A stimulatory Mls-1 superantigen is destroyed by ultraviolet light while other Mtv-7 antigens remain intact. Significance for Mls-1 unresponsiveness.
Accessory cells present Ag together with costimulatory signals as immunogens and without costimulatory signals as tolerogens. Responsiveness and unresponsiveness are thus alternatives of T cell immune reactions to Ag. Superantigens appear to make an exception; being presented by accessory cells capable of providing costimulatory signals, these Ag induce a strong T cell response but leave T cells unresponsive to a secondary challenge (anergy). We show here that T cell anergy is not a mandatory consequence of superantigen-induced activation. Mls-1- BALB/c recipients of DBA/2 spleen cells mount vigorous Mls-1 responses in vivo but their T cells retain the ability to respond to a subsequent Mls-1 challenge in vitro. We tested the possibility that the inability of DBA/2 spleen cells to inactivate Mls-1-reactive BALB/c T cells was the result of excessive costimulatory activity provided by Mls-1+ DBA/2 B cells. Costimulatory accessory cell activity has been reported to be destroyed by UV light. We exposed superantigen-presenting cells to UV radiation and found that they had lost the ability to stimulate an Mls-1 response without, however, gaining the capacity to render Mls-1-specific T cells anergic. Despite their inability to noticeably stimulate Mls-1-reactive T cells, UV-treated Mls-1+ lymphocytes induced an absolute unresponsiveness in Mls-1- recipients to a second challenge with the superantigen. Our data are in agreement with previous evidence, confirmed here, that BALB/c mice establish immunity against Mls-1+ cells, which causes the accelerated rejection of superantigen-bearing lymphocytes. Thus, our data imply that, whereas it takes stimulatory superantigenic Mtv-7 gene products to induce the activation of superantigen-reactive T cells, nonsuperantigenic Mtv-7 gene products may induce an immune response leading to the elimination of Mtv-7+ lymphoid cells.


Enterocyte-Associated Microbiome of the Hadza Hunter-Gatherers.
By means of a recently developed non-invasive ex vivo minimal model based on the interaction of the human enterocyte-like HT29 cell line and fecal slurries, we explored the enterocyte-associated microbiome of 21 Hadza hunter-gatherers and nine urban living Italians. Though reductionist, this model allows inferring the microbiota structural and functional arrangement as it interacts with enterocytes. Microbial suspensions obtained from Hadza or Italian stools were first evaluated for structural integrity by high resolution-scanning electron microscopy and co-incubated with HT29 cell monolayers. The enterocyte adherent microbiota fraction was then characterized by 16S rRNA gene sequencing and predictive functional profiling using PICRUSt. Compared to Italians, the Hadza enterocyte-associated microbiome was characterized by a greater amount of adhesive microorganisms with pathogenic potential, such as Proteobacteria, Erysipelotrichaceae, Enterococcus, Clostridium and Sarcina. These compositional characteristics were reflected in a functional enrichment in membrane transport, signal transduction, signaling molecules and interaction. Our results depict a new interesting mutualistic configuration of the enterocyte-associated microbiome in Hadza, stressing the importance of microbe-host interaction at the mucosal surface along the course of human evolution.


Signal and Charge Enhancement for Protein Analysis by Liquid Chromatography-Mass Spectrometry with Desorption Electrospray Ionization.
We recently reported the use of desorption electrospray ionization (DESI) as a novel interface to couple high-performance liquid chromatography (HPLC) with mass spectrometry (MS) (Chem. Commun. 2011, 47, 4171). One of the benefits of such an interface is that post-column derivatization of separated analytes can be integrated with ionization via a "reactive" DESI approach in which a derivatizing reagent is doped into the spray solvent. The reactive DESI interface allows analyte desorption/ionization from the end of the chromatographic column with prompt MS detection; a short time delay of ~20 ms was demonstrated. In this study, we extended this application by "supercharging" proteins following HPLC separation using a DESI spray solvent containing supercharging reagents, m-nitrobenzyl alcohol (m-NBA) or sulfolane. Proteins (insulin, ubiquitin, lysozyme and α-lactalbumin) eluted out of the LC column can be supercharged with the protein charge state distributions (CSDs) significantly increased (to higher charge), which would be advantageous for subsequent top-down MS analysis of proteins. Interestingly, supercharging combined with reactive DESI enhances tolerance towards trifluoroacetic acid (TFA), which is known to be a superior additive in the mobile phase for premium peptide/protein chromatographic separation but has severe signal suppression effects for conventional electrospray ionization (ESI). In comparison to electrosonic spray ionization (ESSI), a variant form of ESI, the sensitivity of protein analysis using LC/DESI-MS with the mobile phase containing TFA can be improved by up to 70-fold for lysozyme and α-lactalbumin by including m-NBA in the DESI spray solvent. Presumably, by reducing TFA dissociation in the droplet, supercharging agents lower trifluoroacetate anion concentrations and concomitantly reduce ion pairing to analyte cationic sites. The reduced ion pairing therefore decreases the TFA signal suppression effect. The supercharging capability and the reduction of TFA signal suppression suggest that LC/DESI-MS is a valuable method for protein analysis.


Weighing both sides: morality, mortality, and framing contests over obesity.
Despite recent and growing media attention surrounding obesity in the United States, the so-called obesity epidemic remains a highly contested scientific and social fact. This article examines the contemporary obesity debate through systematic examination of the claims and claimants involved in the controversy. We argue that four primary groups-antiobesity researchers, antiobesity activists, fat acceptance researchers, and fat acceptance activists-are at the forefront of this controversy and that these groups are fundamentally engaged in framing contests over the nature and consequences of excess body weight. While members of the fat acceptance groups embrace a body diversity frame, presenting fatness as a natural and largely inevitable form of diversity, members of the antiobesity camp frame higher weights as risky behavior akin to smoking, implying that body weight is under personal control and that people have a moral and medical responsibility to manage their weight. Both groups sometimes frame obesity as an illness, which limits blame by suggesting that weight is biologically or genetically determined but simultaneously stigmatizes fat bodies as diseased. While the antiobesity camp frames obesity as an epidemic to increase public attention, fat acceptance activists argue that concern over obesity is distracting attention from a host of more important health issues for fat Americans. We examine the strategies claimants use to establish their own credibility or discredit their opponents, and explain how the fat acceptance movement has exploited structural opportunities and cultural resources created by AIDS activism and feminism to wield some influence over U.S. public health approaches. We conclude that notions of morality play a central role in the controversy over obesity, as in many medical disputes, and illustrate how medical arguments about body weight can be used to stymie rights claims and justify morality-based fears.


Food marketing to children in the context of a marketing maelstrom.
Childhood obesity is a major public health problem in the United States, yet US children are targeted as never before with marketing for foods high in sugar, fat, salt, and calories. Food marketing to children is highly sophisticated, increasingly well-funded, and takes place within the context of a barrage of other kinds of child-targeted marketing. The proliferation and sophistication of electronic media, the escalation of marketing in schools, changing families, and a political climate that favors deregulation have allowed marketers unprecedented access to children, including babies and toddlers. The notion--promulgated by the food industry--that parents can "just say no" to requests for highly marketed snacks and junk food is simplistic at best and cynical at worst. Instead of being viewed as a familial problem, the current marketing maelstrom should be viewed as a societal issue and addressed as such. Restriction of advertising to children is common in industrial democracies other than the United States--and is just one of many corrective actions that could be taken by our governments.


Incidence of sexually transmitted infections in men who have sex with men and who are at substantial risk of HIV infection - A meta-analysis of data from trials and observational studies of HIV pre-exposure prophylaxis.
Men who have sex with men (MSM) and who engage in condomless anal intercourse with casual partners are at high risk of acquiring sexually transmitted infections (STIs), but reliable epidemiological data are scarce. Studies on HIV pre-exposure prophylaxis (PrEP) enrol MSM who indicate that they engage in behaviour that puts them at high risk of acquiring HIV. Because they also screen for STIs at regular intervals, these studies may serve as a valuable source to estimate incidence rates of STIs in this subpopulation of MSM. We systematically searched for trials and observational studies of PrEP in MSM that reported data on the incidence of STIs during the study period. Incidence rates were calculated as events per 100 person-years (py) with 95% confidence intervals (CI). Data from individual studies were pooled building subgroups along study types and geography. We performed sensitivity analyses, including data only from studies that met pre-defined quality criteria. Twenty-four publications on 20 studies were included. The majority of studies reported that sexual behaviour and/or STI incidence remained stable or decreased during the study period. For syphilis, incidence rates ranged from 1.8/100py to 14.9/100py, the pooled estimate was 9.1/100py (95%-CI: 7.7-10.9). Incidence rates for gonorrhoea and chlamydia of any site ranged from 13.3/100py to 43.0/100py and 15.1/100py to 48.5/100py, respectively. Considering only studies that met the criteria for sensitivity analysis yielded pooled estimates of 39.6/100py (95%-CI: 32.9-47.6) and 41.8/100py (95%-CI: 33.9-51.5), respectively. The overall estimate for hepatitis C incidence was 1.3/100py (95%-CI: 1.0-1.8). Despite partly heterogeneous results, the data depict high incidence rates of STIs among MSM who engage in higher-risk sexual behaviours such as condomless sex with casual partners. This subpopulation of MSM requires access to STI screening at close intervals. By offering access to structures that provide regular STI monitoring and prompt treatment, PrEP may not only decrease HIV incidence but also have beneficial effects in decreasing the burden of STIs.


