.


Field Responses of Bermudagrass and Seashore paspalum Cultivars to Sting and Spiral Nematodes.
Belonolaimus longicaudatus and Helicotylenchus spp. are damaging nematode species on bermudagrass (Cynodon spp.) and seashore paspalum (Paspalum vaginatum) in sandy soils of the southeastern United States. Eight bermudagrass and three seashore paspalum cultivars were tested for responses to both nematode species in field plots for two years in Florida. Soil samples were taken every three months and nematode population densities in soil were quantified. Turfgrass aboveground health was evaluated throughout the growing season. Results showed that all bermudagrass cultivars, except TifSport, were good hosts for B. longicaudatus, and all seashore paspalum cultivars were good hosts for H. pseudorobustus. Overall, bermudagrass was a better host for B. longicaudatus while seashore paspalum was a better host for H. pseudorobustus. TifSport bermudagrass and SeaDwarf seashore paspalum cultivars supported the lowest population densities of B. longicaudatus. Seashore paspalum had a higher percent green cover than bermudagrass in the nematode-infested field. Nematode intolerant cultivars were identified.


Synaptic-like microvesicles, synaptic vesicle counterparts in endocrine cells, are involved in a novel regulatory mechanism for the synthesis and secretion of hormones.
Microvesicles in endocrine cells are the morphological and functional equivalent of neuronal synaptic vesicles. Microvesicles accumulate various neurotransmitters through a transmitter-specific vesicular transporter energized by vacuolar H(+)-ATPase. We found that mammalian pinealocytes, endocrine cells that synthesize and secrete melatonin, accumulate l-glutamate in their microvesicles and secrete it through exocytosis. Pinealocytes use l-glutamate as either a paracrine- or autocrine-like chemical transmitter in a receptor-mediated manner, resulting in inhibition of melatonin synthesis. In this article, we briefly describe the overall features of the microvesicle-mediated signal-transduction mechanism in the pineal gland and discuss the important role of acidic organelles in a novel regulatory mechanism for hormonal synthesis and secretion.


An assessment of the role of chimpanzees in AIDS vaccine research.
Prior to Simian Immunodeficiency Virus (SIV)-infected macaques becoming the 'model of choice' in the 1990s, chimpanzees were widely used in AIDS vaccine research and testing. Faced with the continued failure to develop an effective human vaccine, some scientists are calling for a return to their widespread use. To assess the past and potential future contribution of chimpanzees to AIDS vaccine development, databases and published literature were systematically searched to compare the results of AIDS vaccine trials in chimpanzees with those of human clinical trials, and to determine whether the chimpanzee trials were predictive of the human response. Protective and/or therapeutic responses have been elicited in chimpanzees, via: passive antibody transfer; CD4 analogues; attenuated virus; many types and combinations of recombinant HIV proteins; DNA vaccines; recombinant adenovirus and canarypox vaccines; and many multi-component vaccines using more than one of these approaches. Immunogenicity has also been shown in chimpanzees for vaccinia-based and peptide vaccines. Protection and/or significant therapeutic effects have not been demonstrated by any vaccine to date in humans. Vaccine responses in chimpanzees and humans are highly discordant. Claims of the importance of chimpanzees in AIDS vaccine development are without foundation, and a return to the use of chimpanzees in AIDS research/vaccine development is scientifically unjustifiable.


Herpes Simplex Encephalitis: An Uncommon Presentation.
Herpes Simplex Virus (HSV) encephalitis is an uncommon illness, with about 2 cases per 250,000 per year. Most are caused by HSV-1, with 10% having HSV-2 as the aetiologic factor. We present a case of Herpes simplex type1encephalitis in a 70 year old male with an uncommon presentation. The patient was a known case of endogenous depression with no medical records and on no treatment for the same, reported with acute changes in mental state for the past five days. He was talking irrelevantly, had hallucinations and was unduly aggressive and violent. He was subjected to a thorough clinical and diagnostic work-up which included cerebrospinal fluid analysis, CT head and MRI brain. MRI brain was suggestive of mild subdural effusion which hinted towards infectious cause of encephalitis. The cerebrospinal fluid viral serology panel detected herpes simplex type 1 virus (HSV1) that was later confirmed by CSF Polymerase Chain Reaction (PCR) technique. Hence, acyclovir was initiated by intravenous route at a dosage of 10mg/kg body weight and continued for two weeks. This case holds significance in view of the fact that organic causes must be excluded in suspected cases of psychiatric illness especially in the absence of fever. Also, CSF-PCR testing plays a pivotal role in diagnosing herpes simplex encephalitis.


The burden of invasive infections in neutropenic patients: incidence, outcomes, and use of granulocyte transfusions.
Patients with prolonged neutropenia caused by chemotherapy or underlying marrow disorders are at risk of invasive bacterial and fungal infections. New treatment options alongside targeted antimicrobial therapy that might improve outcomes include granulocyte transfusions (GTX). To inform the research agenda, a prospective observational cohort study was performed in the Netherlands and United Kingdom. The aim was to describe the incidence, characteristics, and outcomes of patients developing invasive infections and assess patients fulfilling criteria for GTX. All patients receiving myeloablative chemotherapy and anticipated to develop 7 or more days of neutropenia (<0.5 × 109 /L) were eligible and followed for the development of invasive infections according to a defined algorithm and mortality up to 100 days. Secondary outcomes were types of infection and eligibility for GTX. A total of 471 patients enrolled at six hematology-oncology departments were followed for 569 neutropenic episodes. Overall, 32.5% of patients developed invasive infections during their first episode. Significant baseline risk factors for developing infections were high comorbidity scores (WHO performance status ≥ 2, hazard ratio [HR], 2.6 [1.7-3.9]; and hematopoietic cell transplantation-comorbidity index score ≥ 2 HR 1.3 [0.9-1.8]). Infections were bacterial (59.4%) and fungal (22.3%). Despite 34 patients (6.3% of all episodes) appearing to meet criteria to receive GTX, only nine patients received granulocytes. The HR for death was 5.8 (2.5-13.0) for patients with invasive infections. This study documents that invasive infections are associated with significant mortality. There is a need for new strategies to prevent and treat infections, which may include better understanding of use GTX.


Ca(2+)-handling proteins and heart failure: novel molecular targets?
Calcium (Ca(2+)) ions are the currency of heart muscle activity. During excitation-contraction coupling Ca(2+) is rapidly cycled between the cytosol (where it activates the myofilaments) and the sarcoplasmic reticulum (SR), the Ca(2+) store. These fluxes occur by the transient activity of Ca(2+)-pumps and -channels. In the failing human heart, changes in activity and expression profile of Ca(2+)-handling proteins, in particular the SR Ca(2+)-ATPase (SERCA2a), are thought to cause an overall reduction in the amount of SR-Ca(2+) available for contraction. In the steady state, the Ca(2+)-content of the SR is essentially a balance between Ca(2+)-uptake via SERCA2a pump and Ca(2+)-release via the cardiac SR Ca(2+)-release channel complex (Ryanodine receptor, RyR2). This review discusses current pharmacological options available to enhance cardiac SR Ca(2+) content and the implications of this approach as an inotropic therapy in heart failure. Two options are considered: (i) activation of the SERCA2a pump to increase SR Ca(2+)-uptake, and (ii) reduction of SR Ca(2+)-leakage through RyR2. RyR2 forms a macromolecular complex with a number of regulatory proteins that either remain permanently bound or that interact in a time- and/or Ca(2+)-dependant manner. These regulatory proteins can dramatically affect RyR2 function, e.g. over-expression of the accessory protein FK 506-binding protein 12.6 (FKBP12.6) has recently been shown to reduce SR Ca(2+)-leak. Recent attempts to design positive inotropes for chronic administrations have focussed on the use of phosphodiesterase III inhibitors (PDE III inhibitors). These compounds, which increase intracellular cAMP-levels, have failed in clinical trials. Therefore medical researchers are seeking new drugs that act through alternative pathways. Novel cardiac inotropes targeting SR Ca(2+)-cycling proteins may have the potential to fill this gap.


