NTP Toxicology and Carcinogenesis Studies of p-Nitroaniline (CAS No. 100-01-6) in B6C3F1 Mice (Gavage Studies).
p-Nitroaniline is an intermediate in the preparation of several azo dyes used for coloring consumer products. Toxicology and carcinogenicity studies were conducted by administering p-nitroaniline (>99% pure) in corn oil by gavage to groups of male and female B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, mouse Iymphoma cells, and Drosophila melanogaster. 14-DAY STUDIES: Groups of five male and five female B6C3F1 mice received p-nitroaniline in corn oil by gavage at doses of 0, 10, 30, 100, 300, or 1,000 mg/kg body weight 5 days per week for 2 weeks. All mice that received 1,000 mg/kg died from chemical-related toxicity by day 4 of the studies. Final mean body weights of mice receiving 300 mg/kg or less were similar to those of the controls. Hematology results were consistent with chemical-related methemoglobinemia and regenerative anemia. Met hemoglobin concentrations in all groups of dosed mice were significantly higher than those in controls. Hematocrit values in mice that received 300 mg/kg and total erythrocyte counts in mice that received 100 or 300 mg/kg were significantly lower than those in controls. Reticulocyte counts in 300 mg/kg male mice and in 100 or 300 mg/kg females were significantly higher than controls. Heinz bodies were observed in erythrocytes of all 300 mg/kg mice and in two 100 mg/kg male mice. The absolute and relative spleen weights of 100 and 300 mg/kg mice were significantly greater than those of the controls. Hematopoiesis and pigment (hemosiderin) accumulation were observed in the splenic red pulp of males and females receiving 300 mg/kg; pigment (hemosiderin) accumulation in Kupffer cells of the liver was also seen in male mice at this dose level. 13-WEEK STUDIES: Groups of 20 male and 20 female B6C3F1 mice received p-nitroaniline in corn oil by gavage at doses of 0, 1, 3, 10, 30, or 100 mg/kg body weight 5 days per week for up to 13 weeks. Eight or nine mice in each group were evaluated at 7 weeks. There were no deaths associated with exposure to p-nitroaniline, and final mean body weights of dosed mice were similar to those of the controls. Hematologic and pathologic findings at 7 and 13 weeks were similar to those seen in the 14-day studies and occurred primarily in the 30 and 100 mg/kg groups. Met hemoglobin concentrations were increased and hematocrit levels and erythrocyte counts were decreased relative to those of the controls. Heinz bodies were observed in erythrocytes and nucleated erythrocytes and reticulocytes were increased in number. Absolute and relative spleen weights of male and female mice receiving 30 and 100 mg/kg were significantly greater than those of controls at 7 and 13 weeks. Absolute and relative liver weights of female mice necropsied at 7 weeks were significantly greater in the 30 and 100 mg/kg groups; by 13 weeks, both absolute and relative liver weights were similar to control values. The incidence or severity of splenic hematopoiesis and pigmentation (hemosiderin) increased with dose at the 7-week interim evaluations and at the end of the studies. Pigment (hemosiderin) was also present in Kupffer cells of the liver in dosed male mice. 2-YEAR STUDIES: Groups of 70 male and 70 female B6C3F1 mice received p-nitroaniline in corn oil by gavage at doses of 0, 3, 30, or 100 mg/kg body weight for 5 days per week for up to 103 weeks. The dose selection was based on the hematologic and pathologic findings of the 13-week studies. Nine or ten mice from each group were evaluated at 9 and 15 months for the presence of chemical-related lesions. Body Weights, Clinical Findings, Survival, and Hematology: Mean body weights of male and female mice that received p-nitroaniline were similar to those of control mice throughout the 2-year studies. There were no clinical findings associated with chemical exposure, and survival of dosed mice was similar to that of controls. The hematology findings at the 9 and 15-month interim evaluations were similar to those in the 14-day and 13-week s 13-week studies. The methemoglobin concentrations were significantly higher in all 30 or 100 mg/kg mice; sulfhemoglobin concentrations were significantly higher at 9 months in all 30 or 100 mg/kg female mice and at 15 months in 100 mg/kg females. Hematocrit and erythrocyte counts in 100 mg/kg mice were significantly lower than those in controls. By 9 months, reticulocyte counts were significantly higher in all 30 or 100 mg/kg mice. At 15 months, only the 100 mg/kg mice exhibited significantly higher reticulocyte counts. Neoplasms and Nonneoplastic Lesions: Lesions related to the administration of p-nitroaniline occurred in the spleen, liver, and bone marrow, primarily in mice receiving 30 or 100 mg/kg; these were observed at the 9- and 15-month interim evaluations and at the end of the studies. There were increases in the incidence or severity of splenic congestion, hematopoiesis, pigment (hemosiderin) accumulation, Kupffer cell pigmentation in the liver, and bone marrow hypercellularity (hyperplasia). The incidences of hemangiosarcoma of the liver (0 ppm, 0/50; 3 ppm, 1/50; 30 ppm, 2/50; 100 ppm, 4/50) and hemangioma or hemangiosarcoma (combined) at all sites (5/50, 3/50, 4/50, 10/50) were marginally increased in 100 mg/kg male mice. The incidence of hepatocellular adenoma or carcinoma (combined) was significantly decreased (25/50, 26/50, 25/50, 13/50) in 100 mg/kg male mice. GENETIC TOXICOLOGY: p-Nitroaniline is mutagenic in vitro. It was tested in two laboratories for induction of gene mutations in several strains of Salmonella typhimurium. Both studies showed positive results in strain TA98, with and without S9 activation; results were negative for all other strains. p-Nitroaniline was tested in two laboratories for induction of sister cremated exchanges and chromosomal aberrations in Chinese hamster ovary cells. In the sister cremated exchange study, one laboratory reported negative results without S9 and positive results with S9; the second laboratory reported equivocal results without S9 and negative results with S9. In the chromosomal aberrations study, both laboratories found positive results with S9. Without S9, one laboratory reported weakly positive results while the other reported negative results. p-Nitroaniline induced trifluorothymidine resistance in L5178Y mouse Iymphoma cells in the absence of S9; no induction of trifluorothymidine resistance was noted with S9. In contrast to the positive results in the previous tests, p-nitroaniline did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster when administered by feeding or injection to adult males or by feeding to larvae. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was equivocal evidence of carcinogenic activity of p-nitroaniline in male B6C3F1 mice based on the increased incidences of hemangiosarcoma of the liver and hemangioma or hemangiosarcoma (combined) at all sites. There was no evidence of carcinogenic activity of p-nitroaniline in female B6C3F1 mice receiving doses of 3, 30, or 100 mg/kg.


Negative regulators of TGF-β1 signaling in renal fibrosis; pathological mechanisms and novel therapeutic opportunities.
Elevated expression of the multifunctional cytokine transforming growth factor β1 (TGF-β1) is causatively linked to kidney fibrosis progression initiated by diabetic, hypertensive, obstructive, ischemic and toxin-induced injury. Therapeutically relevant approaches to directly target the TGF-β1 pathway (e.g., neutralizing antibodies against TGF-β1), however, remain elusive in humans. TGF-β1 signaling is subjected to extensive negative control at the level of TGF-β1 receptor, SMAD2/3 activation, complex assembly and promoter engagement due to its critical role in tissue homeostasis and numerous pathologies. Progressive kidney injury is accompanied by the deregulation (loss or gain of expression) of several negative regulators of the TGF-β1 signaling cascade by mechanisms involving protein and mRNA stability or epigenetic silencing, further amplifying TGF-β1/SMAD3 signaling and fibrosis. Expression of bone morphogenetic proteins 6 and 7 (BMP6/7), SMAD7, Sloan-Kettering Institute proto-oncogene (Ski) and Ski-related novel gene (SnoN), phosphate tensin homolog on chromosome 10 (PTEN), protein phosphatase magnesium/manganese dependent 1A (PPM1A) and Klotho are dramatically decreased in various nephropathies in animals and humans albeit with different kinetics while the expression of Smurf1/2 E3 ligases are increased. Such deregulations frequently initiate maladaptive renal repair including renal epithelial cell dedifferentiation and growth arrest, fibrotic factor (connective tissue growth factor (CTGF/CCN2), plasminogen activator inhibitor type-1 (PAI-1), TGF-β1) synthesis/secretion, fibroproliferative responses and inflammation. This review addresses how loss of these negative regulators of TGF-β1 pathway exacerbates renal lesion formation and discusses the therapeutic value in restoring the expression of these molecules in ameliorating fibrosis, thus, presenting novel approaches to suppress TGF-β1 hyperactivation during chronic kidney disease (CKD) progression.


RNAs: regulators of bacterial virulence.
RNA-based pathways that regulate protein expression are much more widespread than previously thought. Regulatory RNAs, including 5' and 3' untranslated regions next to the coding sequence, cis-acting antisense RNAs and trans-acting small non-coding RNAs, are effective regulatory molecules that can influence protein expression and function in response to external cues such as temperature, pH and levels of metabolites. This Review discusses the mechanisms by which these regulatory RNAs, together with accessory proteins such as RNases, control the fate of mRNAs and proteins and how this regulation influences virulence in pathogenic bacteria.


Are poker players all the same? Latent class analysis.
Poker is the gambling game that is currently gaining the most in popularity. However, there is little information on poker players' characteristics and risk factors. Furthermore, the first studies described poker players, often recruited in universities, as an homogeneous group who played in only one of the modes (land based or on the Internet). This study aims to identify, through latent class analyses, poker player subgroups. A convenience sample of 258 adult poker players was recruited across Quebec during special events or through advertising in various media. Participants filled out a series of questionnaires (Canadian Problem Gambling Index, Beck Depression, Beck Anxiety, erroneous belief and alcohol/drug consumption). The latent class analysis suggests that there are three classes of poker players. Class I (recreational poker players) includes those who have the lowest probability of engaging intensively in different game modes. Participants in class II (Internet poker players) all play poker on the Internet. This class includes the highest proportion of players who consider themselves experts or professionals. They make a living in part or in whole from poker. Class III (multiform players) includes participants with the broadest variety of poker patterns. This group is complex: these players are positioned halfway between professional and recreational players. Results indicate that poker players are not an homogeneous group identified simply on the basis of the form of poker played. The specific characteristics associated with each subgroup points to vulnerabilities that could potentially be targeted for preventive interventions.