Correlated responses to artificial body size selection in growth, development, phenotypic plasticity and juvenile viability in yellow dung flies.
Most life history traits are positively influenced by body size, whereas disadvantages of large body size are poorly documented. To investigate presumed intrinsic costs of large size in the yellow dung fly (Scathophaga stercoraria; Diptera: Scathophagidae), we established two replicates each of three body size laboratory selection lines (small, control and large; selection on males only), and subjected flies of the resulting extended body size range to various abiotic stresses. Response to selection was symmetrical in the small and large lines (realized h(2) = 0.16-0.18). After 24 generations of selection body size had changed by roughly 10%. Female size showed a correlated response to selection on male size, whereas sexual size dimorphism did not change. Development time also showed a correlated response as, similar to food limited flies, small line flies emerged earlier at smaller body size. At the lowest larval food limit possible, flies of all lines emerged at the same small body size after roughly the same development time; so overall phenotypic plasticity in body size and development time strongly increased following selection. Juvenile mortality increased markedly when food was extremely limited, large line flies showing highest mortality. Winter frost disproportionately killed large (line) flies because of their longer development times. Mortality at high temperatures was high but size-selective effects were inconsistent. In all environments the larger males suffered more. Initial growth rate was higher for males and at unlimited food. Small line individuals of both sexes grew slowest at unlimited larval food but fastest at limited larval food, suggesting a physiological cost of fast growth. Overall, extension of the natural body size range by artificial selection revealed some otherwise cryptic intrinsic juvenile viability costs of large size, mediated by longer development or faster growth, but only in stressful environments.


Albumin induces upregulation of matrix metalloproteinase-9 in astrocytes via MAPK and reactive oxygen species-dependent pathways.
Astrocytes are an integral component of the blood-brain barrier (BBB) which may be compromised by ischemic or traumatic brain injury. In response to trauma, astrocytes increase expression of the endopeptidase matrix metalloproteinase (MMP)-9. Compromise of the BBB leads to the infiltration of fluid and blood-derived proteins including albumin into the brain parenchyma. Albumin has been previously shown to activate astrocytes and induce the production of inflammatory mediators. The effect of albumin on MMP-9 activation in astrocytes is not known. We investigated the molecular mechanisms underlying the production of MMP-9 by albumin in astrocytes. Primary enriched astrocyte cultures were used to investigate the effects of exposure to albumin on the release of MMP-9. MMP-9 expression was analyzed by zymography. The involvement of mitogen-activated protein kinase (MAPK), reactive oxygen species (ROS) and the TGF-β receptor-dependent pathways were investigated using pharmacological inhibitors. The production of ROS was observed by dichlorodihydrofluorescein diacetate fluorescence. The level of the MMP-9 inhibitor tissue inhibitor of metalloproteinase (TIMP)-1 produced by astrocytes was measured by ELISA. We found that albumin induces a time-dependent release of MMP-9 via the activation of p38 MAPK and extracellular signal regulated kinase, but not Jun kinase. Albumin-induced MMP-9 production also involves ROS production upstream of the MAPK pathways. However, albumin-induced increase in MMP-9 is independent of the TGF-β receptor, previously described as a receptor for albumin. Albumin also induces an increase in TIMP-1 via an undetermined mechanism. These results link albumin (acting through ROS and the p38 MAPK) to the activation of MMP-9 in astrocytes. Numerous studies identify a role for MMP-9 in the mechanisms of compromise of the BBB, epileptogenesis, or synaptic remodeling after ischemia or traumatic brain injury. The increase in MMP-9 produced by albumin further implicates both astrocytes and albumin in the acute and long-term complications of acute CNS insults, including cerebral edema and epilepsy.


Minimal important difference estimates for patient-reported outcomes: A systematic survey.
The objective of the study was to develop an inventory summarizing all anchor-based minimal important difference (MID) estimates for patient-reported outcome measures (PROMs) available in the medical literature. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and the Patient-Reported Outcome and Quality of Life Instruments Database internal library (January 1989-October 2018). We included primary studies empirically calculating an anchor-based MID estimate for any PROM in adults and adolescents. Pairs of reviewers independently screened and selected studies, extracted data, and evaluated the credibility of the MIDs. We identified 585 eligible studies, the majority conducted in Europe (n = 211) and North America (n = 179), reporting 5,324 MID estimates for 526 distinct PROMs. Investigators conducted their studies in the context of patients receiving surgical (n = 105, 18%), pharmacological (n = 85, 15%), rehabilitation (n = 65, 11%), or a combination of interventions (n = 194, 33%). Of all MID estimates, 59% (n = 3,131) used a global rating of change anchor. Major credibility limitations included weak correlation (n = 1,246, 23%) or no information regarding the correlation (n = 3,498, 66%) between the PROM and anchor and imprecision in the MID estimate (n = 2,513, 47%). A large number of MIDs for assisting in the interpretation of PROMs exist. The MID inventory will facilitate the use of MID estimates to inform the interpretation of the magnitude of treatment effects in clinical research and guideline development.


Molecular dosimetry of ethylene oxide: formation and persistence of 7-(2-hydroxyethyl)guanine in DNA following repeated exposures of rats and mice.
The formation of 7-(2-hydroxyethyl)guanine (7-HEG) in DNA of target and nontarget tissues was investigated in male B6C3F1 mice (20/group) and F344 rats (10/group) exposed to 0, 3, 10, 33, 100, or 300 (rats only) ppm ethylene oxide (ETO) by inhalation for 6 h/day for 4 weeks (5 days/week) and mice exposed to 100 ppm ETO for 1 or 3 days or 1, 2, or 4 weeks (5 days/week). The persistence of 7-HEG was studied in mice killed up to 7 days after cessation of the 4-week time-course study. In addition, the formation of O6-(2-hydroxyethyl)guanine and 3-(2-hydroxyethyl)adenine was evaluated in rats exposed to 300 ppm ETO. DNA samples from control and treated animals were analyzed for 7-HEG using neutral thermal hydrolysis, microconcentration, and high-performance liquid chromatography separation with fluorescence detection. Fluorescence-linked high-performance liquid chromatography was used for O6-(2-hydroxyethyl)guanine quantitation, and immunochromatography and gas chromatography-mass spectrometry were used for 3-(2-hydroxyethyl)adenine detection. Analysis of DNA from tissues of control mice and rats revealed the presence of peaks equivalent to 2-6 pmol 7-HEG/mg DNA. In mice exposed to 100 ppm ETO, 7-HEG accumulated to a similar extent in target and nontarget tissues, with adduct concentrations ranging from 17.5 +/- 3.0 (SE) (testis) to 32.9 +/- 1.9 (lung) pmol adduct/mg DNA after 4 weeks of exposure. Concurrent exposures of mice and rats to 100 ppm ETO for 4 weeks led to 2- to 3-fold lower concentrations of 7-HEG in mouse DNA in all tissues compared to rat DNA. 7-HEG disappeared slowly in a nearly linear fashion from the DNA of mouse kidney (t1/2 = 6.9 days) and rat brain and lung (t1/2 = 5.4-5.8 days), which was consistent with the loss of adduct mainly by chemical depurination. In contrast, a more rapid removal of 7-HEG from other mouse (t1/2 = 1.0-2.3 days) and rat (t1/2 = 2.9-4.8 days) tissues was consistent with adduct loss by depurination and DNA repair. Dose-response relationships for 7-HEG were nonlinear in both mice and rats, with the alkylating efficiency of ETO increasing at high exposures.(ABSTRACT TRUNCATED AT 400 WORDS)


Diarylurea compounds inhibit caspase activation by preventing the formation of the active 700-kilodalton apoptosome complex.
The release of mitochondrial proapoptotic proteins into the cytosol is the key event in apoptosis signaling, leading to the activation of caspases. Once in the cytosol, cytochrome c triggers the formation of a caspase-activating protein complex called the apoptosome, whereas Smac/Diablo and Omi/htra2 antagonize the caspase inhibitory effect of inhibitor of apoptosis proteins (IAPs). Here, we identify diarylurea compounds as effective inhibitors of the cytochrome c-induced formation of the active, approximately 700-kDa apoptosome complex and caspase activation. Using diarylureas to inhibit the formation of the apoptosome complex, we demonstrated that cytochrome c, rather than IAP antagonists, is the major mitochondrial caspase activation factor in tumor cells treated with tumor necrosis factor. Thus, we have identified a novel class of compounds that inhibits apoptosis by blocking the activation of the initiator caspase 9 by directly inhibiting the formation of the apoptosome complex. This mechanism of action is different from that employed by the widely used tetrapeptide inhibitors of caspases or known endogenous apoptosis inhibitors, such as Bcl-2 and IAPs. Thus, these compounds provide a novel specific tool to investigate the role of the apoptosome in mitochondrion-dependent death paradigms.


Identification of a gene conferring resistance to zinc and cadmium ions in the yeast Saccharomyces cerevisiae.
A DNA fragment conferring resistance to zinc and cadmium ions in the yeast Saccharomyces cerevisiae was isolated from a library of yeast genomic DNA. Its nucleotide sequence revealed the presence of a single open reading frame (ORF; 1326 bp) having the potential to encode a protein of 442 amino acid residues (molecular mass of 48.3 kDa). A frameshift mutation introduced within the ORF abolished resistance to heavy metal ions, indicating the ORF is required for resistance. Therefore, we termed it the ZRC1 (zinc resistance conferring) gene. The deduced amino acid sequence of the gene product predicts a rather hydrophobic protein with six possible membrane-spanning regions. While multiple copies of the ZRC1 gene enable yeast cells to grow in the presence of 40 mM Zn2+, a level at which wild-type cells cannot survive, the disruption of the chromosomal ZRC1 locus, though not a lethal event, makes cells more sensitive to zinc ions than are wild-type cells.


Vestibular function after acute vestibular neuritis.
To review the extent and mechanism of the recovery of vestibular function after sudden, isolated, spontaneous, unilateral loss of most or all peripheral vestibular function - usually called acute vestibular neuritis. Critical review of published literature and personal experience. The symptoms and signs of acute vestibular neuritis are vertigo, vomiting, nystagmus with ipsiversive slow-phases, ipsiversive lateropulsion and ocular tilt reaction (the static symptoms) and impairment of vestibulo-ocular reflexes from the ipsilesional semicircular canals on impulsive testing (the dynamic symptoms). Peripheral vestibular function might not improve and while static symptoms invariably resolve, albeit often not totally, dynamic symptoms only improve slightly if at all. The persistent loss of balance that some patients experience after acute vestibular neuritis can be due to inadequate central compensation or to incomplete peripheral recovery and vestibular rehabilitation has a role in the treatment of both.