Immunization with matrix-, nucleoprotein and neuraminidase protects against H3N2 influenza challenge in pH1N1 pre-exposed pigs.
There is an urgent need for influenza vaccines providing broader protection that may decrease the need for annual immunization of the human population. We investigated the efficacy of heterologous prime boost immunization with chimpanzee adenovirus (ChAdOx2) and modified vaccinia Ankara (MVA) vectored vaccines, expressing conserved influenza virus nucleoprotein (NP), matrix protein 1 (M1) and neuraminidase (NA) in H1N1pdm09 pre-exposed pigs. We compared the efficacy of intra-nasal, aerosol and intra-muscular vaccine delivery against H3N2 influenza challenge. Aerosol prime boost immunization induced strong local lung T cell and antibody responses and abrogated viral shedding and lung pathology following H3N2 challenge. In contrast, intramuscular immunization induced powerful systemic responses and weak local lung responses but also abolished lung pathology and reduced viral shedding. These results provide valuable insights into the development of a broadly protective influenza vaccine in a highly relevant large animal model and will inform future vaccine and clinical trial design.


The mobilome of Lactobacillus crispatus M247 includes two novel genetic elements: Tn7088 coding for a putative bacteriocin and the siphovirus prophage ΦM247.
Lactobacillus crispatus is a member of the vaginal and gastrointestinal human microbiota. Here we determined the complete genome sequence of the probiotic strain M247 combining Nanopore and Illumina technologies. The M247 genome is organized in one circular chromosome of 2 336 109 bp, with a GC content of 37.04 % and 2303 ORFs, of which 1962 could be annotated. Analysis of the M247 mobilome, which accounts for 14 % of the whole genome, revealed the presence of: (i) Tn7088, a novel 14 105 bp long integrative and mobilizable element (IME) containing 16 ORFs; (ii) ΦM247, a novel 42 510 bp long siphovirus prophage containing 52 ORFs; (iii) three clustered regularly interspaced short palindromic repeats (CRISPRs); and (iv) 226 insertion sequences (ISs) belonging to 14 different families. Tn7088 has a modular organization including a mobilization module encoding FtsK homologous proteins and a relaxase, an integration/excision module coding for an integrase and an excisionase, and an adaptation module coding for a class I bacteriocin and homologous to the listeriolysin S (lls) locus of Listeria monocytogenes. Genome-wide homology search analysis showed the presence of Tn7088-like elements in 12 out of 23 L. crispatus complete public genomes. Mobilization and integration/excision modules are essentially conserved, while the adaptation module is variable since it is the target site for the integration of different ISs. Prophage ΦM247 contains genes for phage structural proteins, DNA replication and packaging, lysogenic and lytic cycles. ΦM247-like prophages are present in seven L. crispatus complete genomes, with sequence variability mainly due to the integration of ISs. PCR and sequencing showed that the Tn7088 IME excises from the M247 chromosome producing a circular form at a concentration of 4.32×10-5 copies per chromosome, and reconstitution of the Tn7088 chromosomal target site occurred at 6.65×10-4 copies per chromosome. The ΦM247 prophage produces an excised form and a reconstituted target site at a level of 3.90×10-5 and 2.48×10-5 copies per chromosome, respectively. This study identified two novel genetic elements in L. crispatus. Tn7088 represents the first example of an IME carrying a biosynthetic gene cluster for a class I bacteriocin in L. crispatus.


Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: results from SWOG 0421.
Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration-resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value of bone biomarkers in sera from CRPC patients treated on a placebo-controlled phase III trial of docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan (SWOG S0421). Markers for bone resorption (N-telopeptide and pyridinoline) and formation (C-terminal collagen propeptide and bone alkaline phosphatase) were assayed in pretreatment and serial sera. Cox proportional hazards regression models were fit for overall survival. Models were fit with main effects for marker levels and with/without terms for marker-treatment interaction, adjusted for clinical variables, to assess the prognostic and predictive value of atrasentan. Analysis was adjusted for multiple comparisons. Two-sided P values were calculated using the Wald test. Sera from 778 patients were analyzed. Elevated baseline levels of each of the markers were associated with worse survival (P < .001). Increasing marker levels by week nine of therapy were also associated with subsequent poor survival (P < .001). Patients with the highest marker levels (upper 25th percentile for all markers) not only had a poor prognosis (hazard ratio [HR] = 4.3; 95% confidence interval [CI] = 2.41 to 7.65; P < .001) but also had a survival benefit from atrasentan (HR = 0.33; 95% CI = 0.15 to 0.71; median survival = 13 [atrasentan] vs 5 months [placebo]; P interaction = .005). Serum bone metabolism markers have statistically significant independent prognostic value in CRPC. Importantly, a small group of patients (6%) with highly elevated markers of bone turnover appear to preferentially benefit from atrasentan therapy.


Complete congenital heart block in a neonate with a complex congenital heart defect in Africa.
Congenital heart block (CHB) is rare disorder that has a higher mortality when associated with structural congenital heart defects. Very few cases have been reported in Sub-Saharan Africa (SSA). We present a case of complete CHB associated with a complex congenital heart defect in a neonate in Cameroon. A 1-month-old neonate in Cameroon was referred for the evaluation of bradycardia. The obstetrical ultrasound done during pregnancy revealed fetal bradycardia without further evaluation. Clinical examination showed well a developed neonate with bradycardia at 62 beats/minute, and mild cyanosis with oxygen saturation at 93% at room air. There were no signs of heart failure. Twelve lead electrocardiogram (ECG) demonstrated a complete atrioventricular conduction block with a junctional escape rhythm at 59/minute, left axis deviation and bi-ventricular hypertrophy. Two-dimensional echocardiography revealed a complex congenital heart disease with the following abnormalities: dextrocardia, complete atrioventricular canal with a single atrium and mild atrioventricular valve regurgitation and malposition of the great vessels with a posterior aorta and an anterior pulmonary artery. This case report highlights the challenges in the diagnosis and management of complex CHBs in low resource settings. A properly performed pregnancy follow-up with serial echocardiograms could aid in antenatal diagnosis and plan perinatal management when appropriate in order to optimize outcome. This emphasizes the clinical value of high quality antenatal care and proper screening.


Wound-healing defect of CD18(-/-) mice due to a decrease in TGF-beta1 and myofibroblast differentiation.
We studied the mechanisms underlying the severely impaired wound healing associated with human leukocyte-adhesion deficiency syndrome-1 (LAD1) using a murine disease model. In CD18(-/-) mice, healing of full-thickness wounds was severely delayed during granulation-tissue contraction, a phase where myofibroblasts play a major role. Interestingly, expression levels of myofibroblast markers alpha-smooth muscle actin and ED-A fibronectin were substantially reduced in wounds of CD18(-/-) mice, suggesting an impaired myofibroblast differentiation. TGF-beta signalling was clearly involved since TGF-beta1 and TGF-beta receptor type-II protein levels were decreased, while TGF-beta(1) injections into wound margins fully re-established wound closure. Since, in CD18(-/-) mice, defective migration leads to a severe reduction of neutrophils in wounds, infiltrating macrophages might not phagocytose apoptotic CD18(-/-) neutrophils. Macrophages would thus be lacking their main stimulus to secrete TGF-beta1. Indeed, in neutrophil-macrophage cocultures, lack of CD18 on either cell type leads to dramatically reduced TGF-beta1 release by macrophages due to defective adhesion to, and subsequent impaired phagocytic clearance of, neutrophils. Our data demonstrates that the paracrine secretion of growth factors is essential for cellular differentiation in wound healing.