Protease inhibitor exposure and increased risk of cardiovascular disease in HIV-infected patients.
To study the relationship between exposure to protease inhibitor (PI) therapy and increased risk of cardiovascular events in HIV-infected patients. We estimated the risk of cardiovascular disease (CVD) events with PI exposure in a cohort of HIV-infected patients using a time-dependent Cox proportional hazards model adjusting for the major CVD risk factors. Only the first CVD event for each subject was counted. Of a total of 7542 patients, 77% were exposed to PIs. CVD event rates were 9.8/1000 and 6.5/1000 person-years of follow-up (PYFU) in the PI-exposed and nonexposed groups, respectively (P=0.0008). PI exposure >/=60 days was associated with an increased risk of CVD event [adjusted hazards ratio (HR(adj)) 1.71; 95% confidence interval (CI) 1.08-2.74; P=0.03]. Results from a subgroup of patients aged between 35 and 65 years were similar (HR(adj) 1.90; 95% CI 1.13-3.20; P=0.02). Other significant risk factors included smoking status, age, hypertension, diabetes mellitus and pre-existing CVD. Patients exposed to PI therapy had an increased risk of CVD events. Clinicians should evaluate the risk of CVD when making treatment decisions for HIV-infected patients.


A novel protein-protein interaction in the RES (REtention and Splicing) complex.
The retention and splicing (RES) complex is a conserved spliceosome-associated module that was shown to enhance splicing of a subset of transcripts and promote the nuclear retention of unspliced pre-mRNAs in yeast. The heterotrimeric RES complex is organized around the Snu17p protein that binds to both the Bud13p and Pml1p subunits. Snu17p exhibits an RRM domain that resembles a U2AF homology motif (UHM) and Bud13p harbors a Trp residue reminiscent of an UHM-ligand motif (ULM). It has therefore been proposed that the interaction between Snu17p and Bud13p resembles canonical UHM-ULM complexes. Here, we have used biochemical and NMR structural analysis to characterize the structure of the yeast Snu17p-Bud13p complex. Unlike known UHMs that sequester the Trp residue of the ULM ligand in a hydrophobic pocket, Snu17p and Bud13p utilize a large interaction surface formed around the two helices of the Snu17p domain. In total 18 residues of the Bud13p ligand wrap around the Snu17p helical surface in an U-turn-like arrangement. The invariant Trp(232) in Bud13p is located in the center of the turn, and contacts surface residues of Snu17p. The structural data are supported by mutational analysis and indicate that Snu17p provides an extended binding surface with Bud13p that is notably distinct from canonical UHM-ULM interactions. Our data highlight structural diversity in RRM-protein interactions, analogous to the one seen for nucleic acid interactions.


Inhibition of JNK by cellular stress- and tumor necrosis factor alpha-induced AKT2 through activation of the NF kappa B pathway in human epithelial Cells.
Previous studies have demonstrated that AKT1 and AKT3 are activated by heat shock and oxidative stress via both phosphatidylinositol 3-kinase-dependent and -independent pathways. However, the activation and role of AKT2 in the stress response have not been fully elucidated. In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor alpha (TNFalpha) through a phosphatidylinositol 3-kinase-dependent pathway. The activation of AKT2 inhibits UV- and TNF alpha-induced c-Jun N-terminal kinase (JNK) and p38 activities that have been shown to be required for stress- and TNF alpha-induced programmed cell death. Moreover, AKT2 interacts with and phosphorylates I kappa B kinase alpha. The phosphorylation of I kappa B kinase alpha and activation of NF kappa B mediates AKT2 inhibition of JNK but not p38. Furthermore, phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 significantly enhances UV- and TNF alpha-induced apoptosis, whereas expression of constitutively active AKT2 inhibits programmed cell death in response to UV and TNFalpha -induced apoptosis by inhibition of stress kinases and provide the first evidence that AKT inhibits stress kinase JNK through activation of the NF kappa B pathway.


Cell-selective modulation of the Drosophila neuromuscular system by a neuropeptide.
Neuropeptides can modulate physiological properties of neurons in a cell-specific manner. The present work examines whether a neuropeptide can also modulate muscle tissue in a cell-specific manner using identified muscle cells in third-instar larvae of fruit flies. DPKQDFMRFa, a modulatory peptide in the fruit fly Drosophila melanogaster, has been shown to enhance transmitter release from motor neurons and to elicit contractions by a direct effect on muscle cells. We report that DPKQDFMRFa causes a nifedipine-sensitive drop in input resistance in some muscle cells (6 and 7) but not others (12 and 13). The peptide also increased the amplitude of nerve-evoked contractions and compound excitatory junctional potentials (EJPs) to a greater degree in muscle cells 6 and 7 than 12 and 13. Knocking down FMRFamide receptor (FR) expression separately in nerve and muscle indicate that both presynaptic and postsynaptic FR expression contributed to the enhanced contractions, but EJP enhancement was mainly due to presynaptic expression. Muscle ablation showed that DPKQDFMRFa induced contractions and enhanced nerve-evoked contractions more strongly in muscle cells 6 and 7 than cells 12 and 13. In situ hybridization indicated that FR expression was significantly greater in muscle cells 6 and 7 than 12 and 13. Taken together, these results indicate that DPKQDFMRFa can elicit cell-selective effects on muscle fibers. The ability of neuropeptides to work in a cell-selective manner on neurons and muscle cells may help explain why so many peptides are encoded in invertebrate and vertebrate genomes.


Horizontal transfer of BovB and L1 retrotransposons in eukaryotes.
Transposable elements (TEs) are mobile DNA sequences, colloquially known as jumping genes because of their ability to replicate to new genomic locations. TEs can jump between organisms or species when given a vector of transfer, such as a tick or virus, in a process known as horizontal transfer. Here, we propose that LINE-1 (L1) and Bovine-B (BovB), the two most abundant TE families in mammals, were initially introduced as foreign DNA via ancient horizontal transfer events. Using analyses of 759 plant, fungal and animal genomes, we identify multiple possible L1 horizontal transfer events in eukaryotic species, primarily involving Tx-like L1s in marine eukaryotes. We also extend the BovB paradigm by increasing the number of estimated transfer events compared to previous studies, finding new parasite vectors of transfer such as bed bug, leech and locust, and BovB occurrences in new lineages such as bat and frog. Given that these transposable elements have colonised more than half of the genome sequence in today's mammals, our results support a role for horizontal transfer in causing long-term genomic change in new host organisms. We describe extensive horizontal transfer of BovB retrotransposons and provide the first evidence that L1 elements can also undergo horizontal transfer. With the advancement of genome sequencing technologies and bioinformatics tools, we anticipate our study to be a valuable resource for inferring horizontal transfer from large-scale genomic data.


The implementation of a physical activity counseling program in rehabilitation care: findings from the ReSpAct study.
This study aimed to evaluate the implementation of a physical activity counseling program in rehabilitation and to study heterogeneity in received counseling and investigate its association with changes in patients' physical activity outcomes. This prospective cohort study was conducted in 18 rehabilitation institutions. Data were collected using surveys completed by professionals (n= ±70) and patients (n = 1719). Implementation was evaluated using different process outcomes: reach, dosage, satisfaction, maintenance. Patients' physical activity outcomes included changes in total minutes/week of physical activity. Latent class analyses were conducted to identify profiles of received counseling characteristics and multilevel models were used to investigate associations with physical activity outcomes. 5873 Patients were provided with motivational interviewing-based counseling after rehabilitation. Professionals and patients were positive about the program. Sixteen institutions (89%) formally agreed to continue the program. The four identified profiles of counseling characteristics illustrate a large variation in received counseling among patients. No substantial differences in physical activity outcomes were found between profiles. After a three-year program period, the physical activity counseling centers were sustainably implemented in Dutch rehabilitation care. This study illustrated an innovative approach to assess heterogeneity in implementation outcomes (e.g., counseling profiles) in relation to program outcomes (e.g., physical activity).Implications for rehabilitationPhysical activity counseling after rehabilitation is important to support people with disabilities in making the step from rehabilitation-based physical activities to community-based physical activities.Establishing "Physical Activity Counseling Centers" is a promising "disability-overarching" strategy to promote physical activity after rehabilitation.Although the actual received counseling (dosage) varied among patients, this did not coincide with large differences in physical activity outcomes.The training in Motivational Interviewing, the financial incentives, and the advisory support were considered as important or essential ingredients for a successful implementation of the counseling program in rehabilitation practice.


Limitations and perspectives about scaling ozone impacts in trees.
We review the need for scaling effects of ozone (O3) from juvenile to mature forest trees, identify the knowledge presently available, and discuss limitations in scaling efforts. Recent findings on O3/soil nutrient and O3/CO2 interactions from controlled experiments suggest consistent scaling patterns for physiological responses of individual leaves to whole-plant growth, carbon allocation, and water use efficiency of juvenile trees. These findings on juvenile trees are used to develop hypotheses that are relevant to scaling O3 effects to mature trees, and these hypotheses are examined with respect to existing research on differences in response to O3 between juvenile and mature trees. Scaling patterns of leaf-level physiological response to O3 have not been consistent in previous comparisons between juvenile and mature trees. We review and synthesize current understanding of factors that may cause such inconsistent scaling patterns, including tree-size related changes in environment, stomatal conductance, O3 uptake and exposure. carbon allocation to defense, repair, and compensation mechanisms, and leaf production phenology. These factors should be considered in efforts to scale O3 responses during tree ontogeny. Free-air O3 fumigation experiments of forest canopies allow direct assessments of O3 impacts on physiological processes of mature trees, and provide the opportunity to test current hypotheses about ontogenetic variation in O3 sensitivity by comparing O3 responses across tree-internal scales and ontogeny.