Neurodegenerative disorders associated with diabetes mellitus.
More than 20 syndromes among the significant and increasing number of degenerative diseases of neuronal tissues are known to be associated with diabetes mellitus, increased insulin resistance and obesity, disturbed insulin sensitivity, and excessive or impaired insulin secretion. This review briefly presents such syndromes, including Alzheimer disease, ataxia-telangiectasia, Down syndrome/trisomy 21, Friedreich ataxia, Huntington disease, several disorders of mitochondria, myotonic dystrophy, Parkinson disease, Prader-Willi syndrome, Werner syndrome, Wolfram syndrome, mitochondrial disorders affecting oxidative phosphorylation, and vitamin B(1) deficiency/inherited thiamine-responsive megaloblastic anemia syndrome as well as their respective relationship to malignancies, cancer, and aging and the nature of their inheritance (including triplet repeat expansions), genetic loci, and corresponding functional biochemistry. Discussed in further detail are disturbances of glucose metabolism including impaired glucose tolerance and both insulin-dependent and non-insulin-dependent diabetes caused by neurodegeneration in humans and mice, sometimes accompanied by degeneration of pancreatic beta-cells. Concordant mouse models obtained by targeted disruption (knock-out), knock-in, or transgenic overexpression of the respective transgene are also described. Preliminary conclusions suggest that many of the diabetogenic neurodegenerative disorders are related to alterations in oxidative phosphorylation (OXPHOS) and mitochondrial nutrient metabolism, which coincide with aberrant protein precipitation in the majority of affected individuals.


[Stakeholder representations of the role of the intermediate level of the DRC health system].
Intermediate health care structures in the DRC were designed during the setting-up of primary health care in a perspective of health district support. This study was designed to describe stakeholder representations of the intermediate level of the DRC health system during the first 30 years of the primary health care system. This case study was based on inductive analysis of data from 27 key informant interviews.. The intermediate level of the health system, lacking sufficient expertise and funding during the 1980s, was confined to inspection and control functions, answering to the central level of the Ministry of health and provincial authorities. Since the 1990s, faced with the pressing demand for support from health district teams, whose self-management had to deal with humanitarian emergencies, the need to integrate vertical programmes, and cope with the logistics of many different actors, the intermediate heath system developed methods and tools to support heath districts. This resulted in a subsidiary model of the intermediate level, the perceived efficacy of which varies according to the province over recent years. The "subsidiary" model of the intermediary health system level seems a good alternative to the "control" model in DRC.


Vertical structure of stratospheric water vapour trends derived from merged satellite data.
Stratospheric water vapour is a powerful greenhouse gas. The longest available record from balloon observations over Boulder, Colorado, USA shows increases in stratospheric water vapour concentrations that cannot be fully explained by observed changes in the main drivers, tropical tropopause temperatures and methane. Satellite observations could help resolve the issue, but constructing a reliable long-term data record from individual short satellite records is challenging. Here we present an approach to merge satellite data sets with the help of a chemistry-climate model nudged to observed meteorology. We use the models' water vapour as a transfer function between data sets that overcomes issues arising from instrument drift and short overlap periods. In the lower stratosphere, our water vapour record extends back to 1988 and water vapour concentrations largely follow tropical tropopause temperatures. Lower and mid-stratospheric long-term trends are negative, and the trends from Boulder are shown not to be globally representative. In the upper stratosphere, our record extends back to 1986 and shows positive long-term trends. The altitudinal differences in the trends are explained by methane oxidation together with a strengthened lower-stratospheric and a weakened upper-stratospheric circulation inferred by this analysis. Our results call into question previous estimates of surface radiative forcing based on presumed global long-term increases in water vapour concentrations in the lower stratosphere.


Self-acetylation at the active site of phosphoenolpyruvate carboxykinase (PCK1) controls enzyme activity.
Acetylation is known to regulate the activity of cytosolic phosphoenolpyruvate carboxykinase (PCK1), a key enzyme in gluconeogenesis, by promoting the reverse reaction of the enzyme (converting phosphoenolpyruvate to oxaloacetate). It is also known that the histone acetyltransferase p300 can induce PCK1 acetylation in cells, but whether that is a direct or indirect function was not known. Here we initially set out to determine whether p300 can acetylate directly PCK1 in vitro. We report that p300 weakly acetylates PCK1, but surprisingly, using several techniques including protein crystallization, mass spectrometry, isothermal titration calorimetry, saturation-transfer difference nuclear magnetic resonance and molecular docking, we found that PCK1 is also able to acetylate itself using acetyl-CoA independently of p300. This reaction yielded an acetylated recombinant PCK1 with a 3-fold decrease in kcat without changes in Km for all substrates. Acetylation stoichiometry was determined for 14 residues, including residues lining the active site. Structural and kinetic analyses determined that site-directed acetylation of K244, located inside the active site, altered this site and rendered the enzyme inactive. In addition, we found that acetyl-CoA binding to the active site is specific and metal dependent. Our findings provide direct evidence for acetyl-CoA binding and chemical reaction with the active site of PCK1 and suggest a newly discovered regulatory mechanism of PCK1 during metabolic stress.


NMR Metabolomics Defining Genetic Variation in Pea Seed Metabolites.
Nuclear magnetic resonance (NMR) spectroscopy profiling was used to provide an unbiased assessment of changes to the metabolite composition of seeds and to define genetic variation for a range of pea seed metabolites. Mature seeds from recombinant inbred lines, derived from three mapping populations for which there is substantial genetic marker linkage information, were grown in two environments/years and analyzed by non-targeted NMR. Adaptive binning of the NMR metabolite data, followed by analysis of quantitative variation among lines for individual bins, identified the main genomic regions determining this metabolic variability and the variability for selected compounds was investigated. Analysis by t-tests identified a set of bins with highly significant associations to genetic map regions, based on probability (p) values that were appreciably lower than those determined for randomized data. The correlation between bins showing high mean absolute deviation and those showing low p-values for marker association provided an indication of the extent to which the genetics of bin variation might be explained by one or a few loci. Variation in compounds related to aromatic amino acids, branched-chain amino acids, sucrose-derived metabolites, secondary metabolites and some unidentified compounds was associated with one or more genetic loci. The combined analysis shows that there are multiple loci throughout the genome that together impact on the abundance of many compounds through a network of interactions, where individual loci may affect more than one compound and vice versa. This work therefore provides a framework for the genetic analysis of the seed metabolome, and the use of genetic marker data in the breeding and selection of seeds for specific seed quality traits and compounds that have high commercial value.


VUT-MK142 : a new cardiomyogenic small molecule promoting the differentiation of pre-cardiac mesoderm into cardiomyocytes.
Intra-cardiac cell transplantation is a new therapy after myocardial infarction. Its success, however, is impeded by the limited capacity of donor cells to differentiate into functional cardiomyocytes in the heart. A strategy to overcome this problem is the induction of cardiomyogenic function in cells prior to transplantation. Among other approaches, recently, synthetic small molecules were identified, which promote differentiation of stem cells of various origins into cardiac-like cells or cardiomyocytes. The aim of this study was to develop and characterise new promising cardiomyogenic synthetic low-molecular weight compounds. Therefore, the structure of the known cardiomyogenic molecule cardiogenol C was selectively modified, and the effects of the resulting compounds were tested on various cell types. From this study, VUT-MK142 was identified as the most promising candidate with respect to cardiomyogenic activity. Treatment using this novel agent induced the strongest up-regulation of expression of the cardiac marker ANF in both P19 embryonic carcinoma cells and C2C12 skeletal myoblasts. The activity of VUT-MK142 on this marker superseded CgC; moreover, the novel compound significantly up-regulated the expression of other cardiac markers, and promoted the development of beating cardiomyocytes from cardiovascular progenitor cells. We conclude that VUT-MK142 is a potent new cardiomyogenic synthetic agent promoting the differentiation of pre-cardiac mesoderm into cardiomyocytes, which may be useful to differentiate stem cells into cardiomyocytes for cardiac repair. Additionally, an efficient synthesis of VUT-MK142 is reported taking advantage of continuous flow techniques superior to classical batch reactions both in yield and reaction time.


Validity of food frequency questionnaire estimated intakes of folate and other B vitamins in a region without folic acid fortification.
B vitamins have been implicated in major chronic diseases but results have been inconsistent. This study evaluated the accuracy of dietary intakes of folate, vitamin B12, riboflavin and vitamin B6 as measured by the Northern Sweden Food Frequency Questionnaire (FFQ) against repeated 24-h recalls (24HR) and plasma levels, taking into consideration the MTHFR 677C>T polymorphism. B vitamin intakes assessed by a semi-quantitative FFQ designed to measure the intake over the previous year were compared with those from 10 24HR, as well as to plasma levels of folate and vitamin B12, in randomly selected men (n=96) and women (n=99) aged 30-60 years. FFQ-based B-vitamin intakes were also compared with plasma levels of B-vitamins and with MTHFR 677C4T genotype in 878 men, aged 40-61 years. Intakes of vitamins B12 and riboflavin were similar, whereas folate and B6 intakes were 16-27% higher, as estimated by FFQ versus 24HR. Spearman correlation coefficients between the two methods ranged from 0.31 to 0.63 (all P<or=0.002), and were lowest for vitamin B12. Intakes estimated by FFQ were correlated with plasma levels, but coefficients were lower (range: 0.13-0.33), particularly for vitamin B12 in men (0.15-0.18). Folate intake was not correlated with plasma levels in subjects with the MTHFR 677 T/T genotype. The validity of the Northern Sweden FFQ for assessing B vitamin intake is similar to that of many other FFQs used in large-scale studies. The FFQ is suitable for ranking individuals by intake of folate, riboflavin, vitamin B6 and to a lesser extent vitamin B12.


Addressing risk of bias in trials of cognitive behavioral therapy.
A recent network meta-analysis by Zhu and colleagues reported in the Shanghai Archives of Psychiatry compared two different comparators (psychological placebo and waitlist control) in trials assessing the effectiveness of cognitive behavioral therapy (CBT) for the treatment of generalized anxiety disorder (GAD). CBT was superior to both of these control conditions, but psychological placebo was superior to waitlist. However, we argue that the term 'psychological placebo' is a misnomer because the impossibility of effectively blinding participants to treatment allocation in CBT trials makes it impossible to control for placebo effects. This failure to blind participants and therapists - and the resultant high risk of bias - was the main reason Zhu and colleagues found that the overall quality of the evidence supporting the conclusion that CBT is effective for GAD is poor. This is a general problem in all psychotherapy trials, which suffer from well-documented methodological and conceptual problems that prevent adequate placebo control and undermine casual inference. We discuss these problems and suggest potential solutions. We conclude that, while it may be difficult to remove potential bias in randomized controlled trials of psychotherapy, we can improve on the status quo by integrating basic science within applied trials to adjust for these biases and, thus, improve the strength of the causal inferences.