PRIMARY ABANDON-OF-THE-SAC (PAS) TECHNIQUE: PRELIMINARY RESULTS OF A NOVEL MINIMALLY INVASIVE APPROACH FOR INGUINOSCROTAL HERNIA REPAIR.
Laparoscopic best approach of repairing inguinoscrotal hernias are still debatable. Incorrect handling of the distal sac can possibly result in damage to cord structures and negative postoperative outcomes as ischemic orquitis or inguinal neuralgia. To describe a new technique for a minimally invasive approach to inguinoscrotal hernias and to analyze the preliminary results of patients undergoing the procedure. A review of a prospectively maintained database was conducted in patients who underwent minimally invasive repair using the "primary abandon-of-the-sac" (PAS) technique for inguinoscrotal hernias. Patient´s demographics, as well as intraoperative variables and postoperative outcomes were also analyzed. Twenty-six male were submitted to this modified procedure. Mean age of the case series was 53.8 years (range 34-77) and body mass index was 26.8 kg/m2 (range 20.8-34.2). There were no intraoperative complications or conversion. Average length of stay was one day. No surgical site infections, pseudo hydrocele or neuralgia were reported after the procedure and two patients presented seroma. No inguinal hernia recurrence was verified during the mean 21.4 months of follow up. The described technique is safe, feasible and reproducible, with good postoperative results.


Fast skeletal muscle troponin activation increases force of mouse fast skeletal muscle and ameliorates weakness due to nebulin-deficiency.
The effect of the fast skeletal muscle troponin activator, CK-2066260, on calcium-induced force development was studied in skinned fast skeletal muscle fibers from wildtype (WT) and nebulin deficient (NEB KO) mice. Nebulin is a sarcomeric protein that when absent (NEB KO mouse) or present at low levels (nemaline myopathy (NM) patients with NEB mutations) causes muscle weakness. We studied the effect of fast skeletal troponin activation on WT muscle and tested whether it might be a therapeutic mechanism to increase muscle strength in nebulin deficient muscle. We measured tension-pCa relations with and without added CK-2066260. Maximal active tension in NEB KO tibialis cranialis fibers in the absence of CK-2066260 was ∼60% less than in WT fibers, consistent with earlier work. CK-2066260 shifted the tension-calcium relationship leftwards, with the largest relative increase (up to 8-fold) at low to intermediate calcium levels. This was a general effect that was present in both WT and NEB KO fiber bundles. At pCa levels above ∼6.0 (i.e., calcium concentrations <1 µM), CK-2066260 increased tension of NEB KO fibers to beyond that of WT fibers. Crossbridge cycling kinetics were studied by measuring k(tr) (rate constant of force redevelopment following a rapid shortening/restretch). CK-2066260 greatly increased k(tr) at submaximal activation levels in both WT and NEB KO fiber bundles. We also studied the sarcomere length (SL) dependence of the CK-2066260 effect (SL 2.1 µm and 2.6 µm) and found that in the NEB KO fibers, CK-2066260 had a larger effect on calcium sensitivity at the long SL. We conclude that fast skeletal muscle troponin activation increases force at submaximal activation in both wildtype and NEB KO fiber bundles and, importantly, that this troponin activation is a potential therapeutic mechanism for increasing force in NM and other skeletal muscle diseases with loss of muscle strength.


Scientific misconduct. Panel finds scores of suspect papers in German fraud probe.
A new report paints a darker picture of what may be the highest profile case of scientific fraud in postwar Germany. After a 2-year investigation of all 347 scientific articles co-authored by former hematologist and cancer researcher Friedhelm Herrmann, a task force jointly sponsored by Germany's main granting agency, the DFG, and the country's largest cancer charity released a report on 19 June indicating that the scope of the fraud--first uncovered 3 years ago--is far more extensive than previously thought. Although Herrmann and a co-author have left their academic posts, the new revelations could place other careers in jeopardy.


Acidic pH-targeted chitosan capped mesoporous silica coated gold nanorods facilitate detection of pancreatic tumors via multispectral optoacoustic tomography.
We present a cancer nanomedicine based on acidic pH targeted gold nanorods designed for multispectral optoacoustic tomography (MSOT). We have designed gold nanorods coated with mesoporous silica and subsequently capped with chitosan (CMGs). We have conjugated pH-sensitive variant 7 pHLIP peptide to the CMGs (V7-CMG) to provide targeting specificity to the acidic tumor microenvironment. In vitro, treatment of S2VP10 and MiaPaca2 cells with V7-CMG containing gemcitabine resulted in significantly greater cytotoxicity with 97% and 96.5% cell death, respectively than gemcitabine alone 60% and 76% death at pH 6.5 (S2VP10 pH 6.5 p=0.009; MiaPaca2 pH 6.5 p=0.0197). In vivo, the V7-CMGs provided the contrast and targeting specificity necessary for MSOT of retroperitoneal orthotopic pancreatic tumors. In the in vivo S2VP10 model, the V7-CMG particle preferentially accumulated within the tumor at 17.1 MSOT a.u. signal compared with 0.7 MSOT a.u. in untargeted CMG control in tumor (P = 0.0002). Similarly, V7-CMG signal was 9.34 MSOT a.u. in the S2013 model compared with untargeted CMG signal at 0.15 MSOT a.u. (P = 0.0004). The pH-sensitivity of the targeting pHLIP peptide and chitosan coating makes the particles suitable for simultaneous in vivo tumor imaging and drug delivery.


How would the tobacco retail landscape change if tobacco was only sold through liquor stores, petrol stations or pharmacies?
To examine the potential impact of tobacco being available only from pharmacies, only from liquor stores or only from petrol stations on the New Zealand tobacco retail landscape. Tobacco retailers and pharmacies were mapped using GIS. Comparisons were made between tobacco retailers and pharmacies. Simple linear regression was used to assess the relationship between outlet types and deprivation. A total of 5,243 tobacco outlets, including liquor stores and petrol stations, and 1,035 pharmacies were identified. The density of all outlets was greater in areas of higher deprivation. The majority of tobacco retailers and pharmacies were located in urban areas. Outlets were mapped in relation to walking distances from secondary schools; significant differences between outlet types are presented. The policy options examined in this study would considerably reduce the overall availability of tobacco, decrease cues to smoke and reduce the density of tobacco sales around schools. However, inequities in availability would exist with access to tobacco in rural areas disproportionately reduced, and a positive sociodemographic gradient remaining. Implications for public health: Substantially reducing tobacco availability has been identified as a crucial tobacco control strategy. This study provides information on the impact of different policy options to support Smokefree 2025.


Modulation of a small two-domain lipid vesicle by linactants.
Linactants, molecules that preferentially localize at the boundary of lipid membrane domains, are attracting considerable attention in recent years due to the recognition that they might regulate lipid-phase separation and thereby modulate membrane morphology. Recent studies have also shown that clustering of some line active agents enhances their ability to modulate membrane curvature. However, the molecular origin of this phenomenon, and the degree to which it impacts biological membranes, remains poorly understood. In this work, we have investigated how linactants induce shape change in multidomain small unilamallar vesicles (SUVs) using extensive dissipative particle dynamics simulations. The linactant was modeled as a two-tailed hybrid lipid with the two tails differing in preference for different lipid domains. We found that addition of a small amount of linactants (∼1%) to a two-domain vesicle leads to substantial reduction in the line tension and neck curvature at the domain boundary. Using cross-linking as a surrogate for clustering, we further show that linactant clusters substantially enhance the boundary preference and therefore the reduction in neck curvature. Moreover, on the basis of analyses of the corresponding changes in the membrane energetics, we highlight how linactants might stabilize nanoscale domains. These results have important implications for the potential existence and physical explanations of nanosized domains in biological membranes.