Comprehensive analysis of transcript start sites in ly49 genes reveals an unexpected relationship with gene function and a lack of upstream promoters.
Comprehensive analysis of the transcription start sites of the Ly49 genes of C57BL/6 mice using the oligo-capping 5'-RACE technique revealed that the genes encoding the "missing self" inhibitory receptors, Ly49A, C, G, and I, were transcribed from multiple broad regions in exon 1, in the intron1/exon2 region, and upstream of exon -1b. Ly49E was also transcribed in this manner, and uniquely showed a transcriptional shift from exon1 to exon 2 when NK cells were activated in vitro with IL2. Remarkably, a large proportion of Ly49E transcripts was then initiated from downstream of the translational start codon. By contrast, the genes encoding Ly49B and Q in myeloid cells, the activating Ly49D and H receptors in NK cells, and Ly49F in activated T cells, were predominantly transcribed from a conserved site in a pyrimidine-rich region upstream of exon 1. An ∼200 bp fragment from upstream of the Ly49B start site displayed tissue-specific promoter activity in dendritic cell lines, but the corresponding upstream fragments from all other Ly49 genes lacked detectable tissue-specific promoter activity. In particular, none displayed any significant activity in a newly developed adult NK cell line that expressed multiple Ly49 receptors. Similarly, no promoter activity could be found in fragments upstream of intron1/exon2. Collectively, these findings reveal a previously unrecognized relationship between the pattern of transcription and the expression/function of Ly49 receptors, and indicate that transcription of the Ly49 genes expressed in lymphoid cells is achieved in a manner that does not require classical upstream promoters.


A hybrid ultrasonic motor and electrorheological fluid clutch actuator for force-feedback in MRI/fMRI.
This paper presents a safe, electrically powered MR-compatible actuator with a large range of output impedance, which can be used at the entry of the scanner bore. This actuator is composed of an ultrasonic motor (USM) and a torque-controlled electrorheological fluid clutch which modulates the output torque of the USM. This paper describes the developments on the electrorheological fluid (ERF) clutch and its high voltage driver. The performances of the ERF brake constituting the clutch are evaluated, and its torque range is adapted using an epicyclic differential. The transmissible torque of the ERF clutch, i.e., the maximum system output torque, is 94.4 mNm and its drag torque is 2.6 mNm. The MR compatibility of the complete hybrid actuator is shown in extensive tests including subtraction of images and comparison of signal-to-noise ratios in powered and unpowered conditions. This novel MR-compatible actuator may be used to study the neural control of the hand.


Isolation of an N-alkylated benzylamine derivative from Pseudomonas putida BTP1 as elicitor of induced systemic resistance in bean.
Root treatment of Phaseolus vulgaris with the nonpathogenic Pseudomonas putida BTP1 led to significant reduction of the disease caused by the pathogen Botrytis cinerea on leaves. The molecular determinant of P. putida BTP1 mainly responsible for the induced systemic resistance (ISR) was isolated from cell-free culture fluid after growth of the strain in the iron-poor casamino acid medium. Mass spectrometry analyses performed on both the bacterial product and synthetic analogues revealed a polyalkylated benzylamine structure, with the quaternary ammonium substituted by methyl, ethyl, and C13 aliphatic groups responsible for the relative hydrophobicity of the molecule. The specific involvement of the N-alkylated benzylamine derivative (NABD) in ISR elicitation was first evidenced by testing the purified compound that mimicked the protective effect afforded by crude supernatant samples. The evidence was supported by the loss of elicitor activity of mutants impaired in NABD biosynthesis. Our experiments also showed that other iron-regulated metabolites secreted by the strain are not involved in ISR stimulation. Thus, these results indicate a wider variety of Pseudomonas determinants for ISR than reported to date.


2,4'-Dihydroxyacetophenone dioxygenase (EC 126.96.36.199) from Alcaligenes sp. 4HAP: a novel enzyme with an atypical dioxygenase sequence.
2,4'-Dihydroxyacetophenone dioxygenase (EC 22.214.171.124) was purified to homogeneity from Alcaligenes sp. 4HAP grown on 4-hydroxyacetophenone. Measurements of the M(r) of the native enzyme ranged from 81600 to 87000, whereas values of 21000 and 20379 were given by SDS/PAGE and electrospray MS respectively. The enzyme is a homotetramer and contains one atom of iron per molecule of enzyme. From C- and N-terminal analyses, primers for PCR were designed and the dad gene cloned and sequenced. The predicted amino acid sequence of dad, deduced from the nucleotide sequence, confirms the N-terminal amino acid sequencing data and contains the sequence of an internal tryptic peptide. It gave a calculated M(r) of 20364. The gene was expressed in Escherichia coli and yielded active enzyme. The derived amino acid sequence does not show significant similarity to other dioxygenases or any strong similarity to protein sequences presently available in the databases.


The Muscle Morphology of Elite Sprint Running.
This study aimed to investigate the differences in muscle volumes and strength between male elite sprinters, sub-elite sprinters, and untrained controls and to assess the relationships of muscle volumes and strength with sprint performance. Five elite sprinters (100-m season's best equivalent [SBE100], 10.10 ± 0.07 s), 26 sub-elite sprinters (SBE100, 10.80 ± 0.30 s), and 11 untrained control participants underwent 1) 3-T magnetic resonance imaging scans to determine the volume of 23 individual lower limb muscles/compartments and 5 functional muscle groups and 2) isometric strength assessment of lower body muscle groups. Total lower body muscularity was distinct between the groups (controls < sub-elite +20% < elite +48%). The hip extensors exhibited the largest muscle group differences/relationships (elite, +32% absolute and +15% relative [per kg] volume, vs sub-elite explaining 31%-48% of the variability in SBE100), whereas the plantarflexors showed no differences between sprint groups. Individual muscle differences showed pronounced anatomical specificity (elite vs sub-elite absolute volume range, +57% to -9%). Three hip muscles were consistently larger in elite vs sub-elite (tensor fasciae latae, sartorius, and gluteus maximus; absolute, +45%-57%; relative volume, +25%-37%), and gluteus maximus volume alone explained 34%-44% of the variance in SBE100. The isometric strength of several muscle groups was greater in both sprint groups than controls but similar for the sprint groups and not related to SBE100. These findings demonstrate the pronounced inhomogeneity and anatomically specific muscularity required for fast sprinting and provides novel, robust evidence that greater hip extensor and gluteus maximus volumes discriminate between elite and sub-elite sprinters and are strongly associated with sprinting performance.


Effect of ruboxistaurin on the visual acuity decline associated with long-standing diabetic macular edema.
To compare relationships between severity and duration of diabetic macular edema (DME) and visual acuity (VA) observed in the PKC-DRS2 with those from the Early Treatment Diabetic Retinopathy Study (ETDRS) and to assess the effect of the orally administered PKC beta inhibitor ruboxistaurin (RBX) on these parameters. In the PKC-DRS2, patients with moderately severe to very severe nonproliferative diabetic retinopathy (n = 685) were randomly assigned to 32 mg/d RBX or placebo and followed up for 36 months with ETDRS VA measurements and fundus photographs (FP) every 3 to 6 months. Mean VA was calculated across all FP visits for eyes in each level of the ETDRS DME severity scale at those visits. For eyes with baseline VA > or = 20/40, relationships between change in VA from baseline to last visit and duration of severe DME were analyzed with linear regression. Mean VA decreased by approximately 22 letters between the mildest and most severe levels of the DME scale in the PKC-DRS2, compared with 27 letters in the ETDRS. In the placebo group, the rate of decrease in VA over time associated with duration of severe DME was 0.67 letters per month (24 letters over 36 months, compared with 20 letters over 28-36 months in the ETDRS). This rate was 30% less in the RBX group (0.47 letter per month, P = 0.022). The VA decrease in the PKC-DRS2 associated with long-standing DME agrees well with estimates from the ETDRS. RBX appears to ameliorate this decrease, an effect that could be important clinically. (ClinicalTrials.gov number, NCT00604383.).


Retention and risk factors for loss to follow-up of female and male sex workers on antiretroviral treatment in Ivory Coast: a retrospective cohort analysis.
Antiretroviral therapy (ART) for HIV-infected sex workers is an important HIV prevention strategy. However, sex workers may have additional challenges for retention in ART care. The objectives of this study were to assess retention of sex workers on ART in a routine setting in Ivory Coast and identify risk factors for loss to follow-up (LTFU). The design was a retrospective cohort study. An analysis of clinic files was conducted in 2 sites providing ART services to sex workers in Ivory Coast. Demographic, behavior, and clinical data of female and male sex workers on ART were abstracted onto a standardized anonymous data collection form. Data collection took place between May 11 and 28, 2010. A total of 376 female and 38 male sex workers were included in the analysis. The retention probability was 75% at 6 months, 68% at 12 months, 55% at 24 months, and 47% at 36 months. Attrition was mainly because of LTFU. Factors significantly associated with LTFU in bivariate analysis were lower schooling level, later calendar year of starting ART, and not receiving initial adherence counseling. Later year of starting ART and not receiving adherence counseling at ART initiation remained significantly associated with LTFU in a multivariate Cox regression model. To improve the retention of sex workers on ART, there is a need for more in-depth investigation of the role of pre-ART counseling and the increasing rates of LTFU with each calendar year.


Glycosylation of measles virus haemagglutinin protein in infected cells.
Processing of the measles virus haemagglutinin (H) protein was analysed by the pulse-chase method, immunoprecipitation with an anti-H monoclonal antibody and SDS-polyacrylamide gel electrophoresis, combined with the addition of carbonyl cyanide m-chlorophenylhydrazone (CCCP) or monensin (inhibitors of intracellular processing of secretory proteins) to cultures and digestion of the protein with endoglycosidase H or neuraminidase. The apparent Mr of the H protein was increased from 74K to 78K during the chase period. Addition of either CCCP or monensin to the chase medium inhibited the appearance of the 78K H protein, but not the immunoreactivity of the H protein or dimer formation, suggesting that these two events occur in the rough endoplasmic reticulum. The 74K H protein processed in the presence of CCCP was fully sensitive to endoglycosidase H digestion, whereas the 74K H protein processed in the presence of monensin was partially resistant to endoglycosidase H. In experiments using 3H-labelled sugars, [3H]galactose was incorporated into the 74K H protein in the presence of monensin. Neuraminidase treatment increased the electrophoretic mobility of the 78K H protein to 74K. Only the 78K H protein was detected on the surface of untreated cells, and it was resistant to endoglycosidase H digestion. These data suggest that after galactose addition sialic acid is added to the H protein in the trans-Golgi complex and then the mature 78K H protein is transported to the cell surface.