Evaluation of the photon dose calculation accuracy in radiation therapy of malignant pleural mesothelioma.
Photon dose distribution of malignant pleural mesothelioma (MPM) in matched photon-electron technique is influenced by media inhomogeneity, lateral electronic disequilibrium at interfaces and narrow field. These may influence the dose calculation accuracy, calculated by treatment planning systems (TPS). This study aimed to evaluate the dose calculation accuracy of TiGRT TPS in radiation therapy of MPM. 18 MV photon beams of ONCOR Siemens linear accelerator was simulated using EGSnrc Monte Carlo (MC) code. Data of four patients were used to compare TPS and MC results in different regions included: Open and in-field, under shied and out of field regions. Compared to MC results, the TPS overestimated the pleura dose coverage (90% of prescribed dose) about 3-12 mm, and also it overestimated the dose in under the shielded regions of lung (4-74%). While the TPS underestimated the dose profile width about 1-16 mm in low dose region (<50% prescribed dose) as well as the out of field region dose (4-100%). Results showed that TPS underestimated the dose in out of field and overestimated the dose in under the shielded regions. Unlike MC measurements, TPS calculation showed adequate pleural dose coverage. Based on the results, MC calculation can be used in matched photon-electron beam radiation therapy of MPM to modify the TPS photon dose calculations in the presence of heterogeneity, interfaces, and shield in MPM radiotherapy.


Delivery of melanoma-associated immunoglobulin monoclonal antibody and Fab fragments to normal brain utilizing osmotic blood-brain barrier disruption.
Iodinated monoclonal antibodies (IgG 96.5 and two monomeric Fab fragments 96.5 and 48.7) to melanoma-associated antigens were administered after osmotic blood-brain barrier (BBB) opening in normal rats. Osmotic BBB disruption significantly (P less than 0.0001) increased monoclonal antibody delivery to the brain. Following BBB opening and intracarotid administration, there was no difference in the disrupted brain concentration integral area under the curve between Fab and IgG over the 72-h experimental period. However, Fab concentration in the disrupted brain was initially higher than IgG, and the clearance was more rapid (P less than 0.0001), decreasing 50% by approximately 4.5 h compared to 25.5 h for IgG. Plasma clearance was also more rapid for the Fab than IgG. The levels decreased 50% by 1.5 h for Fab and 15 h for IgG. The route and timing of antibody infusion had a significant effect on delivery to the disrupted brain with the Fab fragments but not with the intact IgG. Antibody recovered from disrupted brain retained its immunological reactivity as measured by a cell binding assay for at least 24 h. IgG and Fab delivery to the ipsilateral brain after BBB disruption increased (P less than 0.001) with increasing dose over a more than 3-log dose range. These data provide information applicable to the therapeutic use of monoclonal antibodies in brain tumor treatment.


3D Simulation Modeling of the Tooth Wear Process.
Severe tooth wear is the most common non-caries dental disease, and it can seriously affect oral health. Studying the tooth wear process is time-consuming and difficult, and technological tools are frequently lacking. This paper presents a novel method of digital simulation modeling that represents a new way to study tooth wear. First, a feature extraction algorithm is used to obtain anatomical feature points of the tooth without attrition. Second, after the alignment of non-attrition areas, the initial homogeneous surface is generated by means of the RBF (Radial Basic Function) implicit surface and then deformed to the final homogeneous by the contraction and bounding algorithm. Finally, the method of bilinear interpolation based on Laplacian coordinates between tooth with attrition and without attrition is used to inversely reconstruct the sequence of changes of the 3D tooth morphology during gradual tooth wear process. This method can also be used to generate a process simulation of nonlinear tooth wear by means of fitting an attrition curve to the statistical data of attrition index in a certain region. The effectiveness and efficiency of the attrition simulation algorithm are verified through experimental simulation.


Genome-wide association study of recalcitrant atopic dermatitis in Korean children.
Atopic dermatitis (AD) is a heterogeneous chronic inflammatory skin disease. Most AD during infancy resolves during childhood, but moderate-to-severe AD with allergic sensitization is more likely to persist into adulthood and more often occurs with other allergic diseases. We sought to find susceptibility loci by performing the first genome-wide association study (GWAS) of AD in Korean children with recalcitrant AD, which was defined as moderate-to-severe AD with allergic sensitization. Our study included 246 children with recalcitrant AD and 551 adult control subjects with a negative history of both allergic disease and allergic sensitization. DNA from these subjects was genotyped; sets of common single nucleotide polymorphisms (SNPs) were imputed and used in the GWAS after quality control checks. SNPs at a region on 13q21.31 were associated with recalcitrant AD at a genome-wide threshold of significance (P < 2.0 × 10(-8)). These associated SNPs are more than 1 Mb from the closest gene, protocadherin (PCDH)9. SNPs at 4 additional loci had P values of less than 1 × 10(-6), including SNPs at or near the neuroblastoma amplified sequence (NBAS; 2p24.3), thymus-expressed molecule involved in selection (THEMIS; 6q22.33), GATA3 (10p14), and S-phase cyclin A-associated protein in the ER (SCAPER; 15q24.3) genes. Further analysis of total serum IgE levels suggested 13q21.31 might be primarily an IgE locus, and analyses of published data demonstrated that SNPs at the 15q24.3 region are expression quantitative trait loci for 2 nearby genes, ISL2 and proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), in immune cells. Our GWAS of recalcitrant AD identified new susceptibility regions containing genes involved in epithelial cell function and immune dysregulation, 2 key features of AD, and potentially extend our understanding of their role in pathogenesis.


Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy.
Metronomic chemotherapy refers to the close, regular administration of comparatively low doses of cytotoxic drugs, with minimal or no drug-free breaks, over prolonged periods. It is thought to have an antiangiogenic basis. However, whereas surprisingly durable and potent tumor responses have been observed in a number of preclinical tumor models, relapses usually eventually occur using this type of treatment strategy. We therefore decided to test modified metronomic chemotherapy regimens that might significantly delay such relapses, but still maintain modest and acceptable toxicity profiles. Here, we show that repeated administration of bolus doses (BDs) of cyclophosphamide every 3 or 6 weeks, combined with a daily oral low-dose metronomic (LDM) regimen (20 mg/kg/d cyclophosphamide), improves efficacy and significantly delays progression of transplanted PC-3 human prostate cancer xenografts, syngeneic transplanted EMT-6 breast tumors, and "spontaneous" murine erythroleukemia. Efficacy was superior whereas toxicity was mild and comparable to the LDM regimen, the latter assessed by body weight, neutrophil, lymphocyte, and total white blood counts. Antiangiogenic activity, measured by reduction in circulating endothelial precursor cells, revealed that the greatest degree of suppression occurred using the combination treatment. Overall, our results indicate that the administration of intermittent BD combined with chronic oral LDM cyclophosphamide is a potent treatment regimen for controlling tumor growth, which has a low toxicity profile, over prolonged periods of time.


Xenotransplantation.
The success of clinical transplantation has led to a large discrepancy between donor organ availability and demand; considerable pressure exists to develop an alternative source of organs. The use of animal organs for donation is a possible solution that is not yet clinically applicable. A literature review was performed based on a Medline search to find articles on xenotransplantation. Keywords included hyperacute, acute vascular, xenograft rejection combined with concordant and discordant. Additional references cited in these articles from journals not included in Medline were obtained from the British Library. Limited information on unpublished, preliminary work has been included from sources known to the authors, based on their research work in the field. One hundred and forty-six references and four personal communications have been included in this review article. A greater understanding of the pathogenesis of xenograft rejection is developing rapidly. Strategies to abrogate hyperacute rejection have proved successful, but control of antibody-driven acute vascular rejection has not yet been achieved. The safety and viability of xenotransplantation as a therapeutic modality are still unproven.


Siblings and childhood mental health: evidence for a later-born advantage.
The social and health sciences have often emphasised the negative impacts of large sibship size and late birth order on childhood. For example, it is now well established that, other things being equal, children in large families and/or with many older siblings, receive lower allocations of care time from both parents, are more likely to grow up in conditions of economic hardship, and, as a likely consequence, exhibit relatively poor educational and physical health outcomes. Few researchers have, however, quantitatively assessed how siblings may influence indicators of mental health, where it is conceivable that social interactions with siblings may have a positive influence. Here, using data from a large British cohort survey (the Avon Longitudinal Study of Parents and Children), we explored the effects of sibling configuration on the Strengths and Difficulties Questionnaire, as a multidimensional index for mental health problems. We demonstrate a significant socio-economic gradient in mental health between the ages of three and nine years, but little evidence for negative effects of large sibship size. Rerunning this analysis to examine birth order, a much clearer pattern emerged; the presence of older siblings was associated with relatively good mental health, while the presence of younger siblings was associated with relatively poor mental health. This suggests that being born into a large family, providing the child is not joined by subsequent siblings, may carry important benefits unconsidered by past research. We discuss possible interpretations of this pattern and the wider implications for understanding the family context of child development.


Evaluation of a Novel Screw Position in a Type III Distal Phalanx Fracture Model: An Ex Vivo Study.
Mechanical evaluation of a novel screw position used for repair in a type III distal phalanx fracture model and assessment of solar canal penetration (SCP). Experimental study. Disarticulated equine hooves (n = 24) and 24 isolated distal phalanges. Hooves/distal phalanges cut in a sagittal plane were repaired with 1 of 2 different cortical screw placements in lag fashion. In group 1 (conventional screw placement), the screw was inserted halfway between the proximal border of the solar canal (SC) and the subchondral bone surface on a line parallel to the dorsal cortex, whereas in group 2, the screw was inserted more palmar/plantar, where a perpendicular line drawn from the group 1 position reached the palmar/plantar cortex. Construct strength was evaluated by 3-point bending to failure. SCP was assessed by CT imaging and macroscopically. Screws were significantly longer in group 2 and in forelimbs. Group 2 isolated distal phalanges had a significantly more rigid fixation compared with the conventional screw position (maximum point at failure 31%, bending stiffness 41% higher). Lumen reduction of the SC was observed in 13/52 specimens (all from group 2), of which 9 were forelimbs. More distal screw positioning compared with the conventionally recommended screw position for internal fixation of type III distal phalangeal fractures allows placement of a longer screw and renders a more rigid fracture fixation. The novel screw position, however, carries a higher risk of SCP.