Convergence-Zone Episodic Memory: Analysis and Simulations.
Human episodic memory provides a seemingly unlimited storage for everyday experiences, and a retrieval system that allows us to access the experiences with partial activation of their components. The system is believed to consist of a fast, temporary storage in the hippocampus, and a slow, long-term storage within the neocortex. This paper presents a neural network model of the hippocampal episodic memory inspired by Damasio's idea of Convergence Zones. The model consists of a layer of perceptual feature maps and a binding layer. A perceptual feature pattern is coarse coded in the binding layer, and stored on the weights between layers. A partial activation of the stored features activates the binding pattern, which in turn reactivates the entire stored pattern. For many configurations of the model, a theoretical lower bound for the memory capacity can be derived, and it can be an order of magnitude or higher than the number of all units in the model, and several orders of magnitude higher than the number of binding-layer units. Computational simulations further indicate that the average capacity is an order of magnitude larger than the theoretical lower bound, and making the connectivity between layers sparser causes an even further increase in capacity. Simulations also show that if more descriptive binding patterns are used, the errors tend to be more plausible (patterns are confused with other similar patterns), with a slight cost in capacity. The convergence-zone episodic memory therefore accounts for the immediate storage and associative retrieval capability and large capacity of the hippocampal memory, and shows why the memory encoding areas can be much smaller than the perceptual maps, consist of rather coarse computational units, and are only sparsely connected to the perceptual maps. Copyright 1997 Elsevier Science Ltd.


LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria.
Mutations in LRPPRC are responsible for the French Canadian variant of Leigh syndrome (LSFC), a neurodegenerative disorder caused by a tissue-specific deficiency in cytochrome c oxidase (COX). To investigate the pathogenic mechanism of disease, we studied LRPPRC function in LSFC and control fibroblasts. The level of mutated LRPPRC is reduced in LSFC cells, and this results in decreased steady-state levels of most mitochondrial mRNAs, but not rRNAs or tRNAs, a phenotype that can be reproduced by siRNA-mediated knockdown of LRPPRC in control cells. Processing of the primary transcripts appears normal. The resultant defect in mitochondrial protein synthesis in LSFC cells disproportionately affects the COX subunits, leading to an isolated COX assembly defect. Further knockdown of LRPPRC produces a generalized assembly defect in all oxidative phosphorylation complexes containing mtDNA-encoded subunits, due to a severe decrease in all mitochondrial mRNAs. LRPPRC exists in a high-molecular-weight complex, and it coimmunoprecipitates with SLIRP, a stem-loop RNA-binding protein. Although this interaction does not depend on mitochondrial mRNA, both proteins show reduced stability in its absence. These results implicate LRPPRC in posttranscriptional mitochondrial gene expression as part of a ribonucleoprotein complex that regulates the stability and handling of mature mRNAs.


A nickel iron diselenide-derived efficient oxygen-evolution catalyst.
Efficient oxygen-evolution reaction catalysts are required for the cost-effective generation of solar fuels. Metal selenides have been reported as promising oxygen-evolution catalysts; however, their active forms are yet to be elucidated. Here we show that a representative selenide catalyst, nickel selenide, is entirely converted into nickel hydroxide under oxygen-evolution conditions. This result indicates that metal selenides are unstable during oxygen evolution, and the in situ generated metal oxides are responsible for their activity. This knowledge inspired us to synthesize nanostructured nickel iron diselenide, a hitherto unknown metal selenide, and to use it as a templating precursor to a highly active nickel iron oxide catalyst. This selenide-derived oxide catalyses oxygen evolution with an overpotential of only 195 mV for 10 mA cm(-2). Our work underscores the importance of identifying the active species of oxygen-evolution catalysts, and demonstrates how such knowledge can be applied to develop better catalysts.


High dietary fat and sucrose results in an extensive and time-dependent deterioration in health of multiple physiological systems in mice.
Obesity is associated with metabolic dysfunction, including insulin resistance and hyperinsulinemia, and with disorders such as cardiovascular disease, osteoporosis, and neurodegeneration. Typically, these pathologies are examined in discrete model systems and with limited temporal resolution, and whether these disorders co-occur is therefore unclear. To address this question, here we examined multiple physiological systems in male C57BL/6J mice following prolonged exposure to a high-fat/high-sucrose diet (HFHSD). HFHSD-fed mice rapidly exhibited metabolic alterations, including obesity, hyperleptinemia, physical inactivity, glucose intolerance, peripheral insulin resistance, fasting hyperglycemia, ectopic lipid deposition, and bone deterioration. Prolonged exposure to HFHSD resulted in morbid obesity, ectopic triglyceride deposition in liver and muscle, extensive bone loss, sarcopenia, hyperinsulinemia, and impaired short-term memory. Although many of these defects are typically associated with aging, HFHSD did not alter telomere length in white blood cells, indicating that this diet did not generally promote all aspects of aging. Strikingly, glucose homeostasis was highly dynamic. Glucose intolerance was evident in HFHSD-fed mice after 1 week and was maintained for 24 weeks. Beyond 24 weeks, however, glucose tolerance improved in HFHSD-fed mice, and by 60 weeks, it was indistinguishable from that of chow-fed mice. This improvement coincided with adaptive β-cell hyperplasia and hyperinsulinemia, without changes in insulin sensitivity in muscle or adipose tissue. Assessment of insulin secretion in isolated islets revealed that leptin, which inhibited insulin secretion in the chow-fed mice, potentiated glucose-stimulated insulin secretion in the HFHSD-fed mice after 60 weeks. Overall, the excessive calorie intake was accompanied by deteriorating function of numerous physiological systems.


The genetics of adult-onset neuropsychiatric disease: complexities and conundra?
Genetic factors play a major role in the etiology of adult-onset neurodegenerative and neuropsychiatric disorders. Several highly penetrant genes have been cloned for rare, autosomal-dominant, early-onset forms of neurodegenerative diseases. These genes have provided important insights into the mechanisms of these diseases (often altering neuronal protein processing). However, the genes associated with inherited susceptibility to late-onset neurodegenerative diseases, schizophrenia, and bipolar disorder appear to have smaller effects and are likely to interact with each other (and with nongenetic factors) to modulate susceptibility and/or disease phenotype. Several strategies have recently been applied to address this complexity, leading to the identification of a number of candidate susceptibility loci/genes.


Responsive complementary feeding in rural Bangladesh.
It is now widely recognized that malnutrition can partly be attributed to caregiver-child interaction during feeding episodes. Current conceptual frameworks emphasize the importance of responsiveness (including active and social behaviour), psychomotor abilities of the child to self-feed, and a non-distracting feeding environment. The present observational study had three main objectives: (1) to define operationally key terms such as responsive and active feeding and observe their frequency in a rural Bangladesh sample; (2) to examine whether self-feeding, responsive and active behaviours of the mother and child varied with child's age and amounts eaten; and (3) to determine associations between mother and child behaviours. Fifty-four mother-child pairs were observed during one feeding episode and behaviours were coded for 5 categories, namely self-feeding, responsive, active, social and distracting behaviours. Children were between 8 and 24 months of age. Results indicated that the five behaviours could be observed and reliably coded. Two-thirds of mothers had an active feeding style but only a third were responsive; the two styles did not overlap. With older children, mothers encouraged more eating and more self-feeding, but children did not feed themselves more; instead older children were more negatively responsive (refusing offered food). Positively responsive mothers tended to have active children who explicitly signaled their desire for food or water, and who ate more mouthfuls of food. Positively active mothers adopted different strategies to encourage eating, such as verbally directing the child to eat, focusing, and temporarily diverting. These mothers tended to have children who were negatively responsive and refused food. Children accepted on average 5.31 mouthfuls of food and rejected 2.13. Mothers who used intrusively active strategies (e.g. force feeding) tended to have children who were both positively and negatively responsive, thus partially reinforcing her forceful behaviour. Thus, the responsive feeding framework, once operationalized, has the potential to identify specific behaviours that support or impede mother-child interaction during complementary feeding.