A novel antidoping and medical care delivery model at the 2nd Summer Youth Olympic Games (2014), Nanjing China.
Antidoping and medical care delivery programmes are required at all large international multisport events. To document and critique the novel antidoping and medical care delivery models implemented at the 2nd Summer Youth Olympic Games, Nanjing 2014. The International Olympic Committee implemented two new models of delivery of antidoping and medical care at the YOG. A review of these models as well as the public health programme and two health educational initiatives in the Cultural and Educational Program was undertaken by the International Olympic Committee. The implementation of the new antidoping model was feasible in the setting of the YOG. The antidoping rules and regulations of the International Olympic Committee were respected. This model enhanced the educational initiative and provided financial as well as human resource savings. The execution of the hospital-based venue model of medical care delivery at the YOG was also feasible in this setting. This model provided a practical infrastructure for the delivery of medical care at multisport events with the goal of providing optimum athlete healthcare. A public health prevention programme was implemented and no public health risks were encountered by the participants or the Nanjing citizens during the YOG. Finally, the implementation of the athlete health educational programmes within the Cultural and Educational Program provided athletes with an opportunity to improve their health and performance. To achieve the goal of protecting athlete health, and of employing effective doping control and education, new alternate models of antidoping and medical care delivery can be implemented.


Randomized controlled trial of a computer-tailored multiple health behaviour intervention in general practice: 12-month follow-up results.
Effective strategies to address risk factors of non-communicable diseases are required to curtail the expanding costs of health care. This trial tested the effectiveness over one year of a minimal intervention targeting multiple health behaviours (diet, physical activity, alcohol and smoking) in a general practice setting, through the provision of personalised, computer-tailored feedback. Patients who had attended a general practice in the previous 6 months were recruited from 21 general practitioners in Brisbane, Australia. Baseline data were collected using self-reports on adherence to ten health behaviours and summarised into a health score from 0 to 10. This randomised controlled trial used a 2×2 factorial design, with one arm randomising subjects to the intervention or control group. The other arm was either feedback at baseline (single contact) or an additional assessment with feedback at 3 months (dual contact). As such, 4 study groups created were, to which participants were randomised blindly: A. Intervention with single contact; B. Intervention with dual contact; C. Control with single contact and D. Control with dual contact. All participants were assessed again at 12 months. Of the 4676 participants randomised, 3065 completed questionnaires at 12 months. Both single and dual contact groups improved their 10 item health scores (+0.31 and +0.49 respectively) relative to control group outcomes (+0.02; p<0.01). Improvement in adherence to guidelines for fish intake, type of milk consumed, vegetable and fruit intake, and alcohol intake were observed in single and dual contact intervention groups (p<0.01). Both intervention groups showed greater improvement than controls for individual health behaviours, apart from red meat intake, smoking behaviour, physical activity and body weight. Interestingly, there was an improvement in reported non-smoking rates in both intervention and control groups (3% single contact; 4.5% dual contact). Small but meaningful long-term changes in health behaviours can be achieved with a low-intensity intervention, which may reduce health care costs if implemented on a large scale. Further research is needed to better understand the mechanism by which maintenance of behaviour change can be achieved. The Australian New Zealand Clinical Trials Registry: ACTRN12611001213932.


Human VPS34 is required for internal vesicle formation within multivesicular endosomes.
After internalization from the plasma membrane, activated EGF receptors (EGFRs) are delivered to multivesicular bodies (MVBs). Within MVBs, EGFRs are removed from the perimeter membrane to internal vesicles, thereby being sorted from transferrin receptors, which recycle back to the plasma membrane. The phosphatidylinositol (PI) 3'-kinase inhibitor, wortmannin, inhibits internal vesicle formation within MVBs and causes EGFRs to remain in clusters on the perimeter membrane. Microinjection of isotype-specific inhibitory antibodies demonstrates that the PI 3'-kinase required for internal vesicle formation is hVPS34. In the presence of wortmannin, EGFRs continue to be delivered to lysosomes, showing that their removal from the recycling pathway and their delivery to lysosomes does not depend on inward vesiculation. We showed previously that tyrosine kinase-negative EGFRs fail to accumulate on internal vesicles of MVBs but are recycled rather than delivered to lysosomes. Therefore, we conclude that selection of EGFRs for inclusion on internal vesicles requires tyrosine kinase but not PI 3'-kinase activity, whereas vesicle formation requires PI 3'-kinase activity. Finally, in wortmannin-treated cells there is increased EGF-stimulated tyrosine phosphorylation when EGFRs are retained on the perimeter membrane of MVBs. Therefore, we suggest that inward vesiculation is involved directly with attenuating signal transduction.


Mitochondrial pharmacology: energy, injury and beyond.
While the mitochondrion has long fascinated biologists and the sheer diversity of druggable targets has made it attractive for potential drug development, there has been little success translatable to the clinic. Given the diversity of inborn errors of metabolism and mitochondrial diseases, mitochondrially mediated oxidative stress (myopathies, reperfusion injury, Parkinson's disease, ageing) and the consequences of disturbed energetics (circulatory shock, diabetes, cancer), the potential for meaningful gain with novel drugs targeting mitochondrial mechanisms is huge both in terms of patient quality of life and health care costs. In this themed issue of the British Journal of Pharmacology, we highlight the key directions of the contemporary advances in the field of mitochondrial biology, emerging drug targets and new molecules which are close to clinical application. Authors' contributions are diverse both in terms of species and organs in which the mitochondrially related studies are performed, and from the perspectives of mechanisms under study. Defined roles of mitochondria in disease are updated and previously unknown contributions to disease are described in terms of the interface between basic science and pathological relevance.


The effect of coincidental SARS-CoV-2 infection on pre-operative cardiopulmonary exercise testing.
This case report demonstrates the significant impact active infection with SARS-CoV-2 can have on functional capacity evaluated by cardiopulmonary exercise testing, even in minimally symptomatic individuals. A 75-year-old man underwent cardiopulmonary exercise testing before a right hemicolectomy; SARS-CoV-2 was incidentally diagnosed following his test. The patient underwent a period of isolation and recovery before a second pre-operative cardiopulmonary exercise test 6 weeks later. His resting pulmonary function tests did not vary between tests but his peak work, anaerobic threshold, oxygen pulse, pulse oximetry nadir, ventilation perfusion matching and heart rate response to exercise all improved significantly after this recovery period. These are unique results that add to the existing knowledge of the pathophysiology and management of SARS-CoV-2 in the peri-operative setting. While our patient demonstrated dramatic improvement in his functional capacity following 6 weeks of recovery, he remained in a high-risk group for surgery according to our local guidelines. Cardiopulmonary exercise testing has a valuable role in individualised risk assessment and shared decision-making in complex, urgent surgical cases where the benefits of delaying surgery to recover from SARS-CoV-2 infection should be balanced against the potential risks.


Motivators and hygiene factors among physicians responding to explicit incentives to improve the value of care.
Physician's dissatisfaction is reported to be increasing, especially in primary care. The transition from fee-for-service to outcome-based reimbursements may make matters worse. To investigate influences of provider attitudes and practice settings on job satisfaction/dissatisfaction during transition to quality-based payment models, we assessed self-reported satisfaction/dissatisfaction with practice in a Rochester (New York)-area physician practice association in the process of implementing pay-for-performance. We linked cross-sectional data for 215 survey respondents on satisfaction ratings and behavioral attitudes with medical record data on their clinical behavior and practices, and census data on their catchment population. Factors associated with the odds of being satisfied or dissatisfied were determined via predictive multivariable logistic regression modeling. Dissatisfied physicians were more likely to have larger-than-average patient panels, lower autonomy and/or control, and beliefs that quality incentives were hindering patient care. Satisfied physicians were more likely to have a higher sense of autonomy and control, smaller patient volumes, and a less complex patient mix. Efforts to maintain or improve satisfaction among physicians should focus on encouraging professional autonomy during transitions from volume-based to quality/outcomes-based payment systems. An optimum balance between accountability and autonomy/control might maximize both health care quality and job satisfaction.


Interhospital differences in severity of illness. Problems for prospective payment based on diagnosis-related groups (DRGs).
We evaluated the ability of the diagnosis-related-group (DRG) classification system to account adequately for severity of illness and, by implication, for the costs of medical care. Hospital inpatients on medicine, surgery, obstetrics/gynecology, and pediatrics services in six hospitals were evaluated to provide a spectrum of patient and hospital characteristics. This evaluation was based on data from a generic index of severity of illness obtained by trained personnel from a review of hospital charts after patient discharge. Within each DRG, substantial differences were found in the distribution of severity of illness in different hospitals. Some hospitals treated larger proportions of severely ill patients and had a wide range of severity within each DRG, but these differences did not always agree with the teaching classification or the Health Care Financing Administration's case-mix index. These findings suggest that patient classification by means of unadjusted DRGs does not adequately reflect severity of illness, and they indicate that prospective payment programs based on DRGs alone may unfairly and adversely discriminate against certain hospitals.


Educational and health outcomes of children and adolescents receiving antiepileptic medication: Scotland-wide record linkage study of 766 244 schoolchildren.
Childhood epilepsy can adversely affect education and employment in addition to health. Previous studies are small or highly selective producing conflicting results. This retrospective cohort study aims to compare educational and health outcomes of children receiving antiepileptic medication versus peers. Record linkage of Scotland-wide databases covering dispensed prescriptions, acute and psychiatric hospitalisations, maternity records, deaths, annual pupil census, school absences/exclusions, special educational needs, school examinations, and (un)employment provided data on 766,244 children attending Scottish schools between 2009 and 2013. Outcomes were adjusted for sociodemographic and maternity confounders and comorbid conditions. Compared with peers, children on antiepileptic medication were more likely to experience school absence (Incidence Rate Ratio [IRR] 1.43, 95% CI: 1.38, 1.48), special educational needs (Odds ratio [OR] 9.60, 95% CI: 9.02, 10.23), achieve the lowest level of attainment (OR 3.43, 95% CI: 2.74, 4.29) be unemployed (OR 1.82, 95% CI: 1.60, 2.07), be admitted to hospital (Hazard Ratio [HR] 3.56, 95% CI: 3.42, 3.70), and die (HR 22.02, 95% CI: 17.00, 28.53). Absenteeism partly explained poorer attainment and higher unemployment. Girls and younger children on antiepileptic medication had higher risk of poor outcomes. Children on antiepileptic medication fare worse than peers across educational and health outcomes. In order to reduce school absenteeism and mitigate its effects, children with epilepsy should receive integrated care from a multidisciplinary team that spans education and healthcare.