Flow cytometric immunophenotyping of cerebrospinal fluid.
Leptomeningeal disease is an important adverse complication occurring in patients with B and T cell lymphomas and acute leukemias of lymphoid and myeloid origin. Recent reports suggest that multiparameter flow cytometry immunophenotypic assessment of spinal fluid samples could improve the efficiency of detection of CNS involvement, due to its high specificity and greater sensitivity. However, spinal fluid samples are frequently paucicellular with a rapidly decreasing cell viability. Staining of spinal fluid therefore requires dedicated sample storage/transport, staining, and preparation protocols. The Basic Protocol in this unit outlines a consensus multiparameter (3- to 8-color) flow cytometry immunophenotypic protocol for the evaluation of CNS involvement of cerebrospinal fluid (CSF) samples by neoplastic cells. A Support Protocol describing the simultaneous assessment of surface and cytoplasmic antigens is also provided. Finally, in the Alternate Protocol, we describe a method to calculate absolute numbers of both normal and pathological cell subpopulations by adding counting beads to the assay.


The effect of episodic retrieval on inhibition in task switching.
Inhibition in task switching is inferred from n-2 repetition costs: the observation that ABA task switching sequences are responded to slower than CBA sequences. This is thought to reflect the persisting inhibition of Task A, which slows reactivation attempts. Mayr (2002) reported an experiment testing a critical noninhibitory account of this effect, namely episodic retrieval: If the trial parameters for Task A match across an ABA sequence, responses should be facilitated because of priming from episodic retrieval; a cost would occur if trial parameters mismatch. In a rule-switching paradigm, Mayr reported no significant difference in n-2 repetition cost when the trial parameters repeated or switched across an ABA sequence, in clear contrast to the episodic retrieval account. What remains unclear is whether successful episodic retrieval modulates the n-2 repetition cost. Across 3 experiments-including a close replication of Mayr-we find clear evidence of reduced n-2 task repetition costs when episodic retrieval is controlled. We find that the effect of episodic retrieval on the n-2 task repetition cost is increased when the cue-task relationship is made more abstract, suggesting the effect is because of interference in establishing the relevant attentional set. We also demonstrate that the episodic retrieval effect is not influenced by retrieval of low-level, perceptual, elements. Together, the data suggest the n-2 task repetition cost-typically attributable to an inhibitory mechanism-also reflects episodic retrieval effects. (PsycINFO Database Record


Optimality and saturation in axonal chemotaxis.
Chemotaxis (detecting and following chemical gradients) plays a crucial role in the function of many biological systems. In particular, gradient following by neuronal growth cones is important for the correct wiring of the nervous system. There is increasing interest in the constraints that determine how small chemotacting devices respond to gradients, but little quantitative information is available in this regard for neuronal growth cones. Mortimer et al. ( 2009 ) and Mortimer, Dayan, Burrage, and Goodhill ( 2011 ) proposed a Bayesian ideal observer model that predicts chemotactic performance for shallow gradients. Here we investigated two important aspects of this model. First, we found by numerical simulation that although the analytical predictions of the model assume shallow gradients, these predictions remain remarkably robust to large deviations in gradient steepness. Second, we found experimentally that the chemotactic response increased linearly with gradient steepness for very shallow gradients as predicted by the model; however, the response saturated for steeper gradients. This saturation could be reproduced in simulations of a growth rate modulation response mechanism. Together these results illuminate the domain of validity of the Bayesian model and give further insight into the biological mechanisms of axonal chemotaxis.


Effects of hypnosis on flow states and golf performance.
This study examined the effects of an hypnotic intervention on flow states and golf-chipping performance of 3 participants. The study utilized an ideographic ABA single-subject design combined with a procedure to assess the participants' internal experience (Wollman, 1986). The intervention involved relaxation, imagery, hypnotic induction, hypnotic regression, and trigger control procedures over 5 wk. and 7 trials. Analysis indicated the 3 participants increased their mean golf-chipping performance from the trials in Baseline 1 to intervention, with 2 returning to Baseline 1 performance after the intervention phase at Baseline 2. The intensity of flow experienced by the participants during the performance trials was measured using Jackson and Marsh's 1996 Flow State Scale. Two participants experienced higher flow during the intervention phase and much lower flow during Baselines 1 and 2. Finally, participants indicated the intervention seemed useful in keeping them confident, relaxed, and in control. These results support the hypothesis that an hypnotic intervention can improve golf-chipping performance and increase feelings and cognitions associated with flow.


Determination of viremia and concentration of circulating nonstructural protein 1 in patients infected with dengue virus in Mexico.
Higher levels of viremia and circulating nonstructural protein 1 (NS1) have been associated with dengue disease severity. In this study, viremia and circulating NS1 levels were determined in 225 serum samples collected from patients in Mexico infected with dengue virus serotypes 1 and 2 (DENV-1 and DENV-2). Patients with dengue hemorrhagic fever (DHF) who were infected with DENV-1 showed higher levels of circulating NS1 than patients with dengue fever (DF) (P = 0.0175). Moreover, NS1 levels were higher in patients with primary infections with DENV-1 than in patient infected with DENV-2 (P < 0.0001) and in patients with primary infections with DENV-2 than in patients with secondary infections with DENV-2 (P = 0.0051). Unexpectedly, viremia levels were higher in patients with DF than in those with DHF infected with either DENV-1 or DENV-2 (P = 0.0019 and P = 0.001, respectively) and in patients with primary infections than those with secondary DENV-2 infections (P < 0.0001). Results indicate that levels of circulating NS1 vary according to the infecting serotype, immunologic status (primary or secondary infection), and dengue disease severity.


Use of cardiac resynchronization therapy in patients hospitalized with heart failure.
The frequency and characterization of patients receiving cardiac resynchronization therapy (CRT) are largely unknown since the publication of pivotal clinical trials and subsequent incorporation of CRT into the American College of Cardiology/American Heart Association guidelines for heart failure. We analyzed 33,898 patients admitted from January 2005 through September 2007 to 228 hospitals participating in the American Heart Association's Get With the Guidelines-Heart Failure program. There were 4201 patients (12.4%) discharged alive with CRT, including 811 new implants. Patients discharged with CRT were older (median age, 75 versus 72 years) and had lower median left ventricular ejection fraction (30% versus 38%), more frequent ischemic cardiomyopathy (58% versus 45%), more history of atrial fibrillation (38% versus 27%), and higher rates of beta-blocker and aldosterone antagonist use (P<0.0001 for all) than those without CRT. We found that 4.8% of patients with left ventricular ejection fraction <or=35% were discharged with a new CRT implant, which varied greatly by hospital. Ten percent of patients discharged with a new CRT implant had a left ventricular ejection fraction >35%. Major factors associated with lower rates of new CRT placement were treatment in the northeast (odds ratio, 0.40; 95% confidence interval, 0.30 to 0.53), black race (odds ratio, 0.45; 95% confidence interval, 0.36 to 0.57), increasing left ventricular ejection fraction per 10% (odds ratio, 0.56; 95% confidence interval, 0.52 to 0.60), and increasing age per 10 years in those >70 years of age (odds ratio, 0.56; 95% confidence interval, 0.48 to 0.65). Although CRT is a recent evidence-based therapy for heart failure, patterns of use differ significantly from clinical trials and published guidelines. Important variations also exist for CRT therapy based on race, geographic region, comorbidities, and age and need to be addressed through further study and/or quality-of-care initiatives.


Global competition dictates local suppression in pattern rivalry.
Certain pairs of visual patterns, when superimposed as if transparent, elicit a wavering percept in which one or the other pattern can enjoy temporary periods of exclusive visibility. This multistable perceptual phenomenon is called monocular rivalry or pattern rivalry (PR) and is most pronounced when the component patterns are faint and devoid of detail. The principal mechanisms that give rise to PR continue to be a topic of speculation. In the present study, we examine the determinants of exclusive dominance during PR using a novel stimulus in which a central portion is free of conflict. By observing the properties of suppression in this so-called rivalry-free region, we demonstrate that perception is driven largely by the global and holistic interpretation of the patterns, rather than by the need to resolve local spatial conflict. The suppression of this central region was often complete and varied as a function of the parameters of the global stimulus, including the size of the surround region, its ocular configuration, and stereoscopic depth ordering. Suppression also varied as a function of pattern continuity across the central region as well as with the temporal offset of the overlapping components. These findings demonstrate that the visibility or invisibility of a pattern is not fundamentally a product of local processing, but is instead shaped by the brain's global interpretive assumptions regarding the composition of the stimulus.


Brain regions associated with acquisition and retrieval of verbal episodic memory.
It is widely held that conscious recall of past experiences involves a specific system--episodic memory. Patients with amnesia have gross impairments of episodic memory while other kinds of memory remain intact, suggesting that a separable brain system underlies episodic memory. We have used positron emission tomography (PET) to identify components of this system in normal volunteers. A dual-task interference paradigm was used to isolate brain areas associated with acquisition, and a cueing paradigm to isolate the areas concerned with retrieval from verbal episodic memory. Acquisition was associated with activity in the left prefrontal cortex and the retrosplenial area, whereas retrieval was associated with activity in right prefrontal cortex and the precuneus. Our results provide clear evidence that episodic memory involves a network of specific prefrontal and posterior structures which can be fractionated into different component processes.