Early sexual abuse and clinical depression in adult life.
Sexual abuse in childhood and adolescence was studied in 286 working-class mothers living in Islington, who were contacted on three occasions over a two-year period. The sample was collected primarily to study current vulnerability factors in the onset of depression, but childhood measures were also included to look at longer-term risk factors. Twenty-five women - 9% of the sample - reported sexual abuse involving physical contact before age 17 and, of these, 64% had case depression in a three-year period (which included the year before first interview). While such abuse was related to other earlier stressful experiences such as parental indifference, violence to the child and institutional stay, it was associated with an increased risk of depression over and above these factors. Sexual abuse before age 17 also related to having been divorced/separated or never having married/cohabited.


Intracranial self-stimulation motivates weight-lifting exercise in rats.
The purpose of this study was to determine the feasibility of using a positive reinforcement protocol to motivate weight-lifting exercise in rats. Intracranial self-stimulation was used to induce weight-lifting exercise. Bipolar electrodes were implanted in the ventral tegmental area of rats, and the animals were trained to bar press on a continuous reinforcement schedule for electrical brain stimulation. Animals with response rates of 1,200-1,500 presses/h were then trained with a discriminative light stimulus to alternate between a normally positioned bar and an elevated bar that could be reached only by standing on the hindlimbs. The animals were fitted with a weighted jacket at a starting resistance of 5-10% of their body weight. Weight-training sessions were conducted 5 days/wk for 10 wk. Training consisted of 600 presses/session, alternating every 15 presses between the low and high bars. At the beginning of each subsequent week, the resistance was progressively increased, with some animals eventually training at resistances greater than 50% of their body weight. At the end of the training period, the rats were lifting over 550% of the starting weight. Gastrocnemius size and mean fiber diameter were increased in the weight-lifting animals. This model combines exercise with positive incentive and has the advantages of being relatively easy to implement and not producing any apparent physical or mental trauma in the animal.


Natural variation of poliovirus neutralization epitopes.
Poliovirus-neutralizing monoclonal antibodies were prepared against type 1, type 2, and type 3 wild laboratory (Mahoney, MEF1, and Saukett) and Sabin vaccine strains. Fifty-five poliovirus laboratory strains and field isolates were assayed by neutralization index test with a panel of homotypic monoclonal antibodies. A total of 27 monoclonal antibodies were used. Two categories of neutralization epitopes were found, i.e., cross-reacting (K), which is present on almost all strains of the same serotype, and strain-specific (V, variable), either wild (VW) or Sabin (VS). Several distinct neutralization epitopes were defined for each of the three poliovirus serotypes in almost every category. The study of antigenic variation of the Sabin type 1 vaccine virus during replication in human intestine showed that the VS neutralization epitope may be lost and even replaced by the VW epitopes of the parental Mahoney virus. A late isolate from a vaccine-fed infant recovered the complete neutralization epitope pattern of the Mahoney strain. Upon in vivo virus replication, a different kind of antigenic variation was also detected in which an epitope lost its function in virus neutralization but kept its antigenic conformation unaltered. Neutralization epitope analysis demonstrated that the presence of VS epitopes on a field isolate suggests the Sabin origin of the strain when the isolate displays the same epitope pattern as the original Sabin virus, or confirms it when the VS epitope(s) is mutually exclusive of VW epitopes. The lack of VS epitopes on a field isolate does not rule out its being of Sabin origin.


Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I.
Ubiquitin (Ub) has important roles in a wide range of intracellular signalling pathways. In the conventional view, ubiquitin alters the signalling activity of the target protein through covalent modification, but accumulating evidence points to the emerging role of non-covalent interaction between ubiquitin and the target. In the innate immune signalling pathway of a viral RNA sensor, RIG-I, both covalent and non-covalent interactions with K63-linked ubiquitin chains (K63-Ubn) were shown to occur in its signalling domain, a tandem caspase activation and recruitment domain (hereafter referred to as 2CARD). Non-covalent binding of K63-Ubn to 2CARD induces its tetramer formation, a requirement for downstream signal activation. Here we report the crystal structure of the tetramer of human RIG-I 2CARD bound by three chains of K63-Ub2. 2CARD assembles into a helical tetramer resembling a 'lock-washer', in which the tetrameric surface serves as a signalling platform for recruitment and activation of the downstream signalling molecule, MAVS. Ubiquitin chains are bound along the outer rim of the helical trajectory, bridging adjacent subunits of 2CARD and stabilizing the 2CARD tetramer. The combination of structural and functional analyses reveals that binding avidity dictates the K63-linkage and chain-length specificity of 2CARD, and that covalent ubiquitin conjugation of 2CARD further stabilizes the Ub-2CARD interaction and thus the 2CARD tetramer. Our work provides unique insights into the novel types of ubiquitin-mediated signal-activation mechanism, and previously unexpected synergism between the covalent and non-covalent ubiquitin interaction modes.


Osteoporosis treated with magnesium lactate.
33 patients with senile, 18 patients with postmenopausal and 9 patients with medicamentous (corticosteroids) osteoporosis were treated with single therapy of Mg lactate (37 patients) and with the combined one of Mg lactate and Na fluoride (23 patients). They were evaluated in three periods of half a year, one year, two years. The better results were achieved with the single therapy than with the combined one and in the senile and postmenopausal osteoporosis than in the medicamentous one. Pain and restricted spine movement were influenced favourably. Kyphosis and x-ray findings were stabilized.


Dietary habits and supplement use in relation to national pregnancy recommendations: data from the EuroPrevall birth cohort.
Assessing maternal dietary habits across Europe during pregnancy in relation to their national pregnancy recommendations. A collaborative, multi-centre, birth cohort study in nine European countries was conducted as part of European Union funded EuroPrevall project. Standardised baseline questionnaire data included details of food intake, nutritional supplement use, exposure to cigarette smoke during pregnancy and socio-demographic data. Pregnancy recommendations were collected from all nine countries from the appropriate national organisations. The most commonly taken supplement in pregnancy was folic acid (55.6 % Lithuania-97.8 % Spain) and was favoured by older, well-educated mothers. Vitamin D supplementation across the cohort was very poor (0.3 % Spain-5.1 % Lithuania). There were significant differences in foods consumed in different countries during pregnancy e.g. only 2.7 % Dutch mothers avoided eating peanut, while 44.4 % of British mothers avoided it. Some countries have minimal pregnancy recommendations i.e. Lithuania, Poland and Spain while others have similar, very specific recommendations i.e. UK, the Netherlands, Iceland, Greece. Allergy specific recommendations were associated with food avoidance during pregnancy [relative rate (RR) 1.18 95 % CI 0.02-1.37]. Nutritional supplement recommendations were also associated with avoidance (RR 1.08, 1.00-1.16). Maternal dietary habits and the use of dietary supplements during pregnancy vary significantly across Europe and in some instances may be influenced by national recommendations.


Identifying and overcoming the barriers to bedside rounds: a multicenter qualitative study.
The use of bedside rounds in teaching hospitals has declined, despite recommendations from educational leaders to promote this effective teaching strategy. The authors sought to identify reasons for the decrease in bedside rounds, actual barriers to bedside rounds, methods to overcome trainee apprehensions, and proposed strategies to educate faculty. A qualitative inductive thematic analysis using transcripts from audio-recorded, semistructured telephone interviews with a purposive sampling of 34 inpatient attending physicians from 10 academic U.S. institutions who met specific inclusion criteria for "bedside rounds" was performed in 2010. Main outcomes were themes pertaining to barriers, methods to overcome trainee apprehensions, and strategies to educate faculty. Quotations highlighting themes are reported. Half of respondents (50%) were associate or full professors, averaging 14 years in academic medicine. Primary reasons for the perceived decline in bedside rounds were physician- and systems related, although actual barriers encountered related to systems, time, and physician-specific issues. To address resident apprehensions, six themes were identified: build partnerships, create safe learning environments, overcome with experience, make bedside rounds educationally worthwhile, respect trainee time, and highlight positive impact on patient care. Potential strategies for educating faculty were identified, most commonly faculty development initiatives, divisional/departmental culture change, and one-on-one shadowing opportunities. Bedside teachers encountered primarily systems- and time-related barriers and overcame resident apprehensions by creating a learner-oriented environment. Strategies used by experienced bedside teachers can be used for faculty development aimed at promoting bedside rounds.


