Physiology of a Hybrid Pathway for Nicotine Catabolism in Bacteria.
Nicotine is a major N-heterocyclic aromatic alkaloid produced in tobacco plants and the main toxic chemical in tobacco waste. Due to its complex physiological effects and toxicity, it has become a concern both in terms of public health and the environment. A number of bacteria belonging to the genera Arthrobacter and Pseudomonas can degrade nicotine via the pyridine and pyrrollidine pathways. Recently, a novel hybrid of the pyridine and pyrrolidine pathways (also known as the VPP pathway) was found in the Rhizobiale group bacteria Agrobacterium tumefaciens S33, Shinella sp. HZN7 and Ochrobactrum sp. SJY1 as well as in other group bacteria. The special mosaic pathway has attracted much attention from microbiologists in terms of the study of their molecular and biochemical mechanisms. This will benefit the development of new biotechnologies in terms of the use of nicotine, the enzymes involved in its catabolism, and the microorganisms capable of degrading the alkaloid. In this pathway, some metabolites are hydroxylated in the pyridine ring or modified in the side chain with active groups, which can be used as precursors for the synthesis of some important compounds in the pharmaceutical and agricultural industries. Moreover, some enzymes may be used for industrial biocatalysis to transform pyridine derivatives into desired chemicals. Here, we review the molecular and biochemical basis of the hybrid nicotine-degrading pathway and discuss the electron transport in its oxidative degradation for energy conservation and bacterial growth.


Serum concentrations of alpha tocopherol, beta carotene, and retinol preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus.
Because oxidative damage has been implicated in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus, this study was designed to see if serum concentrations of alpha tocopherol, beta carotene, and retinol, substances believed to be involved in the prevention or repair of oxidative damage, might be lower among persons who develop rheumatoid arthritis or systemic lupus erythematosus than among those who do not. For this prospective case-control study, persons with rheumatoid arthritis and systemic lupus erythematosus that developed two to 15 years after donating blood for a serum bank in 1974 were designated as cases. For each case, four controls were selected from the serum bank donors, matched for race, sex, and age. Stored serum samples from cases and controls were assayed for alpha tocopherol, beta carotene, and retinol. Cases of both diseases had lower serum concentrations of alpha tocopherol, beta carotene, and retinol in 1974 than their matched controls. For rheumatoid arthritis, the difference for beta carotene (-29%) was statistically significant. These findings support those of a previous study that low antioxidant status is a risk factor for rheumatoid arthritis. They suggest a similar association for systemic lupus erythematosus.


One-Year Multicenter Double-Blind Randomized Clinical Trial on the Efficacy and Safety of Generic Cyclosporine (Iminoral) in De Novo Kidney Transplant Recipients.
Iminoral is the generic microemulsion of cyclosporine. We performed a randomized double-blind multicenter trial to evaluate its efficacy and safety compared with the innovator medication Neoral for preventing acute rejection episodes in adult patients during the first year after renal transplant. We used 221 de novo renal transplant recipients from 6 transplant centers in Iran enrolled between April 2008, and January 2010. They were randomized to receive either Iminoral or Neoral as the calcineurin inhibitor component of the immunosuppressive regimen in addition to mycophenolate mofetil and oral corticosteroids. They were followed-up for 1 year. The primary endpoint was the rate of acute allograft rejection. Secondary endpoints consisted of 1-year graft survival rates, daily dosages of cyclosporine, trough and C2 cyclosporine blood level, serum creatinine levels, patient death rates, discontinuing the study drug, tolerability, and adverse events. The risk of acute rejection episode during the first month after transplant was 9% for Iminoral and 10% for Neoral; these declined to 4% and 2% during next 11 months. One-year graft survival rate was 0.86 for both groups. Renal function stabilized during the first month. Declination of the creatinine levels was similar between the 2 groups and reached a stable value of 114.9 μmol/L five months after the transplant. The frequency of clinical complications was similar between the groups. Iminoral is safe and effective when used in de novo kidney transplant patients as an immunosuppressive medication.


Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization Practices (ACIP).
During spring 2005, two tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) products formulated for use in adolescents (and, for one product, use in adults) were licensed in the United States (BOOSTRIX, GlaxoSmithKline Biologicals, Rixensart, Belgium [licensed May 3, 2005, for use in persons aged 10-18 years], and ADACEL, sanofi pasteur, Toronto, Ontario, Canada [licensed June 10, 2005, for use in persons aged 11-64 years]). Prelicensure studies demonstrated safety and efficacy against tetanus, diphtheria, and pertussis when Tdap was administered as a single booster dose to adolescents. To reduce pertussis morbidity in adolescents and maintain the standard of care for tetanus and diphtheria protection, the Advisory Committee on Immunization Practices (ACIP) recommends that: 1) adolescents aged 11-18 years should receive a single dose of Tdap instead of tetanus and diphtheria toxoids vaccine (Td) for booster immunization against tetanus, diphtheria, and pertussis if they have completed the recommended childhood diphtheria and tetanus toxoids and whole cell pertussis vaccine (DTP)/ diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) vaccination series (five doses of pediatric DTP/DTaP before the seventh birthday; if the fourth dose was administered on or after the fourth birthday, the fifth dose is not needed) and have not received Td or Tdap. The preferred age for Tdap vaccination is 11-12 years; 2) adolescents aged 11-18 years who received Td, but not Tdap, are encouraged to receive a single dose of Tdap to provide protection against pertussis if they have completed the recommended childhood DTP/DTaP vaccination series. An interval of at least 5 years between Td and Tdap is encouraged to reduce the risk for local and systemic reactions after Tdap vaccination. However, an interval less than 5 years between Td and Tdap can be used; and 3) vaccine providers should administer Tdap and tetravalent meningococcal conjugate vaccine (Menactra, sanofi pasteur, Swiftwater, Pennsylvania) to adolescents aged 11-18 years during the same visit if both vaccines are indicated and available. This statement 1) reviews tetanus, diphtheria and pertussis vaccination policy in the United States, with emphasis on adolescents; 2) describes the clinical features and epidemiology of pertussis among adolescents; 3) summarizes the immunogenicity, efficacy, and safety data of the two Tdap vaccines licensed for use among adolescents; and 4) presents recommendations for tetanus, diphtheria, and pertussis vaccination among adolescents aged 11-18 years.


Pharmacotherapeutics of chloramphenicol in veterinary medicine.
Since its discovery in 1947, chloramphenicol has enjoyed a prominent place in the veterinarian's drug arsenal. Some of the reasons for its popularity are: (1) Antimicrobial activity--effective against a variety of infective pathogens, including staphylococci, salmonellae, pasturellae, Bordetella, Haemophilus, coliform organisms, chlamydiae, and rickettsiae, many of which may be resistant to other antimicrobial agents; (2) Kinetic properties--allowing production and maintenance of effective therapeutic concentrations in body fluids and tissues, with a practicable dosage schedule in most species; (3) Safety--toxic reactions to chloramphenicol encountered thus far in animals have not warranted any serious limitations on its use in veterinary medicine.


Nucleotide sequence of the tcml gene (ribosomal protein L3) of Saccharomyces cerevisiae.
The yeast tcml gene, which codes for ribosomal protein L3, has been isolated by using recombinant DNA and genetic complementation. The DNA fragment carrying this gene has been subcloned and we have determined its DNA sequence. The 20 amino acid residues at the amino terminus as inferred from the nucleotide sequence agreed exactly with the amino acid sequence data. The amino acid composition of the encoded protein agreed with that determined for purified ribosomal protein L3. Codon usage in the tcml gene was strongly biased in the direction found for several other abundant Saccharomyces cerevisiae proteins. The tcml gene has no introns, which appears to be atypical of ribosomal protein structural genes.


Limitations of the use of 5-fluorouracil as a selective agent for the isolation of leptospirae.
It has been shown that some component of Fletcher medium is able to annul the inhibitory action of 5-fluorouracil (400 mug/ml) on bacteria other than leptospirae. The most likely ingredient which can be implicated in this context appears to be beef extract.