Anatomic GreenLight laser vaporization-incision technique for benign prostatic hyperplasia using the XPS LBO-180W system: How I do it.
For men experiencing lower urinary tract symptoms (LUTS) refractory to medical therapy, there have been numerous developments in the treatment options offered for benign prostatic hyperplasia (BPH) in the recent years. Transurethral resection of the prostate (TURP) has remained the reference standard for men with prostates sized 30 cc-80 cc, while open prostatectomy is universally guidelines-recommended in the absence of enucleation, for men with prostates larger than 80 cc-100 cc. While these techniques are effective, they have the potential for bleeding complications requiring transfusions, electrolyte abnormalities such as TURP syndrome, and often require prolonged hospitalization. GreenLight photoselective vaporization (GL-PVP) with the XPS LBO-180W system offers a minimally invasive treatment that can be carried out on essential any sized prostate gland. In addition, the GL-PVP procedure can be done as a same day discharge surgery requiring no overnight hospital admission and allows patients to continue any necessary anti-coagulants given the significantly reduced risks of bleeding complications or TURP syndrome. In 2005, the anatomic vaporization-incision technique (VIT) using the XPS LBO-180W system was described to address larger prostate volumes. VIT combines principles of traditional GL-PVP and enucleation techniques to identify the reference surgical capsule early-on into the surgery and resect portions of prostate adenoma without the need for tissue morcellation. Early studies comparing anatomic VIT to standard PVP outcomes demonstrated significant improvements of IPSS and uroflowmetry parameters, along with statistically significant greater PSA reduction at 6 months, particularly in prostate volumes greater than 80 cc. The objective of this article is to detail our surgical approach to the anatomic GreenLight laser vaporization-incision technique using the XPS LBO-180W system, based on extensive personal experience with both enucleation and vaporization techniques using various laser technologies. Standardization of the VIT based on proper cystoscopy, knowledge of prostate anatomy with preoperative ultrasound, and routine technique is essential to developing consistent, reproducible and optimal surgical outcomes.


An ecological quantification of the relationships between water, sanitation and infant, child, and maternal mortality.
Water and sanitation access are known to be related to newborn, child, and maternal health. Our study attempts to quantify these relationships globally using country-level data: How much does improving access to water and sanitation influence infant, child, and maternal mortality? Data for 193 countries were abstracted from global databases (World Bank, WHO, and UNICEF). Linear regression was used for the outcomes of under-five mortality rate and infant mortality rate (IMR). These results are presented as events per 1000 live births. Ordinal logistic regression was used to compute odds ratios for the outcome of maternal mortality ratio (MMR). Under-five mortality rate decreased by 1.17 (95%CI 1.08-1.26) deaths per 1000, p < 0.001, for every quartile increase in population water access after adjustments for confounders. There was a similar relationship between quartile increase of sanitation access and under-five mortality rate, with a decrease of 1.66 (95%CI 1.11-1.32) deaths per 1000, p < 0.001. Improved water access was also related to IMR, with the IMR decreasing by 1.14 (95%CI 1.05-1.23) deaths per 1000, p < 0.001, with increasing quartile of access to improved water source. The significance of this relationship was retained with quartile improvement in sanitation access, where the decrease in IMR was 1.66 (95%CI 1.11-1.32) deaths per 1000, p < 0.001. The estimated odds ratio that increased quartile of water access was significantly associated with increased quartile of MMR was 0.58 (95%CI 0.39-0.86), p = 0.008. The corresponding odds ratio for sanitation was 0.52 (95%CI 0.32-0.85), p = 0.009, both suggesting that better water and sanitation were associated with decreased MMR. Our analyses suggest that access to water and sanitation independently contribute to child and maternal mortality outcomes. If the world is to seriously address the Millennium Development Goals of reducing child and maternal mortality, then improved water and sanitation accesses are key strategies.


Chronic thalidomide and chemoembolization for hepatocellular carcinoma.
Transcatheter arterial chemoembolization (TACE) has been used to curtail tumor vasculature and delay tumor progression in hepatocellular carcinoma (HCC). We conducted a phase I trial to evaluate the efficacy and toxicity of thalidomide when combined with TACE in patients with advanced HCC. Between June 2000 and November 2003, 56 patients with unresectable HCC and amenable to TACE were enrolled. The starting dose of thalidomide was 200 mg/day and was escalated every 2 weeks as tolerated to a maximum dose of 1,000 mg/day. Dose reductions and discontinuation were determined by toxicity. TACE was performed 4 weeks after initiation of thalidomide therapy and repeated as necessary. Overall, 47 and 55 patients were evaluable for response and toxicity, respectively; the median dose of thalidomide given was 200 mg/day. Three patients (6.38%) patients achieved complete responses, whereas 10 (21.3%) had partial responses, for an overall response rate of 27.7%, and 27 (57.5%) had stable disease. Median progression-free survival was 7 months (95% confidence interval [CI]: 5-10 months), and median OS was 21 months (95% CI: 16-28 months) (Fig. 1). Fatigue and lethargy (49.1%), constipation (47.3%), and nausea (43.6%) were common. Grade 3-4 toxicities consisted mostly of increased aspartate aminotransferase (43.6%) and elevated alanine aminotransferase (38.2%) (Table 1). Thalidomide and TACE were commonly associated with nonhematologic side effects, with fatigue and constipation being prominent. With a lack of clear therapeutic benefit, this combination is unlikely to be pursued for HCC.


Physical activity and mental well-being in older people participating in the Better Ageing Project.
Increasing evidence suggests that physical activity can prevent some aspects of mental illness in older people such as depression, dementia and Alzheimer's disease. Additionally, limited research has shown that engagement in structured exercise can improve aspects of psychological well-being such as mood and self-perceptions in older adults. However, the relationship between incidental daily activity such as walking or time spent sedentary, with psychological well-being has not been investigated. The Better Ageing Project provided an opportunity to assess well-being and quality of life using standardised questionnaires with 176 adults aged 70 and over. Accelerometry was used to objectively assess daily energy expended in physical activity at different levels of intensity. In addition, an assessment of the impact of the 12-month Better Ageing structured group exercise programme was assessed through questionnaires and interviews. Total daily physical activity energy expenditure (joules/day) and amount of time spent in activity of at least moderate intensity were weakly related (r = 0.20-0.28) to quality of life, subjective well-being and physical self-perceptions. Time spent sedentary (min/day) was weakly and negatively related to several mental health indicators. The quantitative data showed only minor psychological benefits of the exercise intervention. In contrast, interviews with 27 research participants and 4 exercise leaders suggested that important improvements in perceived function and social benefits had been experienced.


Genetic variation of serotonin function and cognitive control.
Although it is widely accepted that serotonin plays a pivotal role in the modulation of anxiety- and depression-related personality traits as well as in the pathogenesis of anxiety disorders and depression, the role of serotonin in cognition is less clear. In the present study, we investigated the involvement of serotonin in cognitive behaviors by examining the impact of genetic variation in key regulators of serotonergic neurotransmission on behavioral measures in a cognitive control task. Eighty-five healthy participants performed a cued continuous performance task (the AX Continuous Performance Task [AXCPT]) and were genotyped for polymorphisms in the transcriptional control regions of the tryptophan hydroxylase 2 gene (TPH2 G-703T; rs4570625) and the serotonin transporter gene (5-HTTLPR). The core result was that individuals lacking the rare TPH2 T allele were not faster than T allele carriers, but committed fewer errors and were less variable in responding. These findings parallel those of a recent study where an enhancement of executive control in individuals without the rare TPH2 T/T genotype was observed. Together with recent evidence that individuals without the T allele exhibit higher scores in anxiety- and depression-related personality traits, our results underscore the role of the TPH2 G-703T polymorphism in the modulation of behavior and raise the intriguing possibility that genetic variants associated with higher negative emotionality may have beneficial effects on some cognitive functions.


Improved inhibitor tolerance in xylose-fermenting yeast Spathaspora passalidarum by mutagenesis and protoplast fusion.
The xylose-fermenting yeast Spathaspora passalidarum showed excellent fermentation performance utilizing glucose and xylose under anaerobic conditions. But this yeast is highly sensitive to the inhibitors such as furfural present in the pretreated lignocellulosic biomass. In order to improve the inhibitor tolerance of this yeast, a combination of UV mutagenesis and protoplast fusion was used to construct strains with improved performance. Firstly, UV-induced mutants were screened and selected for improved tolerance towards furfural. The most promised mutant, S. passalidarum M7, produced 50% more final ethanol than the wild-type strain in a synthetic xylose medium containing 2 g/l furfural. However, this mutant was unable to grow in a medium containing 75% liquid fraction of pretreated wheat straw (WSLQ), in which furfural and many other inhibitors were present. Hybrid yeast strains, obtained from fusion of the protoplasts of S. passalidarum M7 and a robust yeast, Saccharomyces cerevisiae ATCC 96581, were able to grow in 75% WSLQ and produce around 0.4 g ethanol/g consumed xylose. Among the selected hybrid strains, the hybrid FS22 showed the best fermentation capacity in 75% WSLQ. Phenotypic and partial molecular analysis indicated that S. passalidarum M7 was the dominant parental contributor to the hybrid. In summary, the hybrids are characterized by desired phenotypes derived from both parents, namely the ability to ferment xylose from S. passalidarum and an increased tolerance to inhibitors from S. cerevisiae ATCC 96581.


UK science press officers, professional vision and the generation of expectations.
Science press officers can play an integral role in helping promote expectations and hype about biomedical research. Using this as a starting point, this article draws on interviews with 10 UK-based science press officers, which explored how they view their role as science reporters and as generators of expectations. Using Goodwin's notion of 'professional vision', we argue that science press officers have a specific professional vision that shapes how they produce biomedical press releases, engage in promotion of biomedical research and make sense of hype. We discuss how these insights can contribute to the sociology of expectations, as well as inform responsible science communication.