Resource use trends in extracorporeal membrane oxygenation in adults: an analysis of the Nationwide Inpatient Sample 1998-2009.
The study objective was to determine whether significant trends over time have occurred in resource use associated with the use of extracorporeal membrane oxygenation in critically ill adults. All adult admissions involving extracorporeal membrane oxygenation were examined by using the Nationwide Inpatient Sample database (years 1998-2009). Trends in volume, outcome, and resource use (including hospital charges, length of stay, and charges per day) were analyzed. An estimated total of 8753 admissions involved extracorporeal membrane oxygenation over the study period. Overall length of stay was 18.3 ± 1.3 days. Total hospital charges averaged $344,009 ± $30,707 per admission, with average charges per day of $40,588 ± $3099. Cumulative national charges for extracorporeal membrane oxygenation admissions increased significantly from $109.0 million in 1998 to $764.7 million in 2009 (P = .0016). Charges per patient and length of stay also increased significantly (P = .0032 and .0321, respectively). The increasing trend in the number of extracorporeal membrane oxygenation admissions during the study period was not statistically significant (P = .19). The post-cardiotomy group had more favorable outcomes and lower resource use. A shift was observed in the relative case-mix of extracorporeal membrane oxygenation admissions over the study period, with a relative decrease in the post-cardiotomy group and increases in the cardiogenic shock, respiratory failure, and lung transplant groups. These results suggest that dramatic increases in resource use associated with extracorporeal membrane oxygenation are not solely the result of increased volume, but in part are due to a shift toward extracorporeal membrane oxygenation use in patient groups (other than in the post-cardiotomy setting) with greater resource use and worse outcomes.


Collegiate and high school athlete neck strength in neutral and rotated postures.
A knowledge of neck strength is important for developing conditioning protocols and for evaluating the relationship between neck strength and head and neck injury, but very few studies have examined neck strength in relationship to athletic participation. The purpose of this study was to quantify isometric neck strength in collegiate and high school athletes. We hypothesized that (a) male athletes would have significantly greater neck strength than females; (b) collegiate athletes would be significantly stronger than high school athletes; and (c) neck strength would vary significantly with head posture. A total of 149 subjects participated (77 men and 72 women; 90 college and 59 high school level). Flexion, extension, and lateral flexion neck strength were measured in neutral and rotated head and neck postures. Neck strength varied significantly according to participants' sex, age, and posture (p < 0.05). Male college students were stronger than those in all other groups (female college students, male high school students, and female high school students). The average female neck strength was 61, 54, and 56% of the average male neck strength for extension, flexion, and lateral flexion, respectively. High school athletes' neck strength was 75, 68, and 65% of collegiate athletes' neck strength for extension, flexion, and lateral flexion, respectively. On average, neck strength was the greatest for extension compared with other force directions. The subjects showed large variation in neck strength with posture, but in general, there were no consistent trends among the subjects. This finding suggests that those whose neck strength was considerably lower in nonneutral postures may consider training to increase strength in rotated postures. These data provide important baseline information for future studies evaluating injury risk or training protocols.


Naturally occurring, nonregressing canine oral papillomavirus infection: host immunity, virus characterization, and experimental infection.
Papillomaviruses occasionally cause severe, nonregressing or recurrent infections in their human and animal hosts. The mechanisms underlying these atypical infections are not known. Canine oral papillomavirus (COPV) typically regresses spontaneously and is an important model of mucosal human papillomavirus infections. A severe, naturally occurring, nonregressing COPV infection provided an opportunity to investigate some aspects of viral pathogenicity and host immunity. In this case, the papillomas proved refractory to surgical and medical treatments, including autogenous vaccination and vaccination with capsid (L1) virus-like particles. High levels of induced anti-L1 antibodies appeared to have no effect on the infection. The papillomas spread to oesophageal mucosa, perioral haired skin, and remote cutaneous sites. Isolation of COPV from the animal and sequencing of several regions of the viral genome showed no differences to the COPV prototype. Experimental infection of beagle dogs with this viral isolate resulted in the uncomplicated development and regression of oral warts within the usual period, indicating that the virus was not an unusual pathogenic variant. These findings support the hypothesis that the recurrent lesions seen in some human papillomavirus infections, such as recurrent laryngeal papillomatosis, are associated with specific defects in host immunity rather than variations in viral pathogenicity.


3D Hollow Framework Silver Nanowire Electrodes for High-Performance Bottom-Contact Organic Transistors.
We successfully fabricated high performance bottom-contact organic field-effect transistors (OFETs) using silver nanowire (AgNW) network electrodes by spray deposition. The synthesized AgNWs have the dimensions of 40-80 nm in diameter and 30-80 μm in length and are randomly distributed and interconnected to form a 3D hollow framework. The AgNWs networks, deposited by spray coating, yield an average optical transmittance of up to 88% and a sheet resistance as low as 10 ohm/sq. For using AgNWs as source/drain electrodes of OFETs with a bottom-contact configuration, the large contact resistance at the AgNWs/organic channel remains a critical issue for charge injection. To enhance charge injection, we fabricate semiconductor crystals on the AgNW using an adsorbed residual poly(N-vinylpyrrolidone) layer. The resulting bottom-contact OFETs exhibit high mobility up to 1.02 cm(2)/(V s) and are similar to that of the top-contact Au electrodes OFETs with low contact resistance. A morphological study shows that the pentacene crystals coalesced to form continuous morphology on the nanowires and are highly interconnected with those on the channel. These features contribute to efficient charge injection and encourage the improvement of the bottom-contact device performance. Furthermore, the large contact area of individual AgNWs spreading out to the channel at the edge of the electrode also improves device performance.


Brain natriuretic peptide for prediction of mortality in patients with sepsis: a systematic review and meta-analysis.
Early identification of septic patients at high risk of dying remains a challenge. The prognostic role of brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) in septic patients remains controversial. The purpose of this systematic review and meta-analysis was to investigate the value of elevated BNP or NT-proBNP in predicting mortality in septic patients. PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched (up to February 18, 2011). Studies were included if they had prospectively collected data on all-cause mortality in adult septic patients with either plasma BNP or NT-proBNP measurement. Studies that failed to construct a 2 × 2 table of results were excluded. Two authors independently determined the validity of included studies and extracted data. 12 studies with a total of 1,865 patients were included. Elevated natriuretic peptides were significantly associated with increased risk of mortality (odds ratio (OR) 8.65, 95% confidence interval (CI) 4.94 to 15.13, P < 0.00001). The association was consistent for BNP (OR 10.44, 95% CI 4.99 to 21.58, P < 0.00001) and NT-proBNP (OR 6.62, 95% CI 2.68 to 16.34, P < 0.0001). The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 79% (95% CI 75 to 83), 60% (95% CI 57 to 62), 2.27 (95% CI 1.83 to 2.81) and 0.32 (95% CI 0.22 to 0.46), respectively. Our results suggested that an elevated BNP or NT-proBNP level may prove to be a powerful predictor of mortality in septic patients. Future larger and more adequately powered prospective studies are warranted to clarify the assay standardization, the optimal cut-off, and the prognostic value of BNPs in conjunction with other biomarkers.