Genetic heterogeneity revealed by sequence analysis of Mycobacterium tuberculosis isolates from extra-pulmonary tuberculosis patients.
Tuberculosis remains a major public health problem. Clinical tuberculosis manifests often as pulmonary and occasionally as extra-pulmonary tuberculosis. The emergence of drug resistant tubercle bacilli and its association with HIV is a formidable challenge to curb the spread of tuberculosis. There have been concerted efforts by whole genome sequencing and bioinformatics analysis to identify genomic patterns and to establish a relationship between the genotype of the organism and clinical manifestation of tuberculosis. Extra-pulmonary TB constitutes 15-20 percent of the total clinical cases of tuberculosis reported among immunocompetent patients, whereas among HIV patients the incidence is more than 50 percent. Genomic analysis of M. tuberculosis isolates from extra pulmonary patients has not been explored. The genomic DNA of 5 extra-pulmonary clinical isolates of M. tuberculosis derived from cerebrospinal fluid, lymph node fine needle aspirates (FNAC) / biopsies, were sequenced. Next generation sequencing approach (NGS) was employed to identify Single Nucleotide Variations (SNVs) and computational methods used to predict their consequence on functional genes. Analysis of distribution of SNVs led to the finding that there are mixed genotypes in patient isolates and that many SNVs are likely to influence either gene function or their expression. Phylogenetic relationship between the isolates correlated with the origin of the isolates. In addition, insertion sites of IS elements were identified and their distribution revealed a variation in number and position of the element in the 5 extra-pulmonary isolates compared to the reference M. tuberculosis H37Rv strain. The results suggest that NGS sequencing is able to identify small variations in genomes of M. tuberculosis isolates including changes in IS element insertion sites. Moreover, variations in isolates of M. tuberculosis from non-pulmonary sites were documented. The analysis of our results indicates genomic heterogeneity in the clinical isolates.


Pulpal blood flow changes due to rapid maxillary expansion.
To determine the pulpal blood flow (PBF) changes in anchorage teeth associated with the high forces of a rapid maxillary expansion (RME) appliance. The study was performed with 14 girls and 7 boys for a total of 21 patients between 10 and 15 years of age (mean, 13.1 +/- 1.39 years). A modified acrylic bonded RME appliance was used as an expansion appliance. Laser Doppler flowmetry was used for the pulpal perfusion measurements. Records were taken from 42 upper central incisors, 28 canines, and 42 first molars at the following time intervals: just before expansion (T1); at the first week of expansion (T2); at the end of the expansion process (T3); and at the third (T4), seventh (T5), and 12th weeks of retention (T6). The data gained were statistically evaluated by parametric tests. PBF values of the anchorage teeth were doubled at the first week of expansion; however, these values began to decrease because of separation of the median palatal suture. PBF values tended to reach their initial values during the retention period. Pulpal perfusion changes of all examined anchorage teeth were similar to each other from the beginning to the end of the evaluation. PBF changes that occur with RME are reversible.


Use of a public telephone hotline to detect urban plague cases.
Current methods for vector-borne disease surveillance are limited by time and cost. To avoid human infections from emerging zoonotic diseases, it is important that the United States develop cost-effective surveillance systems for these diseases. This study examines the methodology used in the surveillance of a plague epizootic involving tree squirrels (Sciurus niger) in Denver Colorado, during the summer of 2007. A call-in centre for the public to report dead squirrels was used to direct animal carcass sampling. Staff used these reports to collect squirrel carcasses for the analysis of Yersinia pestis infection. This sampling protocol was analysed at the census tract level using Poisson regression to determine the relationship between higher call volumes in a census tract and the risk of a carcass in that tract testing positive for plague. Over-sampling owing to call volume-directed collection was accounted for by including the number of animals collected as the denominator in the model. The risk of finding an additional plague-positive animal increased as the call volume per census tract increased. The risk in the census tracts with >3 calls a month was significantly higher than that with three or less calls in a month. For tracts with 4-5 calls, the relative risk (RR) of an additional plague-positive carcass was 10.08 (95% CI 5.46-18.61); for tracts with 6-8 calls, the RR = 5.20 (2.93-9.20); for tracts with 9-11 calls, the RR = 12.80 (5.85-28.03) and tracts with >11 calls had RR = 35.41 (18.60-67.40). Overall, the call-in centre directed sampling increased the probability of locating plague-infected carcasses in the known Denver epizootic. Further studies are needed to determine the effectiveness of this methodology at monitoring large-scale zoonotic disease occurrence in the absence of a recognized epizootic.