Effect of theophylline on CD11b and L-selectin expression and density of eosinophils and neutrophils in vitro.
The nonspecific phosphodiesterase inhibitor theophylline, widely used in asthma therapy, may cause a decrease in inflammatory responses of airways. In asthma, eosinophils migrate to the airway wall and become activated. Activated eosinophils are characterized by low cell density, as well as increased expression of CD11b and reduced expression of L-selectin, two adhesion molecules involved in transendothelial migration. To study the anti-inflammatory effect of theophylline on granulocyte adhesion molecules in vitro, the platelet-activating factor (PAF)-induced density shift was determined by density centrifugation and the modulation of CD11b and L-selectin expression by flow cytometry on eosinophils and neutrophils in human whole blood. A relatively high concentration of theophylline (10(-3) M) inhibited the increase in the percentage of hypodense eosinophils and neutrophils in whole-blood samples after PAF stimulation in vitro. A more pharmacological concentration (10(-4) M) inhibited the CD11b upregulation and L-selectin shedding induced by PAF (10(-7) M) on both eosinophils and neutrophils. The effect of isoproterenol on the inhibitory effect of theophylline was mainly additive, but a small synergistic effect could not be excluded. In conclusion theophylline can attenuate eosinophil and neutrophil activation in vitro at the level of adhesion molecule expression and changes in cell density. This may have implications for transendothelial migration of these cells in asthma.


Whiteboard icons to support the blood-test process in an emergency department: an observational study of temporal patterns.
The competent treatment of emergency department (ED) patients requires an effective and efficient process for handling laboratory tests such as blood tests. This study investigates how ED clinicians go about the process, from ordering blood tests to acknowledging their results and, specifically, assesses the use of whiteboard icons to support this process. On the basis of observation and interviews we find that the blood-test process is intertwined with multiple other temporal patterns in ED work. The whiteboard icons, which indicate four temporally distinct steps in the blood-test process, support the nurses in maintaining the flow of patients through the ED and the physicians in assessing test results at timeouts. The main results of this study are, however, that the blood-test process is temporally and collaboratively complex, that the whiteboard icons pass by most of this complexity, that attending to the icons is yet another temporally sensitive activity to remember, and that whereas the assessment of test results is integral to patient treatment, the acknowledgement of having seen the results is a formal add-on, the responsibility for which is sometimes unclear.


Interprofessional Communication: Integrating Evidence to Enhance Systems During a Pandemic.
The COVID-19 pandemic placed challenges on interprofessional communication patterns among clinical care teams at a time when effective communication was greatly needed. The development of enhanced systems for communication that integrate the latest evidence and communication technologies can offer a solution to this crisis. This article provides a framework for ways in which nursing teams can develop evidence-based enhanced interprofessional communication systems during a pandemic. Based on communication models and related technologies, this article reviews strategies to enhance interprofessional communication. Two case studies are included that illustrate how nursing teams can enhance communication during a pandemic. To improve communication during a pandemic, clinicians can incorporate interprofessional communication models in clinical practice and apply enhanced communication strategies.


The use of discriminant analysis for examining the histological feathers of oral keratoses and lichen planus.
In a retrospective survey of 235 cases in which the diagnosis on biopsy was lichen planus, keratosis or leukoplakia, the histological features were re-assessed as objectively as possible and without reference to the original diagnosis.The tissue changes were recorded under 39 headings, and many were assessed on a roughly quantitative basis. In addition, two clinical features were included; whether the biopsy was from the buccal mucosa (as opposed to some other intraoral site) and whether the lesions involved multiple intraoral sites. For each possible pair of diagnostic categories (keratosis and leukoplakia, lichen planus and keratosis, lichen planus and leukoplakia) the recorded findings were subjected to discriminant analysis in order to provide a quantitative assessment of the value of each individual feature for discriminating between the two diagnostic groups. The computer programme also provided for the application of these calculated values to yield a "score" for each case, and for an assessment of the significance of the separation of the diagnostic groups thus achieved. In general, the values calculated by the computer for the discriminatory value of each tissue change accorded with our subjective impressions, but a number of features that were given a relatively high value had not previously been recognized as important in differential diagnosisA discriminant analysis was also performed on those cases of leukoplakia known to have later developed a carcinoma, in comparison with the leukoplakia cases that did not develop carcinoma. High values were accorded mainly to the well-known features of epithelial atypia, but a similar high value was indicated for the presence of Russell bodies. we had not previously realized that the presence of Russell bodies was of prognostic significance in this context.When the total scores for the groups of cases were analysed, it was found that the separation of each pair of diagnostic groups was significant at the 1% level. The separation of leukoplakia cases that subsequently developed carcinoma, from those that did not develop carcinoma, was significant at the 5% level. In this latter analysis, a better separation might be achieved with larger numbers of cases, but there will always be the complicating factor that an unknown number of leukoplakia cases would develop carcinoma if the patient had received no treatment.


The effects of home monitoring by public health nurse on individuals' diabetes control.
Diabetes is an important health problem that changes the lifestyle of individuals. The ability of individuals to control their disease is directly related to their adaptation to the disease and self-care. The purpose of this study was to determine the effect of home monitoring of individuals with diabetes for the purpose of developing their self-care and their adaptation to diabetes. The research used a quasi-experimental (time series) design study. A convenient sample of 34 patients receiving outpatient diabetes care at Hacettepe University Adult Hospital Endocrinology Clinic participated in the study on a voluntary basis. After being seen for the first time in the clinic, they were followed up for a 6-month period in their homes. At the end of the home monitoring period, these patients with diabetes had a statistically significant decrease in HbA(1c) (glycated hemoglobin; p = .000), fasting blood glucose (p = .001), postmeal blood glucose (p = .000), and systolic blood pressure (p = .007) measurements. Diabetes is a quite frequently seen chronic and progressive disease. Nursing monitoring is important to develop an individual's skills in self-care and to support compliance to diabetes. This study supports the finding that the home monitoring of individuals with diabetes by community health nurse improves diabetic control. It is recommended that individuals with diabetes be monitored not only in the hospital but also in their homes for a comprehensive evaluation.


Rabies response, One Health and more-than-human considerations in Indigenous communities in northern Australia.
Australia is currently canine rabies free; however, the spread of rabies in eastern Indonesia poses an increasing risk to northern Australia. Domestic dogs are numerous in East Arnhem Land (EAL) and the Northern Peninsular Area (NPA), usually unrestrained and living in close relationships with humans. The response to any rabies outbreak on Australian territory will focus on dog vaccination, controlling dog movements and depopulation. A One Health approach to zoonotic disease control should seek to co-promote human and animal health, whilst also seeking to accommodate the preferences of affected communities. We report on 5 collaborative workshops and 28 semi-structured interviews conducted between January 2017 and June 2018 with: (i) EAL and NPA community members; (ii) Indigenous Rangers in EAL and NPA; and (iii) residents of Cairns, the local regional centre. Storyboard methodologies were used to work with participants and explore what rabies response measures they thought were justified or unacceptable, why they held these views, and what other steps they believed needed to be taken. Key findings include that the capacity of the NPA and EAL communities to contribute/adapt to a biosecurity response is limited by structural disadvantage including poor infrastructure (such as lockable premises and intact fences) and appropriate information, dominant cultural norms and food security concerns. Dogs and dingoes can have great cultural and social importance; key interventions might be accommodated within cultural beliefs and long-standing norms of dog management if sufficient effort is made to adapt interventions to local contexts and community preferences. Adopting such a 'strengths-based' approach mandates that the communities at greatest risk need help to prepare for and develop strategies to manage a biosecurity response to a rabies incursion. This would include listening to individual and community concerns and attending to the educational and infrastructural needs for supporting different groups to respond appropriately.


Hope, quality of life, and benefit from treatment in women having chemotherapy for platinum-resistant/refractory recurrent ovarian cancer: the gynecologic cancer intergroup symptom benefit study.
Chemotherapy for platinum-resistant/refractory ovarian cancer is motivated by the hope of benefit. We sought to determine the relationships between: (a) trait hope, expectation of symptom benefit from chemotherapy, and anxiety and depression; (b) hope and perceived efficacy of chemotherapy; and (c) unfulfilled hope (where expectations for benefit are not fulfilled) and depression. Methods. Adult patients enrolled within stage 1 of the Gynecologic Cancer Intergroup Symptom Benefit Study were included. Patient. Reported outcomes were collected from 126 women with predominantly platinum-resistant ovarian cancer at baseline, prior to the first four treatment cycles (12-16 weeks), and four weeks after completing chemotherapy or at disease progression, whichever came first. Associations were assessed with Spearman rank correlation coefficient (r) and odds ratio. Results. Trait hope and expectation of symptom benefit from chemotherapy were weakly correlated with each other (r = 0.25). Trait hope, but not expectation of symptom benefit, was negatively correlated with anxiety (r = -0.43) and depression (r = -0.50). The smaller the discrepancy between perceived and expected symptom benefit, the less likely the patient was to have scores indicative of depression (odds ratio: 0.68; 95% confidence interval: 0.49-0.96; p = .026). Conclusion. Trait hope and expectation of symptom benefit from chemotherapy appear to be distinct and independent of the aspects of quality of life and scores for depression. Hope did not appear to affect perceived efficacy of chemotherapy in alleviating symptoms, but women whose expectation of symptom benefit from chemotherapy was not fulfilled were more likely to have scores indicative of depression. It may be preferable to encourage hope toward achievable goals rather than toward benefits from chemotherapy.


Digestion studies in captive Hippopotamidae: a group of large ungulates with an unusually low metabolic rate.
We performed intake and digestibility studies in four common (Hippopotamus amphibius) and four pygmy (Hexaprotodon liberiensis) hippos from two zoological institutions, using acid detergent lignin as an internal marker for the quantification of faecal output. In the case of one pygmy hippo, where total faecal collection was also possible, there was no distinct difference between the two methods of faecal output quantification. Two animals from each species were tested on a conventional zoo diet of hay and concentrates (diet HC) and on hay only (diet H). The other two animals received fresh grass at two different levels of intake (diets G1 and G2). Dry matter (DM) intake was higher on HC than on H or G diets, and averaged 37 +/- 11 for common and 35 +/- 14 g/kg(0.75) for pygmy hippos. There were no species differences in the average digestibility (aD) coefficients. Non-dietary faecal nitrogen averaged 65 +/- 4% of total faecal nitrogen, aD of crude protein (CP) averaged 67 +/- 9% and true protein digestibility 89 +/- 3%. Average digestibility of DM and crude fibre averaged 54 +/- 11% and 45 +/- 17%, respectively. In comparison with ruminants, hippos generally achieve lower aD for DM, organic matter and fibre parameters, but equal or higher aD CP coefficients. This is most likely due to the absence of significant fermentative activity in the hindgut and the corresponding low metabolic faecal nitrogen losses. Digestible energy intake was higher on HC than on H or G diets and averaged 0.30 +/- 0.11 MJ/kg(0.75) metabolic body mass. This value is extremely low for ungulates, supporting earlier suspicions that hippos have particularly low metabolic rates, and explains the proneness of this species to obesity in captivity when fed energy-dense pelleted feeds.