Lung cancer serum biomarker discovery using label-free liquid chromatography-tandem mass spectrometry.
Lung cancer remains the leading cause of cancer-related death with poor survival due to the late stage at which lung cancer is typically diagnosed. Given the clinical burden from lung cancer and the relatively favorable survival associated with early-stage lung cancer, biomarkers for early detection of lung cancer are of important potential clinical benefit. We performed a global lung cancer serum biomarker discovery study using liquid chromatography-tandem mass spectrometry in a set of pooled non-small cell lung cancer case sera and matched controls. Immunoaffinity subtraction was used to deplete the top most abundant serum proteins; the remaining serum proteins were subjected to trypsin digestion and analyzed in triplicate by liquid chromatography-tandem mass spectrometry. The tandem mass spectrum data were searched against the human proteome database, and the resultant spectral counting data were used to estimate the relative abundance of proteins across the case/control serum pools. The spectral counting-derived abundances of some candidate biomarker proteins were confirmed with multiple reaction monitoring mass spectrometry assays. A list of 49 differentially abundant candidate proteins was compiled by applying a negative binomial regression model to the spectral counting data (p < 0.01). Functional analysis with Ingenuity Pathway Analysis tools showed significant enrichment of inflammatory response proteins, key molecules in cell-cell signaling and interaction network, and differential physiological responses for the two common non-small cell lung cancer subtypes. We identified a set of candidate serum biomarkers with statistically significant differential abundance across the lung cancer case/control pools, which, when validated, could improve lung cancer early detection.


Suitability and limitations of portion-specific abattoir data as part of an early warning system for emerging diseases of swine in Ontario.
Abattoir data have the potential to provide information for geospatial disease surveillance applications, but the quality of the data and utility for detecting disease outbreaks is not well understood. The objectives of this study were to 1) identify non-disease factors that may bias these data for disease surveillance and 2) determine if major disease events that took place during the study period would be captured using multi-level modelling and scan statistics. We analyzed data collected at all provincially-inspected abattoirs in Ontario, Canada during 2001-2007. During these years there were outbreaks of porcine circovirus-associated disease (PCVAD), porcine reproductive and respiratory syndrome (PRRS) and swine influenza that produced widespread disease within the province. Negative binomial models with random intercepts for abattoir, to account for repeated measurements within abattoirs, were created. The relationships between partial carcass condemnation rates for pneumonia and nephritis with year, season, agricultural region, stock price, and abattoir processing capacity were explored. The utility of the spatial scan statistic for detecting clusters of high partial carcass condemnation rates in space, time, and space-time was investigated. Non-disease factors that were found to be associated with lung and kidney condemnation rates included abattoir processing capacity, agricultural region and season. Yearly trends in predicted condemnation rates varied by agricultural region, and temporal patterns were different for both types of condemnations. Some clusters of high condemnation rates of kidneys with nephritis in time and space-time preceded the timeframe during which case clusters were detected using traditional laboratory data. Yearly kidney condemnation rates related to nephritis lesions in eastern Ontario were most consistent with the trends that were expected in relation to the documented disease outbreaks. Yearly lung condemnation rates did not correspond with the timeframes during which major respiratory disease outbreaks took place. This study demonstrated that a number of abattoir-related factors require consideration when using abattoir data for quantitative disease surveillance. Data pertaining to lungs condemned for pneumonia did not provide useful information for predicting disease events, while partial carcass condemnations of nephritis were most consistent with expected trends. Techniques that adjust for non-disease factors should be considered when applying cluster detection methods to abattoir data.


Past body mass index and risk of mortality among women.
Epidemiologic studies of body mass index (BMI) in relation to mortality commonly exclude persons with health conditions and/or a history of smoking to prevent bias resulting from illness-related weight loss ('reverse causation'). Analysis of BMI from an earlier time period may minimize reverse causation without requiring exclusion of participants based on disease or smoking history. We prospectively examined BMI based on technician measurements of weight and height from 10 years prior to start of follow-up in relation to subsequent mortality in a cohort of 50 186 women who were 40-93 years old at baseline in 1987-1989. Deaths were ascertained through the US National Death Index. Proportional hazards regression was used to estimate hazard ratios (HRs) of mortality, adjusted for age, education, race/ethnicity, income, menopausal hormone use, smoking and physical activity. During 10 years of follow-up through 1997, 5201 women died. Overall, we observed a J-shaped association between BMI and mortality, with increased risk for women who were underweight, overweight or obese. The HRs and 95% confidence intervals of mortality for BMI categories of <18.5, 18.5-20.9, 21.0-23.4 (reference), 23.5-24.9, 25.0-27.4, 27.5-29.9, 30.0-34.9 and 35.0+ kg m(-2) were 1.43 (1.19, 1.72), 1.07 (0.98, 1.17), 1.00 (reference), 1.10 (1.00, 1.20), 1.20 (1.11, 1.31), 1.23 (1.11, 1.37), 1.60 (1.44, 1.77) and 1.92 (1.64, 2.24). There was little evidence that pre-existing conditions (heart disease, diabetes and/or cancer) or smoking history modified the past BMI and mortality relation (P=0.54 and 0.76). In this large cohort of women, BMI based on technician measurements of weight and height from 10 years prior to baseline showed increased risk for mortality across the range of overweight and obesity, regardless of disease and smoking history. Observed associations between overweight, obesity and mortality in healthy individuals may also apply to persons with a history of disease or smoking.


Meta-analysis of individual patient data in randomised trials of self monitoring of blood glucose in people with non-insulin treated type 2 diabetes.
To assess the effectiveness of self monitoring blood glucose levels in people with non-insulin treated type 2 diabetes compared with clinical management without self monitoring, and to explore the effects in specific patient groups. Meta-analysis based on individual participant data. Medline, Embase, and a recent systematic review of trials on self monitoring of blood glucose. Chief investigators of trials published since 2000 were approached for additional information and individual patient data. Randomised controlled trials in patients with non-insulin treated type 2 diabetes comparing an intervention using self monitoring of blood glucose with clinical management not using self monitoring. Trials published from 2000 with at least 80 participants were included. Individual patient data were collected from electronic files and checked for integrity. All randomised participants were analysed using the intention to treat principle. A random effects model of complete cases was used to assess efficacy, a sensitivity analysis comprised imputed data, and prespecified subgroup analyses were carried out for age, sex, previous use of self monitoring, duration of diabetes, and levels of glycated haemoglobin (HbA(1c)) at baseline. 2552 patients were randomised in the six included trials. A mean reduction in HbA(1c) level of -2.7 mmol/mol (95% confidence interval -3.9 to -1.6; 0.25%) was observed for those using self monitoring of blood glucose levels compared with no self monitoring at six months. The mean reduction in HbA(1c) level between groups was 2.0 mmol/mol (3.2 to 0.8; 0.25%) at three months (five trials) and 2.5 mmol/mol (4.1 to 0.9; 0.35%) at 12 months (three trials). These estimates were unchanged after imputing missing data, and estimates of effect in trials with higher loss to follow-up or a possibility of co-intervention compared with those with lower loss to follow-up and no co-intervention did not differ significantly (P=0.21). The difference in HbA(1c) levels between groups was consistent across age, baseline HbA(1c) level, sex, and duration of diabetes, although the numbers of older and younger people and those with HbA(1c) levels >86 mmol/mol (10%) were insufficient for interpretation. No changes occurred in systolic blood pressure (-0.2 mm Hg, 95% confidence interval -1.4 to 1.0), diastolic blood pressure (-0.1 mm Hg, -0.9 to 0.6), or total cholesterol level (-0.1 mol/L, 95% confidence interval -0.2 to 0.1). Evidence from this meta-analysis of individual patient data was not convincing for a clinically meaningful effect of clinical management of non-insulin treated type 2 diabetes by self monitoring of blood glucose levels compared with management without self monitoring, although the difference in HbA(1c) level between groups was statistically significant. The difference in levels was consistent across subgroups defined by personal and clinical characteristics.