Contrast adaptation and infomax in visual cortical neurons.
In the primary visual cortex (V1) the contrast response function of many neurons saturates at high contrast and adapts depending on the visual stimulus. We propose that both effects - contrast saturation and adaptation - can be explained by a fast and a slow component in the synaptic dynamics. In our model the saturation is an effect of fast synaptic depression with a recovery time constant of about 200 ms. Fast synaptic depression leads to a contrast response function with a high gain for only a limited range of contrast values. Furthermore, we propose that slow adaptation of the transmitter release probability at the geniculocortical synapses is the underlying neural mechanism that accounts for contrast adaptation on a time scale of about 7 sec. For the functional role of contrast adaptation we make the hypothesis that it serves to achieve the best visual cortical representation of the geniculate input. This representation should maximize the mutual information between the cortical activity and the geniculocortical input by increasing the release probability in a low contrast environment. We derive an adaptation rule for the transmitter release probability based on this infomax principle. We show that changes in the transmitter release probability may compensate for changes in the variance of the geniculate inputs - an essential requirement for contrast adaptation. Also, we suggest that increasing the release probability in a low contrast environment is beneficial for signal extraction, because neurons remain sensitive only to an increase in the presynaptic activity if it is synchronous and, therefore, likely to be stimulus related. Our hypotheses are tested in numerical simulations of a network of integrate-and-fire neurons for one column of V1 using fast synaptic depression and slow synaptic adaptation. The simulations show that changing the synaptic release probability of the geniculocortical synapses is a better model for contrast adaptation than the adaptation of the synaptic weights: only in the case of changing the transmitter release probability does our model reproduce the experimental finding that the average membrane potential (DC component) adapts much more strongly than the stimulus modulated component (F1 component). In the case of changing the synaptic weights, however, the average membrane potential (DC) as well as the stimulus modulated component (F1 component) would adapt. Furthermore, changing the release probability at the recurrent cortical synapses cannot account for contrast adaptation, but could be responsible for establishing oscillatory activity often observed in recordings from visual cortical cells.


Effective gene delivery using stimulus-responsive catiomer designed with redox-sensitive disulfide and acid-labile imine linkers.
A dual stimulus-responsive mPEG-SS-PLL(15)-glutaraldehyde star (mPEG-SS-PLL(15)-star) catiomer is developed and biologically evaluated. The catiomer system combines redox-sensitive removal of an external PEG shell with acid-induced escape from the endosomal compartment. The design rationale for PEG shell removal is to augment intracellular uptake of mPEG-SS-PLL(15)-star/DNA complexes in the presence of tumor-relevant glutathione (GSH) concentration, while the acid-induced dissociation is to accelerate the release of genetic payload following successful internalization into targeted cells. Size alterations of complexes in the presence of 10 mM GSH suggest stimulus-induced shedding of external PEG layers under redox conditions that intracellularly present in the tumor microenvironment. Dynamic laser light scattering experiments under endosomal pH conditions show rapid destabilization of mPEG-SS-PLL(15)-star/DNA complexes that is followed by facilitating efficient release of encapsulated DNA, as demonstrated by agarose gel electrophoresis. Biological efficacy assessment using pEGFP-C1 plasmid DNA encoding green fluorescence protein and pGL-3 plasmid DNA encoding luciferase as reporter genes indicate comparable transfection efficiency of 293T cells of the catiomer with a conventional polyethyleneimine (bPEI-25k)-based gene delivery system. These experimental results show that mPEG-SS-PLL(15)-star represents a promising design for future nonviral gene delivery applications with high DNA binding ability, low cytotoxicity, and high transfection efficiency.