Life span and reproductive cost explain interspecific variation in the optimal onset of reproduction.
Fitness can be profoundly influenced by the age at first reproduction (AFR), but to date the AFR-fitness relationship only has been investigated intraspecifically. Here, we investigated the relationship between AFR and average lifetime reproductive success (LRS) across 34 bird species. We assessed differences in the deviation of the Optimal AFR (i.e., the species-specific AFR associated with the highest LRS) from the age at sexual maturity, considering potential effects of life history as well as social and ecological factors. Most individuals adopted the species-specific Optimal AFR and both the mean and Optimal AFR of species correlated positively with life span. Interspecific deviations of the Optimal AFR were associated with indices reflecting a change in LRS or survival as a function of AFR: a delayed AFR was beneficial in species where early AFR was associated with a decrease in subsequent survival or reproductive output. Overall, our results suggest that a delayed onset of reproduction beyond maturity is an optimal strategy explained by a long life span and costs of early reproduction. By providing the first empirical confirmations of key predictions of life-history theory across species, this study contributes to a better understanding of life-history evolution.


Effects of racial and ethnic group and health literacy on responses to genomic risk information in a medically underserved population.
Few studies have examined how individuals respond to genomic risk information for common, chronic diseases. This randomized study examined differences in responses by type of genomic information (genetic test/family history) and disease condition (diabetes/heart disease), and by race/ethnicity in a medically underserved population. 1,057 English-speaking adults completed a survey containing 1 of 4 vignettes (2-by-2 randomized design). Differences in dependent variables (i.e., interest in receiving genomic assessment, discussing with doctor or family, changing health habits) by experimental condition and race/ethnicity were examined using chi-squared tests and multivariable regression analysis. No significant differences were found in dependent variables by type of genomic information or disease condition. In multivariable models, Hispanics were more interested in receiving a genomic assessment than Whites (OR = 1.93; p < .0001); respondents with marginal (OR = 1.54; p = .005) or limited (OR = 1.85; p = .009) health literacy had greater interest than those with adequate health literacy. Blacks (OR = 1.78; p = .001) and Hispanics (OR = 1.85; p = .001) had greater interest in discussing information with family than Whites. Non-Hispanic Blacks (OR = 1.45; p = .04) had greater interest in discussing genomic information with a doctor than Whites. Blacks (β = -0.41; p < .001) and Hispanics (β = -0.25; p = .033) intended to change fewer health habits than Whites; health literacy was negatively associated with number of health habits participants intended to change. Findings suggest that race/ethnicity may affect responses to genomic risk information. Additional research could examine how cognitive representations of this information differ across racial/ethnic groups. Health literacy is also critical to consider in developing approaches to communicating genomic information.


Overcoming the effects of rogue taxa: Evolutionary relationships of the bee flies.
Bombyliidae (5000 sp.), or bee flies, are a lower brachyceran family of flower-visiting flies that, as larvae, act as parasitoids of other insects. The evolutionary relationships are known from a morphological analysis that yielded minimal support for higher-level groupings. We use the protein-coding gene CAD and 28S rDNA to determine phylogeny and to test the monophyly of existing subfamilies, the divisions Tomophtalmae, and 'the sand chamber subfamilies'. Additionally, we demonstrate that consensus networks can be used to identify rogue taxa in a Bayesian framework. Pruning rogue taxa post-analysis from the final tree distribution results in increased posterior probabilities. We find 8 subfamilies to be monophyletic and the subfamilies Heterotropinae and Mythicomyiinae to be the earliest diverging lineages. The large subfamily Bombyliinae is found to be polyphyletic and our data does not provide evidence for the monophyly of Tomophthalmae or the 'sand chamber subfamilies'.


Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon.
Appearance of autoantibodies and clinical manifestations of autoimmunity in melanoma patients treated with adjuvant interferon (IFN)-alpha2b was reported to be associated with improved prognosis. We assessed the association of the appearance of autoantibodies after initiation of treatment with recurrence-free interval in two randomized trials that compared intermediate doses of IFN with observation for the treatment of melanoma patients. Serum levels of anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined using enzyme-linked immunosorbent assays in 187 and 356 patients in the European Organization for Research and Treatment of Cancer (EORTC) 18952 and Nordic IFN trials, respectively, immediately before and up to 3 years after random assignment. The association of the presence of at least one of the three autoantibodies with risk of recurrence was assessed by three Cox models in patients negative for all three autoantibodies at baseline (125 from the EORTC 18952 trial and 230 from the Nordic IFN trial): 1) a model that considered appearance of autoantibodies as a time-independent variable, 2) one that considered a patient autoantibody positive once a positive test for an autoantibody was obtained, and 3) a model in which the status of the patient was defined by the most recent autoantibody test. All statistical tests were two-sided. When treated as a time-independent variable (model 1), appearance of autoantibodies was associated with improved relapse-free interval in both trials (EORTC 18952, hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.25 to 0.68, P < .001; and Nordic IFN, HR = 0.51, 95% CI = 0.34 to 0.76, P < .001). However, on correction for guarantee-time bias, the association was weaker and not statistically significant (model 2: EORTC 18952, HR = 0.81, 95% CI = 0.46 to 1.40, P = .44; and Nordic IFN, HR = 0.85, 95% CI = 0.55 to 1.30, P = .45; model 3: EORTC 18952, HR = 1.05, 95% CI = 0.59 to 1.87, P = .88; and Nordic IFN, HR = 0.78, 95% CI = 0.49 to 1.24, P = .30). In two randomized trials of IFN for the treatment of melanoma patients, appearance of autoantibodies was not strongly associated with improved relapse-free interval when correction was made for guarantee-time bias.


Regulation of antibiotic sales in Mexico: an analysis of printed media coverage and stakeholder participation.
Restricting antibiotics sales to those with medical prescriptions only is a central strategy for promoting appropriate use and containing antibiotic resistance; however, many low and middle income countries have not enforced policies that prevent widespread self-medication with antibiotics. In 2010, the Mexican government announced the enforcement of antibiotic sales regulations, a policy that gained media prominence. This study analyzes media coverage of issues, stakeholder representation, and positions taken during policy agenda setting, drafting, and implementation to shed light on policy making to promote appropriate antibiotic utilization. We carried out a quantitative content analysis of 322 newspaper articles published between January 2009 and December 2010 in 18 national and regional newspapers. Additionally, we conducted a qualitative content analysis to understand the positions adopted and strategies developed by nine key stakeholders. Framing theory guided the analysis. The Ministry of Health dominated media coverage, justifying the enforcement policy by focusing on risks of self-medication, and to a lesser degree dangers of increasing antibiotic resistance. Pharmacy associations appeared to be the leading opponents, arguing that the policy created logistical difficulties and corruption, and had negative economic impact for pharmacies and their clients. The associations developed strategies against the regulation such as attempting to delay implementation and installing physicians' consultation offices within pharmacies. While medical associations and academic institutions called for a comprehensive strategy to combat antibiotic resistance, improve prescription quality, and create public awareness, these issues had little impact on media coverage. Consumer groups and legislators received very little media coverage. The narrowly-focused and polarized media coverage ─centred on problems of self- medication and economic impact ─ was a missed opportunity to publicly discuss and to develop a comprehensive national strategy on antibiotic use in Mexico. It highlights the need for discussing and developing interventions within the framework of a pharmaceutical policy.


Blood pressure-lowering treatment strategies based on cardiovascular risk versus blood pressure: A meta-analysis of individual participant data.
Clinical practice guidelines have traditionally recommended blood pressure treatment based primarily on blood pressure thresholds. In contrast, using predicted cardiovascular risk has been advocated as a more effective strategy to guide treatment decisions for cardiovascular disease (CVD) prevention. We aimed to compare outcomes from a blood pressure-lowering treatment strategy based on predicted cardiovascular risk with one based on systolic blood pressure (SBP) level. We used individual participant data from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) from 1995 to 2013. Trials randomly assigned participants to either blood pressure-lowering drugs versus placebo or more intensive versus less intensive blood pressure-lowering regimens. We estimated 5-y risk of CVD events using a multivariable Weibull model previously developed in this dataset. We compared the two strategies at specific SBP thresholds and across the spectrum of risk and blood pressure levels studied in BPLTTC trials. The primary outcome was number of CVD events avoided per persons treated. We included data from 11 trials (47,872 participants). During a median of 4.0 y of follow-up, 3,566 participants (7.5%) experienced a major cardiovascular event. Areas under the curve comparing the two treatment strategies throughout the range of possible thresholds for CVD risk and SBP demonstrated that, on average, a greater number of CVD events would be avoided for a given number of persons treated with the CVD risk strategy compared with the SBP strategy (area under the curve 0.71 [95% confidence interval (CI) 0.70-0.72] for the CVD risk strategy versus 0.54 [95% CI 0.53-0.55] for the SBP strategy). Compared with treating everyone with SBP ≥ 150 mmHg, a CVD risk strategy would require treatment of 29% (95% CI 26%-31%) fewer persons to prevent the same number of events or would prevent 16% (95% CI 14%-18%) more events for the same number of persons treated. Compared with treating everyone with SBP ≥ 140 mmHg, a CVD risk strategy would require treatment of 3.8% (95% CI 12.5% fewer to 7.2% more) fewer persons to prevent the same number of events or would prevent 3.1% (95% CI 1.5%-5.0%) more events for the same number of persons treated, although the former estimate was not statistically significant. In subgroup analyses, the CVD risk strategy did not appear to be more beneficial than the SBP strategy in patients with diabetes mellitus or established CVD. A blood pressure-lowering treatment strategy based on predicted cardiovascular risk is more effective than one based on blood pressure levels alone across a range of thresholds. These results support using cardiovascular risk assessment to guide blood pressure treatment decision-making in moderate- to high-risk individuals, particularly for primary prevention.