Trends in Tennessee Medicaid acute care: use and expenditures, 1974-1978.
Because person-level data are not currently available at the Federal level, many questions regarding the use and expenditures of Medicaid services remain unanswered. This article demonstrates the capability of State Medicaid Management Information Systems (MMIS) to provide data that can address a variety of Medicaid program issues at both the State and Federal levels. Using data from the Tennessee Medicaid files, we analyze MMIS data to demonstrate the utility of person level statistics and to indicate methodologies useful for future analytic efforts, particularly in constructing utilization rates for policy and program management activities. While total Tennessee Medicaid enrollment is declining, the number of disabled enrollees and the proportion of aged enrollees are increasing. Tennessee Medicaid average covered lengths of stay exhibit a downward trend, but covered days of care rates are increasing due to higher admission rates. Medicaid payments per enrollee increased drastically, primarily due to increases in average payments per day and, to a lesser extent, increased utilization. Medicaid utilization and expenditures are highly skewed toward aged and disabled enrollees and toward those with less than six consecutive quarters of enrollment. Similarly, whites exhibit a disproportionate use of inpatient services. Analyses of diagnostic case-mix indicate stable patterns of both AFDC and disabled enrollees over time. Differences in case-mix and length of stay between the two eligibility groups are consistent with the respective characteristics of these populations.


Yoga's impact on inflammation, mood, and fatigue in breast cancer survivors: a randomized controlled trial.
To evaluate yoga's impact on inflammation, mood, and fatigue. A randomized controlled 3-month trial was conducted with two post-treatment assessments of 200 breast cancer survivors assigned to either 12 weeks of 90-minute twice per week hatha yoga classes or a wait-list control. The main outcome measures were lipopolysaccharide-stimulated production of proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), and scores on the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), the vitality scale from the Medical Outcomes Study 36-item Short Form (SF-36), and the Center for Epidemiological Studies-Depression (CES-D) scale. Immediately post-treatment, fatigue was not lower (P > .05) but vitality was higher (P = .01) in the yoga group compared with the control group. At 3 months post-treatment, fatigue was lower in the yoga group (P = .002), vitality was higher (P = .01), and IL-6 (P = .027), TNF-α (P = .027), and IL-1β (P = .037) were lower for yoga participants compared with the control group. Groups did not differ on depression at either time (P > .2). Planned secondary analyses showed that the frequency of yoga practice had stronger associations with fatigue at both post-treatment visits (P = .019; P < .001), as well as vitality (P = .016; P = .0045), but not depression (P > .05) than simple group assignment; more frequent practice produced larger changes. At 3 months post-treatment, increasing yoga practice also led to a decrease in IL-6 (P = .01) and IL-1β (P = .03) production but not in TNF-α production (P > .05). Chronic inflammation may fuel declines in physical function leading to frailty and disability. If yoga dampens or limits both fatigue and inflammation, then regular practice could have substantial health benefits.


Fibrous polymer nanomaterials for biomedical applications and their transport by fluids: an overview.
Over the past few decades, there has been strong interest in the development of new micro- and nanomaterials for biomedical applications. Their use in the form of capsules, particles or filaments suspended in body fluids is associated with conformational changes and hydrodynamic interactions responsible for their transport. The dynamics of fibres or other long objects in Poiseuille flow is one of the fundamental problems in a variety of biomedical contexts, such as mobility of proteins, dynamics of DNA or other biological polymers, cell movement, tissue engineering, and drug delivery. In this review, we discuss several important applications of micro and nanoobjects in this field and try to understand the problems of their transport in flow resulting from material-environment interactions in typical, crowded, and complex biological fluids. Our aim is to elucidate the relationship between the nano- and microscopic structures of elongated polymer particles and their flow properties, thus opening the possibility to design nanoobjects that can be efficiently transported by body fluids for targeted drug release or local tissue regeneration.


Development and validation of a simple, rapid and sensitive LC-MS/MS method for the measurement of urinary neurotransmitters and their metabolites.
Neurotransmitters play crucial roles in physiological functions and their imbalances have demonstrated association in the pathology of several diseases. The measurement of neurotransmitters possesses a great potential as a significant clinical tool. This study presents the development and validation of an LC-MS/MS method for simultaneous quantification of multi-class neurotransmitters associated with dopamine, tryptophan and glutamate-γ-aminobutyric acid pathways. A total of ten neurotransmitters and their metabolites (dopamine, epinephrine, metanephrine, tryptophan, serotonin, kynurenic acid, kynurenine, anthranilic acid, GABA, glutamic acid) were determined based on a simple and rapid 'dilute and shoot' method using minimal urine volume. The chromatographic separation was achieved using a Poroshell 120 Bonus-RP LC Column in combination with a gradient elution within an 8.5-min time frame. The method exhibited good sensitivity as the limits of quantification ranged between 0.025 and 0.075 μg/mL with acceptable matrix effects (< ± 14.5%), no carryover and good linearity (r 2 > 0.98). The accuracy and precision for all analytes were within tolerances, at < ± 9.9% mean relative error (MRE) and < 8.6% relative standard deviation (RSD), respectively. The method was successfully applied in measuring the neurotransmitter concentrations in urine of healthy donors. Furthermore, the undertaken stability experiments indicated that acidified urine specimens allowed the analytes to be stable for prolonged durations in comparison to those untreated. The study also reveals the performance of the method is unaffected by the absence of expensive deuterated reference standards under the experimental conditions employed which further simplifies the analytical procedures and provides a significant cost saving for running the assay. Graphical abstract The quantification of multi-class neurotransitters associated with the dopamine, tryptophan and GABA-glutamate pathways using a simple 'dilute and shoot' LC-MS/MS method.


Predicting stroke recovery: three- and six-month rates of patient-centered functional outcomes based on the orpington prognostic scale.
To provide recovery rates after stroke for specific functions using the Orpington Prognostic Scale (OPS). Prospective cohort. Hospital and community. 413 stroke survivors entered the study 3 to 14 days after suffering a stroke. A cohort of hospitalized stroke survivors were recruited 3 to 14 days after stroke and assessed at 1, 3, and 6 months poststroke for neurological, functional, and health status. Baseline OPS score was used to predict five functional outcomes at 3 and 6 months using development and validation datasets and receiver operating characteristic (ROC) curves. In 413 stroke survivors, functional recovery rates at 3 and 6 months were similar. Baseline OPS predicted significant differences in recovery rates for all five outcomes (P < .0001 for all five outcomes at 3 and 6 months). Personal care dependence was present at 3 months in only 3% of persons with baseline OPS scores of 3.2 or less compared with over 50% with OPS of 4.8 or higher. Independent personal care, meal preparation, and self-administration of medication were achieved by 80% who had baseline OPS scores of 2.4 or lower compared with less than 20% when OPS scores were 4.4 or higher. Independent community mobility was achieved in 50% of those who had OPS scores of 2.4 or lower but only 3% of those with OPS scores of 4.4 or higher. The area under ROC curves assessing OPS scores against each of the five outcomes ranged from 0.805 to 0.863 at 3 months and 0.74 to 0.806 at 6 months. OPS scores can predict widely differing rates of functional recovery in five important functional abilities. These estimates can be useful to survivors, families, providers, and healthcare systems who need to plan for the future.


Examining life course trajectories of lesbian, gay and bisexual people in England - exploring convergence and divergence among a heterogeneous population of older people.
Because of limitations in collecting sexuality data, there are very few studies that quantitatively explore the life courses of lesbian, gay, bisexual (LGB) individuals. Likewise it is rare that normative patterns of life course trajectories are assessed in terms of their applicability to LGB individuals. We review the current literature on LGB life course trajectories and discuss potential reasons for gaps in the literature. We explore approaches for defining LGB status. We use data from a cohort of people aged 50 and over (English Longitudinal Study of Ageing) to explore the tempo and occurrences of transitions to adulthood and to older age, and establish some of the differences based on sexual orientation. We examine the connecting health behaviours and life course turning points that may explain some of the differences described above. We show that while the first quartile of transitions to adulthood are experienced fairly uniformly by sexual orientation, differences open up thereafter. LGB people's life course trajectories are marked by different patterns of care, with LGB people less likely to provide care in the form of parenthood, but potentially more likely to provide care earlier to close friends or relatives. Analyses of connecting events suggest that LGB life course trajectories may be marred by higher levels of volatility, including higher risk financial hardship. Caveats to these results are outlined in full in the paper.