A 3-month, Multicenter, Randomized, Open-label Study to Evaluate the Impact on Wound Healing of the Early (vs Delayed) Introduction of Everolimus in De Novo Kidney Transplant Recipients, With a Follow-up Evaluation at 12 Months After Transplant (NEVERWOUND Study).
The risk of wound healing complications (WHCs) and the early use of mammalian target of rapamycin inhibitors after kidney transplantation (KT) have not been fully addressed. The NEVERWOUND study is a 3-month, multicenter, randomized, open-label study designed to evaluate whether a delayed (ie, 28 ± 4 d posttransplant) immunosuppression regimen based on everolimus (EVR) reduces the risk of WHC versus EVR started immediately after KT. Secondary endpoints were treatment failure (biopsy-proven acute rejection, graft loss, or death), delayed graft function, patient and graft survival rates, and renal function. Overall, 394 KT recipients were randomized to receive immediate (N = 197) or delayed (N = 197) EVR after KT. At 3 months, WHC-free rates in the immediate EVR versus delayed EVR arm, considering the worst- and best-case scenario approach, were 0.68 (95% confidence interval [CI], 0.62-0.75) versus 0.62 (95% CI, 0.55-0.68) (log-rank P = 0.56) and 0.70 (95% CI, 0.64-0.77) versus 0.72 (95% CI, 0.65-0.78) (log-rank P = 0.77), respectively. The 3- and 12-month treatment failure rates, delayed graft function and renal function, and patient and graft survival were not different between the arms. The early introduction of EVR after KT did not increase the risk of WHC, showing good efficacy and safety profile.


Optimizing de novo common wheat transcriptome assembly using short-read RNA-Seq data.
Rapid advances in next-generation sequencing methods have provided new opportunities for transcriptome sequencing (RNA-Seq). The unprecedented sequencing depth provided by RNA-Seq makes it a powerful and cost-efficient method for transcriptome study, and it has been widely used in model organisms and non-model organisms to identify and quantify RNA. For non-model organisms lacking well-defined genomes, de novo assembly is typically required for downstream RNA-Seq analyses, including SNP discovery and identification of genes differentially expressed by phenotypes. Although RNA-Seq has been successfully used to sequence many non-model organisms, the results of de novo assembly from short reads can still be improved by using recent bioinformatic developments. In this study, we used 212.6 million pair-end reads, which accounted for 16.2 Gb, to assemble the hexaploid wheat transcriptome. Two state-of-the-art assemblers, Trinity and Trans-ABySS, which use the single and multiple k-mer methods, respectively, were used, and the whole de novo assembly process was divided into the following four steps: pre-assembly, merging different samples, removal of redundancy and scaffolding. We documented every detail of these steps and how these steps influenced assembly performance to gain insight into transcriptome assembly from short reads. After optimization, the assembled transcripts were comparable to Sanger-derived ESTs in terms of both continuity and accuracy. We also provided considerable new wheat transcript data to the community. It is feasible to assemble the hexaploid wheat transcriptome from short reads. Special attention should be paid to dealing with multiple samples to balance the spectrum of expression levels and redundancy. To obtain an accurate overview of RNA profiling, removal of redundancy may be crucial in de novo assembly.


Exercise in claudicants increase or decrease walking ability and the response relates to mitochondrial function.
Exercise of patients with intermittent claudication improves walking performance. Exercise does not usually increase blood flow, but seems to increase muscle mitochondrial enzyme activities. Although exercise is beneficial in most patients, it might be harmful in some. The mitochondrial response to exercise might therefore differ between patients. Our hypothesis was that changes in walking performance relate to changes in mitochondrial function after 8 weeks of exercise. At a subgroup level, negative responders decrease and positive responders increase mitochondrial capacity. Two types of exercise were studied, calf raising and walking (n = 28). We wanted to see whether there were negative and positive responders, independent of type of exercise. Measurements of walking performance, peripheral hemodynamics, mitochondrial respiration and content (citrate synthase activity) were obtained on each patient before and after the intervention period. Multiple linear regression was used to test whether changes in peak walking time relate to mitochondrial function. Subgroups of negative (n = 8) and positive responders (n = 8) were defined as those that either decreased or increased peak walking time following exercise. Paired t test and analysis of covariance was used to test changes within and between subgroups. Changes in peak walking time were related to changes in mitochondrial respiration supported by electron transferring flavoprotein (ETF + CI)P (p = 0.004), complex I (CI + ETF)P (p = 0.003), complex I + complex II (CI + CII + ETF)P (p = 0.037) and OXPHOS coupling efficiency (p = 0.046) in the whole group. Negative responders had more advanced peripheral arterial disease. Mitochondrial respiration supported by electron transferring flavoprotein (ETF + CI)P (p = 0.0013), complex I (CI + ETF)P (p = 0.0005), complex I + complex II (CI + CII + ETF)P (p = 0.011) and electron transfer system capacity (CI + CII + ETF)E (p = 0.021) and OXPHOS coupling efficiency decreased in negative responders (p = 0.0007) after exercise. Positive responders increased citrate synthase activity (p = 0.010). Changes in walking performance seem to relate to changes in mitochondrial function after exercise. Negative responders have more advanced peripheral arterial disease and decrease, while positive responders increase mitochondrial capacity. Trial registration ClinicalTrials.gov ID: NCT023110256.


Artificial vision: principles and prospects.
The aim of this article is to give an overview of the strategies and technologies currently under development to return vision to blind patients and will answer the question: What options exist for artificial vision in patients blind from retinal disease; how close are these to clinical practice? Retinal approaches will be the focus of this review as they are most advanced in terms not only of development, but entry into the imagination of the general public; they are technologies patients ask about, but may be less familiar to practicing neurologists.The prerequisites for retinal survivor cell stimulation are discussed, followed by consideration of the state of the art of four promising methods making use of this principle: electronic prostheses, stem cells, gene therapy and the developing field of ophthalmic optogenetics. Human applications of artificial vision by survivor cell stimulation are certainly with us in the research clinic and very close to commercialization and general use. This, together with their place in the public consciousness, makes the overview provided by this review particularly helpful to practicing neurologists.


Women report more severe sensations from 2 mA and 4 mA transcranial direct current stimulation than men.
Interest in transcranial direct current stimulation (tDCS) to alter cortical excitability, facilitate neural plasticity, and improve performance is increasing. Subjects often report temporary stimulation-related sensations, which might distract from the task being performed or compromise blinding. tDCS is also prone to high outcome irregularity and one potential variability source is the biological sex of the subject. The purpose of this study was to re-analyze existing tolerability data to ascertain any sex differences in sensation severity and blinding guesses from tDCS at 2 mA and 4 mA. Each subject underwent tDCS at three randomly ordered intensities (sham, 2 mA, 4 mA), reported the severity sensations experienced, and guessed which tDCS condition they underwent (blinding). Women reported higher sensation severities than men from 2 mA and 4 mA tDCS and higher severities with increasing intensity (sham < 2 mA < 4 mA). Men reported similar severities in all stimulation conditions. Both sexes distinguished sham from 2 mA and 4 mA, and neither were able to discriminate between 2 mA from 4 mA. This study highlights differences in severity reports between women and men and adds to the growing body of literature, indicating that current sham methodologies might be inadequate to maintain blinding.


Meta-analysis of molecular association studies: vitamin D receptor gene polymorphisms and BMD as a case study.
With the rise of molecular and genetic epidemiology, molecular association studies are increasingly common; however, meta-analysis of these studies has been a neglected area. This study performed a meta-analysis of the association of the vitamin D receptor (VDR) gene polymorphisms and BMD. We also highlight methodological issues that need to be resolved. With the rise of molecular and genetic epidemiology, molecular association studies are increasingly common; however, meta-analysis of these studies has been a neglected area. This study performed a meta-analysis of the association of vitamin D receptor (VDR) gene polymorphisms and BMD/osteoporosis and highlights methodological issues. Studies published from 1994 to 2001 were identified through Medline using PubMed software. The reference lists of the articles retrieved were also reviewed. Where eligible papers had insufficient information, we contacted authors by mail (up to three mailings) for additional information. Any observational study, which tested the association between VDR BsmI genotypes and either BMD or osteoporosis at the femoral neck or spine in adult women, was included in the review. Data were extracted independently by two reviewers (AT and JA) using a standardized data extraction form. The B allele was significantly associated with BMD at the spine; it seemed to follow a recessive model, with the BB genotype having lower BMD than Bb/bb genotypes at baseline, which led to greater bone mineral loss over time. Highlighted methodological lessons included the need to check Hardy-Weinberg equilibrium and the importance of exploring heterogeneity, pooling data in a manner that is sensitive to genetic models, and avoiding multiple comparisons. With the proliferation of molecular association studies, there will be an increased need to quantify the magnitude of the risk associated with genetic polymorphisms. This will likely entail meta-analytic methods, and this meta-analysis highlights some of the methodological issues that will need to be resolved.


Weight loss in obese women--exercise v. dietary education.
It was postulated that a nutrition-education programme was as effective an adjunct to a diet-based weight-loss programme as an exercise regimen. Forty-five obese female volunteers were placed on the same 5,000 kJ diet and were then assigned to each of three therapy groups: (i) an exercise group, involving three 1-hour exercise sessions per week (15 women); (ii) a lecture group involving a weekly 1-hour group lecture session (15); and (iii) a control group (15) who received only the diet and no activity. Weight loss, body fat loss (%) and daily energy intake reductions were equally reduced in the subjects in all three groups who completed the programme. There was, however, a significantly higher dropout rate in the control group. Taking this into account, the weight loss in the two test groups was similar and greater than that of the control group. We conclude that, in the short term, dietary education was as effective as exercise in promoting dietary compliance and weight loss.