Health Care Service Use Among Elderly Seasonal Migrators.
Elderly seasonal migrators share time between homes in different states, presenting challenges for care coordination and patient attribution methods. Medicare has prioritized alternative payment models, putting health care providers at risk for quality and value of services delivered to their attributed patients, regardless of the location of care. Little research is available to guide providers and payers on the service use of seasonal migrators. The authors use claims data on fee-for-service (FFS) Medicare beneficiaries' locations throughout the year to (1) identify seasonal migrators and (2) describe the care they receive in each seasonal home, focusing on primary care and emergency department (ED) visits and the relationships between the two. In all, 5.5% of the Medicare aged FFS population were identified as seasonal migrators, with 4.1% following the traditional snowbird pattern of migration, spending warm months in the north and cold months in the south. Migrators had higher rates of ED visits and primary care treatable (PCT) ED visits than the nonmigratory groups, controlling for location, age, race, sex, Medicaid status, season, and comorbidities. They also had more visits with specialist physicians, more days with outpatient services, and more days seeing a physician in any setting. Having local primary care strongly reduced rates of both PCT ED visits and total ED visits for all migration categories, with the greatest reduction seen in PCT ED visits by migrators (local primary care was associated with a 58% reduction in PCT ED visits by snowbirds and a 65% reduction in PCT ED visits by other migrators).


Combination of astaxanthin and fish oil supplementation alters antioxidant enzyme profile of dental pulp tissue.
To evaluate the effect of administration of astaxanthin (ASTA) and fish oil (FO) on enzymatic antioxidant parameters of dental pulp tissue from healthy rats. Thirty-two healthy Wistar rats were divided into four groups: untreated control, ASTA-treated (1 mg kg(-1) body weight), FO-treated (10 mg eicosapentaenoic acid per kg BW and 7 mg docosahexaenoic acid per kg BW) and FO plus ASTA-treated. A prophylactic dose was administered in each group daily by gavage, 5 days a week, for 45 days. After treatment, the rats were killed and all incisor dental pulps were removed. Superoxide dismutase (SOD), catalase, glutathione (GSH) peroxidase and reductase activities were determined. Data were compared by anova and the Tukey's post-test ( P < 0.05). Treatment with FO, ASTA and FO plus ASTA caused a reduction in SOD and GSH reductase activities in dental pulp tissue compared to untreated control rats ( P < 0.05). ASTA partially stimulated catalase activity. The preventive administration of ASTA and FO changed the enzymatic antioxidant system of dental pulp tissue, possibly by controlling oxidative stress.


Systematic evaluation of factors controlling Perkinsus marinus transmission dynamics in lower Chesapeake Bay.
The transmission of Perkinsus marinus in eastern oysters Crassostrea virginica in relation to water temperature, host oyster mortality, and water-column abundance of anti-P. marinus antibody-labeled cells was systematically examined for 20 mo at a site in the lower York River, Virginia, USA. Uninfected sentinel oysters were naturally exposed to the parasite at 2 wk intervals throughout the course of the study to determine the periodicity and rates of parasite transmission. The timing and magnitude of disease-associated oyster mortalities in a local P. marinus-infected oyster population were estimated by monitoring a captive subset of the local oyster population. Flow cytometric immunodetection methods were employed to estimate the abundance of P. marinus cells in water samples collected 3 times each week. The acquisition of P. marinus infections by naïve sentinel oysters occurred sporadically at all times of the year; however, the highest incidence of infection occurred during the months of August and September. This window of maximum parasite transmission coincided with the death of infected hosts within the captive local oyster population. Counts of antibody-labeled cells ranged from 10 to 11900 cells l(-1), with the highest abundances in July and August coincident with maximum summer temperatures. A statistically significant relationship between water-column parasite abundance and infection-acquisition rate was not observed; however, highest parasite-transmission rates in both years occurred during periods of elevated water-column abundance of parasite cells. These results support the prevailing model of P. marinus transmission dynamics by which maximum transmission rates are observed during periods of maximum P. marinus-associated host mortality. However, our results also indicate that transmission can occur when host mortality is low or absent, so alternative mortality-independent dissemination mechanisms are likely. The results also suggest that atypically early-summer oyster mortality from Haplosporidium nelsoni infection, at a time when infections of P. marinus are light, has a significant indirect influence on P. marinus transmission dynamics. Elimination of these hosts prior to late-summer P. marinus infection-intensification effectively reduces the overall number of P. marinus cells disseminated.


Genome wide association analysis on semen volume and milk yield using different strategies of imputation to whole genome sequence in French dairy goats.
Goats were domesticated 10,500 years ago to supply humans with useful resources. Since then, specialized breeds that are adapted to their local environment have been developed and display specific genetic profiles. The VarGoats project is a 1000 genomes resequencing program designed to cover the genetic diversity of the Capra genus. In this study, our main objective was to assess the use of sequence data to detect genomic regions associated with traits of interest in French Alpine and Saanen breeds. Direct imputation from the GoatSNP50 BeadChip genotypes to sequence level was investigated in these breeds using FImpute and different reference panels: within-breed, all Capra hircus sequenced individuals, European goats and French mainland goats. The best results were obtained with the French goat panel with allele and genotype concordance rates reaching 0.86 and 0.75 in the Alpine and 0.86 and 0.73 in the Saanen breed respectively. Mean correlations tended to be low in both breeds due to the high proportion of variants with low frequencies. For association analysis, imputation was performed using FImpute for 1129 French Alpine and Saanen males using within-breed and French panels on 23,338,436 filtered variants. The association results of both imputation scenarios were then compared. In Saanen goats, a large region on chromosome 19 was significantly linked to semen volume and milk yield in both scenarios. Significant variants for milk yield were annotated for 91 genes on chromosome 19 in Saanen goats. For semen volume, the annotated genes include YBOX2 which is related to azoospermia or oligospermia in other species. New signals for milk yield were detected on chromosome 2 in Alpine goats and on chromosome 5 in Saanen goats when using a multi-breed panel. Even with very small reference populations, an acceptable imputation quality can be achieved in French dairy goats. GWAS on imputed sequences confirmed the existence of QTLs and identified new regions of interest in dairy goats. Adding identified candidates to a genotyping array and sequencing more individuals might corroborate the involvement of identified regions while removing potential imputation errors.


Hypolipidemic effects and safety of Lactobacillus reuteri 263 in a hamster model of hyperlipidemia.
We aimed to verify the beneficial effects of probiotic strain Lactobacillus reuteri 263 (Lr263) on hypolipidemic action in hamsters with hyperlipidemia induced by a 0.2% cholesterol and 10% lard diet (i.e., high-cholesterol diet (HCD)). Male Golden Syrian hamsters were randomly divided into two groups: normal (n = 8), standard diet (control), and experimental (n = 32), a HCD. After a two-week induction followed by a six-week supplementation with Lr263, the 32 hyperlipidemic hamsters were divided into four groups (n = 8 per group) to receive vehicle or Lr263 by oral gavage at 2.1, 4.2, or 10.5 × 10(9) cells/kg/day for 6 weeks, designated the HCD, 1X, 2X and 5X groups, respectively. The efficacy and safety of Lr263 supplementation were evaluated by lipid profiles of serum, liver and feces and by clinical biochemistry and histopathology. HCD significantly increased serum levels of total cholesterol (TC), triacylglycerol (TG) cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio, hepatic and fetal TC and TG levels, and degree of fatty liver as compared with controls. Lr263 supplementation dose dependently increased serum HDL-C level and decreased serum TC, TG, LDL-C levels, LDL-C/HDL-C ratio, hepatic TC and TG levels, and fecal TG level. In addition, Lr263 supplementation had few subchronic toxic effects. Lr263 could be a potential agent with a hypolipidemic pharmacological effect.


Prevention of delirium (POD) for older people in hospital: study protocol for a randomised controlled feasibility trial.
Delirium is the most frequent complication among older people following hospitalisation. Delirium may be prevented in about one-third of patients using a multicomponent intervention. However, in the United Kingdom, the National Health Service has no routine delirium prevention care systems. We have developed the Prevention of Delirium Programme, a multicomponent delirium prevention intervention and implementation process. We have successfully carried out a pilot study to test the feasibility and acceptability of implementation of the programme. We are now undertaking preliminary testing of the programme. The Prevention of Delirium Study is a multicentre, cluster randomised feasibility study designed to explore the potential effectiveness and cost-effectiveness of the Prevention of Delirium Programme. Sixteen elderly care medicine and orthopaedic/trauma wards in eight National Health Service acute hospitals will be randomised to receive the Prevention of Delirium Programme or usual care. Patients will be eligible for the trial if they have been admitted to a participating ward and are aged 65 years or over. The primary objectives of the study are to provide a preliminary estimate of the effectiveness of the Prevention of Delirium Programme as measured by the incidence of new onset delirium, assess the variability of the incidence of new-onset delirium, estimate the intracluster correlation coefficient and likely cluster size, assess barriers to the delivery of the Prevention of Delirium Programme system of care, assess compliance with the Prevention of Delirium Programme system of care, estimate recruitment and follow-up rates, assess the degree of contamination due to between-ward staff movements, and investigate differences in financial costs and benefits between the Prevention of Delirium Programme system of care and standard practice. Secondary objectives are to investigate differences in the number, severity and length of delirium episodes (including persistent delirium); length of stay in hospital; in-hospital mortality; destination at discharge; health-related quality of life and health resource use; physical and social independence; anxiety and depression; and patient experience. This feasibility study will be used to gather data to inform the design of a future definitive randomised controlled trial. ISRCTN01187372 . Registered 13 March 2014.


Transgenerational effects in asexually reproduced offspring of Populus.
The response of trees to a changing climate can be affected by transgenerational phenotypic plasticity, i.e. phenotypic variation that is conserved and transferred to the offspring. Transgenerational plasticity that is influenced by epigenetics (heritable changes in gene function that do not result from changes in DNA sequence) during both sexual and asexual reproduction are of major relevance for adaptation of plants to climate change. To understand the transgenerational effects on the responses of vegetatively propagated poplar (Populus deltoides and P. trichocarpa) ramets (cuttings) to a changing environment, we tested whether the temperature and photoperiod experienced by the mother trees (genets) persistently affects the phenology of the cuttings grown in a common environment. We weekly monitored the bud phenology of the cuttings collected from the parent trees that have been growing across Europe along a >2100 km latitudinal gradient for at least 18 years. In addition, we asked whether there was variation in DNA methylation as measured by Methylation Sensitive Amplified Fragment Length Polymorphism (MSAPs) in the clones due to the different environmental conditions experienced by the parent trees. Our results indicate a transgenerational effect on bud phenology in the asexually reproduced offspring (vegetative cuttings). The temperatures experienced by the parent tree clones (from different geographic regions) altered the bud flush of the cuttings in the common garden. However, no significant epigenetic variation was detected in the cuttings of the parent trees within single genotypes growing under different climates. In sum, our results show that trees have the potential to respond to rapid climate change but the mechanism behind these changes needs to be further investigated by more powerful molecular methods like whole-genome bisulphite sequencing techniques.


Metal-catalyst-free growth of single-walled carbon nanotubes on substrates.
In this communication, we have demonstrated that SiO(2) nanoparticles can be generated by simply scratching the quartz or silicon wafer with a SiO(2) layer and confirmed it to be active for the growth of SWNTs for the first time. Furthermore, the SWNTs from SiO(2) has a much narrower size distribution. This may open a way to control the diameter of the SWNTs. More importantly, our work has found a series of oxides including Al(2)O(3), TiO(2), and rare earth oxides to be active for SWNT growth as well. These findings not only provide an alternative new type of catalysts for the growth of SWNTs but also give more insight into the role of the catalysts and a deeper understanding of the growth mechanism of SWNTs. The effective catalysts and catalytic activity for SWNT growth seem to be more size-dependent than the catalysts. Long oriented SWNTs generated from these catalysts enable us to rule out the relationship between the catalysts and the structures of the SWNTs. Thus controlled growth of SWNTs including the diameter and chirality is expected to be eventually realized.


18F-FDG PET/CT and lung cancer: value of fourth and subsequent posttherapy follow-up scans for patient management.
The Centers for Medicare and Medicaid Services recently ruled that only 3 posttherapy follow-up (18)F-FDG PET/CT scans are funded for a tumor type per patient and any additional follow-up PET/CT scans will be funded at the discretion of the local Medicare administrator. The purpose of this study was to evaluate the added value of 4 or more follow-up PET/CT scans to clinical assessment and impact on patient management. This was an institutional review board-approved, retrospective study. A total of 1,171 patients with biopsy-proven lung cancer who had undergone (18)F-FDG PET/CT at a single tertiary center from 2001 to 2013 were identified. Among these, 85 patients (7.3%) had undergone 4 or more follow-up PET/CT scans, for a total of 285 fourth and subsequent follow-up PET/CT scans. Median follow-up from the fourth follow-up PET/CT scan was 31.4 mo (range, 0-155.2 mo). The follow-up PET/CT scan results were correlated with clinical assessment and treatment changes. Of the 285 fourth and subsequent follow-up PET/CT scans, 149 (52.28%) were interpreted as positive and 136 (47.7%) as negative for recurrence or metastasis. A total of 47 patients (55.3%) died during the study period. PET/CT identified recurrence or metastasis in 44.3% of scans performed without prior clinical suspicion and ruled out recurrence or metastasis in 24.2% of scans performed with prior clinical suspicion. The PET/CT scan resulted in a treatment change in 28.1% (80/285) of the patients. New treatment was initiated for 20.4% (58/285) of the scans, treatment was changed in 5.6% (16/285), and ongoing treatment was stopped in 2.1% (6/285). The fourth and subsequent (18)F-FDG PET/CT scans performed during follow-up after completion of primary treatment added value to clinical assessment and changed management 28.1% of the time.


Adjuvant chemotherapy decisions in clinical practice for early-stage node-negative, estrogen receptor-positive, HER2-negative breast cancer: challenges and considerations.
Decisions regarding adjuvant chemotherapy for patients with estrogen receptor (ER)-positive, HER2-negative, lymph node-negative breast cancer have traditionally relied on clinical and pathologic parameters. However, the molecular heterogeneity and the complex tumor genome demand more sophisticated approaches to the problem. Several multigene-based assays have been developed to better prognosticate the risk of recurrence and death and predict benefit of therapy in this patient population. Oncologists are often faced with the challenge of incorporating these various complex genome-based biomarkers along with the traditional biomarkers in clinical decision-making. The NCCN Clinical Practice Guidelines in Oncology for Breast Cancer are helpful in providing a general recommendation. However, uncertainty remains in the absence of definitive data for various clinical scenarios. This case report describes a postmenopausal woman with stage I breast cancer that is low-grade and ER-rich, and has an intermediate Oncotype DX recurrence score of 28.


Apomixis in plant reproduction: a novel perspective on an old dilemma.
Seed is one of the key factors of crop productivity. Therefore, a comprehension of the mechanisms underlying seed formation in cultivated plants is crucial for the quantitative and qualitative progress of agricultural production. In angiosperms, two pathways of reproduction through seed exist: sexual or amphimictic, and asexual or apomictic; the former is largely exploited by seed companies for breeding new varieties, whereas the latter is receiving continuously increasing attention from both scientific and industrial sectors in basic research projects. If apomixis is engineered into sexual crops in a controlled manner, its impact on agriculture will be broad and profound. In fact, apomixis will allow clonal seed production and thus enable efficient and consistent yields of high-quality seeds, fruits, and vegetables at lower costs. The development of apomixis technology is expected to have a revolutionary impact on agricultural and food production by reducing cost and breeding time, and avoiding the complications that are typical of sexual reproduction (e.g., incompatibility barriers) and vegetative propagation (e.g., viral transfer). However, the development of apomixis technology in agriculture requires a deeper knowledge of the mechanisms that regulate reproductive development in plants. This knowledge is a necessary prerequisite to understanding the genetic control of the apomictic process and its deviations from the sexual process. Our molecular understanding of apomixis will be greatly advanced when genes that are specifically or differentially expressed during embryo and embryo sac formation are discovered. In our review, we report the main findings on this subject by examining two approaches: i) analysis of the apomictic process in natural apomictic species to search for genes controlling apomixis and ii) analysis of gene mutations resembling apomixis or its components in species that normally reproduce sexually. In fact, our opinion is that a novel perspective on this old dilemma pertaining to the molecular control of apomixis can emerge from a cross-check among candidate genes in natural apomicts and a high-throughput analysis of sexual mutants.


The HOPE social media intervention for global HIV prevention in Peru: a cluster randomised controlled trial.
Social media technologies offer new approaches to HIV prevention and promotion of testing. We examined the efficacy of the Harnessing Online Peer Education (HOPE) social media intervention to increase HIV testing among men who have sex with men (MSM) in Peru. In this cluster randomised controlled trial, Peruvian MSM from Greater Lima (including Callao) who had sex with a man in the past 12 months, were 18 years of age or older, were HIV negative or serostatus unknown, and had a Facebook account or were willing to create one (N=556) were randomly assigned (1:1) by concealed allocation to join intervention or control groups on Facebook for 12 weeks. For the intervention, Peruvian MSM were trained and assigned to be HIV prevention mentors (peer-leaders) to participants in Facebook groups. The interventions period lasted 12 weeks. Participants in control groups received an enhanced standard of care, including standard offline HIV prevention available in Peru and participation in Facebook groups (without peer leaders) that provided study updates and HIV testing information. After accepting a request to join the groups, continued participation was voluntary. Participants also completed questionnaires on HIV risk behaviours and social media use at baseline and 12 week follow-up. The primary outcome was the number of participants who received a free HIV test at a local community clinic. The facebook groups were analysed as clusters to account for intracluster correlations. This trial is registered with ClinicalTrials.gov, number NCT01701206. Of 49 peer-leaders recruited, 34 completed training and were assigned at random to the intervention Facebook groups. Between March 19, 2012, and June 11, 2012, and Sept 26, 2012, and Dec 19, 2012, 556 participants were randomly assigned to intervention groups (N=278) or control groups (N=278); we analyse data for 252 and 246. 43 participants (17%) in the intervention group and 16 (7%) in the control groups got tested for HIV (adjusted odds ratio 2·61, 95% CI 1·55–4·38). No adverse events were reported. Development of peer-mentored social media communities seemed to be an efficacious method to increase HIV testing among high-risk populations in Peru. Results suggest that the HOPE social media intervention could improve HIV testing rates among MSM in Peru. National Institute of Mental Health.


Echinacea purpurea polysaccharide reduces the latency rate in herpes simplex virus type-1 infections.
During the latency period of herpes simplex virus type-1 (HSV-1), the virus can occasionally reactivate, travel back to the eye and cause recurrent ocular disease. As this condition arises from the ability of HSV-1 to produce a dormant infection, effective medication to prevent the virus enter a latent state should prevent it. In this study, we applied Echinacea polysaccharide (EP) fraction as prophylactic mediator for latency prevention. In order to investigate the protective properties of EP, we evaluated its immunostimulatory functions on different immune aspects that play important roles in latency prevention (particularly IFN-gamma as one of the main indicators of cellular immunity and latency). Finally, we assessed establishment of latency by detection of thymidine kinase gene in trigeminal ganglia of BALB/c mice. We demonstrated that EP promotes immune response, leading to a reduced latency rate, and it has a promising effect on latency prevention. EP was able to exert an antiviral action on the development of recurrent HSV-1 disease when supplied prior to infection.


One-year outcomes of inhaled controller therapies added to systemic corticosteroids after asthma-related hospital discharge.
Much of the evidence on the early use of inhaled controllers after severe asthma exacerbations is about their short-term benefit, leaving a gap in evidence on their longer-term outcomes. We used administrative health data from British Columbia, Canada (2001-2012) to evaluate readmission rate (primary outcome), adherence to controller medications, and use of reliever medications associated with different inhaled controller treatments as an add-on to systemic corticosteroids (SCS) over one-year following discharge from an asthma-related admission in individuals 12-55 years of age. Exposure was assessed in the 60 days after discharge, and categorized as monotherapy with SCS (SCS-only) versus SCS plus inhaled controller therapy (SCS + inhaler); the latter was further divided into SCS + inhaled corticosteroid (SCS + ICS) and SCS + ICS and long-acting beta agonists (SCS + ICS/LABA). Propensity score-adjusted regression models were used to estimate relative rates (RR) of outcomes across exposure groups. The final cohort included 2,272 post-discharge periods (43.0% SCS-only, 26.9% SCS + ICS, and 30.1% SCS + ICS/LABA). Readmission rate was significantly lower in the SCS + inhaler versus SCS-only (RR = 0.74 [95%CI 0.59-0.93]), but similar between SCS + ICS and SCS + ICS/LABA (RR = 0.78 [95%CI 0.59-1.04]). Long-term adherence, defined as medication possession ratio, to controller medications was 83% higher in SCS + inhaler than SCS-only, and 64% higher in SCS + ICS/LABA than in SCS + ICS. The use of reliever medications was similar across exposure groups. Early initiation of inhaled controllers after discharge from an asthma-related hospitalization was associated with significantly better long-term adherence to controller medications as well as reduced rate of readmissions. Combination therapy with ICS/LABA seems to be at least as effective as mono-therapy with ICS in reducing the risk of readmission, with the added benefit of better long-term adherence.


Does the site of anastomosis for esophagectomy affect long-term quality of life?
Long-term survival after esophagectomy is improving, and hence, quality of life (QOL) of these patients has become a priority. There has been extensive debate regarding the optimal site of surgical anastomosis (cervical or intrathoracic). We aimed to evaluate the impact of anastomotic site on long-term QOL postesophagectomy. Quality of life questionnaires (European Organisation for Research and Treatment of Cancer [EORTC] C-30 and OG-25) were sent to patients surviving over 3 years following esophagectomy. The data were analyzed by site of esophagogastric anastomosis: intrathoracic or cervical. EORTC C-30 data were compared against the reference population data. Of the patients, 62 responded (82%) with a median time postsurgery of 6.1 years (range 3-12 years). Patient demographics were comparable. There was no significant difference between cervical or intrathoracic anastomosis groups for functional or symptom scores, focusing on dysphagia (cervical = 8.8 vs. intrathoracic = 17.6, P = 0.24), odynophagia (cervical = 13.4 vs. intrathoracic = 16.1, P = 0.68) and swallowing problems (cervical = 8.1 vs. intrathoracic = 13.4, P = 0.32). There was no difference in overall health score between groups (cervical = 70.5 vs. intrathoracic = 71.6, P = 0.46). Overall general health score was comparable with the reference population (esophagectomy group P = 70.9 ± 22.1 vs. reference population = 71.2 ± 22.4, P = 0.93). There is no difference in long-term QOL after esophagectomy between patients with a cervical or intrathoracic anastomosis. Scores compare favorably with EORTC reference data. Survival after esophagectomy is associated with recovery of QOL in the long term, regardless of site of anastomosis and despite worse gastrointestinal-related symptoms.


A Practical Methodological Approach Towards Identifying Core Competencies in Medical Education Based on Literature Trends: A Feasibility Study Based on Vestibular Schwannoma Science.
Competency-based medical education (CBME) is gaining momentum in postgraduate residency and fellowship training. While randomized trials, consensus statements, and practice guidelines can help delineate some of the core competencies for CBME, they are not applicable to all clinical scenarios. To propose and assess the feasibility of a practical methodology for addressing this issue using radiosurgery for vestibular schwannoma (VS) science as an example. The Web of Science electronic database was searched using relevant terms. A 3-step review of titles and abstracts was used. Studies were classified independently and in duplicate as either efficacy or effectiveness analyses. Cohen's kappa score was used to assess inter-rater agreement. Overall, 1818 surgical and 943 radiosurgical publications were identified. The number of effectiveness studies surpassed that of efficacy studies in the late 1980s for surgical studies, and in the early-to-mid 1990s among radiosurgical studies. The publication rate was higher for radiosurgery in the mid 1990s, but it paralleled that of surgical studies beyond the early 2000s. Variations in this overall trend corresponded to the emergence of studies that assessed the role of endoscopy and the utility of dose reduction in radiosurgery. We have confirmed the feasibility and accuracy of this objective methodological approach. By understanding how the peer-reviewed literature reflects actual practice interests, educators can tailor curricula to ensure that trainees remain current. While further validation studies are needed, this methodology can serve as a supplemental strategy for identifying additional core competencies in CBME.


A controlled, double-blind study of the effect of quazolast on nasal challenge with ragweed antigen.
Quazolast is a potent mediator release inhibitor as determined by in vitro and in vivo testing. A placebo-controlled, double-blind, two-way crossover study compared the safety and efficacy of Quazolast, 400 mg bid orally, with placebo in 23 subjects with ragweed (RW) allergy, out of season. Subjects were assigned to two 7-day treatments in a random sequence with an 8-day washout. Subjects were challenged on days 1 and 7 of each trial with serial dilutions (10, 100, 1000, 1350, and 2700 PNU/0.135 mL) of RW, using metered pump spray bottles, (two sprays delivered 0.135 mL), preceded by saline control. Efficacy evaluation consisted of nasal flow rates measured by rhinomanometry, sneeze counts, nasal itchiness scores, and weight of nasal secretions during challenges. During Quazolast treatment, subjects had significantly lower (P less than .05) mean percent decreases in nasal flow rate at 1350 and 2700 PNU. Nasal itchiness scores were significantly lower (P less than .05) during Quazolast treatment than at placebo at 1000, 1350, and 2700 PNU. Although sneeze counts were lower during treatment with Quazolast than with placebo, the results did not reach statistical significance. No significant improvement was seen in the weight of nasal secretions. Adverse experiences, clinical laboratory results, and physical examinations were unremarkable, posttreatment. Quazolast was superior to placebo in protecting against nasal congestion and nasal itchiness after ragweed nasal challenge.


Whither regulation, risk and water safety plans? Case studies from Malaysia and from England and Wales.
We explore the interplay between preventative risk management and regulatory style for the implementation of water safety plans in Malaysia and in England and Wales, two jurisdictions with distinct philosophies of approach. Semi-structured interviews were conducted with 32 water safety professionals in Malaysia, 23 in England and Wales, supported by 6 Focus Group Discussions (n = 53 participants). A grounded theory approach produced insights on the transition from drinking water quality surveillance to preventative risk management. Themes familiar to this type of regulatory transition emerged, including concerns about compliance policy; overseeing the risk management controls of regulatees with varied competencies and funds available to drive change; and the portfolio of interventions suited to a more facilitative regulatory style. Because the potential harm from waterborne illness is high where pathogen exposures occur, the transition to risk-informed regulation demands mature organisational cultures among water utilities and regulators, and a laser-like focus on ensuring risk management controls are delivered within water supply systems.


Multi-scale correlations in continuous genomic data.
Functional genomic quantities such as histone modifications, chromatin accessibility, and evolutionary constraint can now be measured in a nearly continuous fashion across the genome. The genome is highly heterogeneous, and the relationships between different functional annotations may be fluid. Here we present an approach for visualizing, quantifying, and determining the statistical significance of local and regional correlations between high-density continuous genomic datasets. We use wavelets to generate a multi-scale view of each component data set and calculate correlations between data types as a function of genome position over a continuous range of scales in sliding window fashion. We determine the statistical significance of correlations using a non-parametric sampling approach. We apply the wavelet correlation method to histone modification and chromatin accessibility (DNasel sensitivity) data from the NHGRI ENCODE project. We show that DNaseI sensitivity is broadly correlated (though to differing degrees) with a number of different activating histone modifications. We examine the continuous relationship between the repressive histone modification H3K27me3 and the activating mark H3K4me2, and find these modifications to display significant duality, with both significant positively and negatively correlated genomic territories. While the former appear to recapitulate in definitive cells the so-called "bi-valent" pattern originally proposed as a signature of pluripotency, the presence of negatively correlated regions suggests that the regulatory events that underlie the observed modification patterns are complex and highly regionalized in the genome.


Analysis of the proteome of Mycobacterium tuberculosis in silico.
Novel bioinformatics routines have been used to provide a more detailed definition of the proteome of Mycobacterium tuberculosis H37Rv. Over half of the current proteins result from gene duplication or domain shuffling events while one-sixth show no similarity to polypeptides described in other organisms. Prominent among the genes that appear to have been duplicated on numerous occasions are those involved in fatty acid metabolism, regulation of gene expression, and the unusually glycine-rich PE and PPE proteins. Protein similarity analysis, coupled with inspection of the genetic neighbourhood, was used to explore possible functional relatedness. This uncovered four large mce operons whose proteins may mediate initial interactions between the tubercle bacillus and host cells, together with a cluster of genes that might encode components of a structure required for secretion of ESAT-6 like proteins. Close linkage of the mmpL genes, encoding large membrane proteins, with those required for fatty acid metabolism suggests involvement in lipid transport. Compared to free-living bacteria, M. tuberculosis has a significantly smaller transport protein repertoire and this may reflect its intracellular lifestyle.


Transdentinal cytotoxicity of carbodiimide (EDC) and glutaraldehyde on odontoblast-like cells.
To evaluate the transdentinal cytotoxicity of three different concentrations of carbodiimide (EDC) or 5% glutaraldehyde (GA) on MDPC-23 cells. Seventy 0.4-mm-thick dentin disks obtained from human molars were adapted to artificial pulp chambers. MDPC-23 cells were seeded on the pulpal surface of the disks. After 48 hours, the occlusal dentin was acid-etched and treated for 60 seconds with one of the following solutions (n=10): no treatment (negative control); 0.1 M, 0.3 M, or 0.5 M EDC; 5% GA; Sorensen buffer; or 29% hydrogen peroxide (positive control). Cell viability and morphology were assessed by methyltetrazolium assay and scanning electron microscopy (SEM), respectively. The eluates were collected after the treatments and applied on MDPC-23 seeded in a 24-well plate to analyze cell death, total protein (TP), and collagen production. The last two tests were performed 24 hours and seven days after the challenge. Data were analyzed by Kruskal-Wallis and Mann-Whitney tests (p<0.05). EDC at all test concentrations did not reduce cell viability, while 5% GA did increase cell metabolism. Cell death by necrosis was not elicited by EDC or 5% GA. At the 24-hour period, 0.3 M and 0.5 M EDC reduced TP production by 18% and 36.8%, respectively. At seven days, increased TP production was observed in all groups. Collagen production at the 24-hour period was reduced when 0.5 M EDC was used. After seven days, no difference was observed among the groups. SEM showed no alteration in cell morphology or number, except in the hydrogen peroxide group. Treatment of acid-etched dentin with EDC or GA did not cause transdentinal cytotoxic effects on odontoblast-like cells.