A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies.
THESIAS (Testing Haplotype EffectS In Association Studies) is a popular software for carrying haplotype association analysis in unrelated individuals. In addition to the command line interface, a graphical JAVA interface is now proposed allowing one to run THESIAS in a user-friendly manner. Besides, new functionalities have been added to THESIAS including the possibility to analyze polychotomous phenotype and X-linked polymorphisms. The software package including documentation and example data files is freely available at http://genecanvas.ecgene.net. The source codes are also available upon request.


The filamentous phage XacF1 causes loss of virulence in Xanthomonas axonopodis pv. citri, the causative agent of citrus canker disease.
In this study, filamentous phage XacF1, which can infect Xanthomonas axonopodis pv. citri (Xac) strains, was isolated and characterized. Electron microscopy showed that XacF1 is a member of the family Inoviridae and is about 600 nm long. The genome of XacF1 is 7325 nucleotides in size, containing 13 predicted open reading frames (ORFs), some of which showed significant homology to Ff-like phage proteins such as ORF1 (pII), ORF2 (pV), ORF6 (pIII), and ORF8 (pVI). XacF1 showed a relatively wide host range, infecting seven out of 11 strains tested in this study. Frequently, XacF1 was found to be integrated into the genome of Xac strains. This integration occurred at the host dif site (attB) and was mediated by the host XerC/D recombination system. The attP sequence was identical to that of Xanthomonas phage Cf1c. Interestingly, infection by XacF1 phage caused several physiological changes to the bacterial host cells, including lower levels of extracellular polysaccharide production, reduced motility, slower growth rate, and a dramatic reduction in virulence. In particular, the reduction in virulence suggested possible utilization of XacF1 as a biological control agent against citrus canker disease.


Cycloviolacin O2 (CyO2) suppresses productive infection and augments the antiviral efficacy of nelfinavir in HIV-1 infected monocytic cells.
Human immunodeficiency virus type-1 (HIV-1), the etiologic agent of acquired immune deficiency syndrome (AIDS), is a global pandemic causing millions of deaths annually. Highly active antiretroviral therapy (HAART) greatly enhances lifespan but eventually causes debilitating side effects, in part, due to their chronic administration required to suppress HIV-1 replication. If treatment is discontinued, viral suppression is lost and dormant replication-competent monocytic cell reservoirs become reactivated, leading to viral recrudescence and progression to AIDS. Therefore, novel strategies to circumvent obstacles to HIV-1 therapy are critically needed. We evaluated the potentially therapeutic effects of cycloviolacin O2 (CyO2) on cell viability (MTT assay), membrane disruption (SYTOX Green uptake), p24 production [enzyme-linked immunosorbent assays (ELISA)], and proviral integration (PCR amplification) in U1 cells; a monocytic cell model of HIV-1 latency and reactivation. We demonstrate, for the first time, that CyO2 (0.5-5.0 μM) kills productively infected cells. Sub-toxic concentrations (<0.5 μM) of CyO2 disrupted plasma membranes in both latently-infected and productively-infected U1 cells and enhanced the antiviral efficacy of nelfinavir, a HIV-1 protease inhibitor (HPI). Interestingly, CyO2 also decreased virus production by activated U1 cells; however, this effect was not due to suppression of integrated provirus in U1 cells. This suggested that, in addition to the known pore-forming ability of cyclotides, a novel mode of antiviral activity may exist for CyO2. Our data indicate that CyO2 may be a promising candidate for the targeting HIV-1 reservoirs in monocytes, and their inclusion in adjuvant therapy approaches may augment the efficacy of HPIs and ultimately facilitate virus elimination.


Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.
Both the processes of atherosclerosis and plaque rupture are indicated to be influenced by matrix metalloproteinase (MMP) activity. We therefore searched for common functional variation in the matrix metalloelastase (MMP-12) gene locus that may be implicated in coronary artery disease. Single-strand conformation polymorphism analysis of DNA from healthy individuals detected a common polymorphism within the MMP-12 gene promoter (an A-to-G substitution at position -82). The frequency of the G allele was 0. 19. The polymorphism influences the binding of the transcription factor activator protein-1 (AP-1) in electromobility shift assay. A higher binding affinity of AP-1 to the A allele was associated with higher MMP-12 promoter activity in vitro in transient transfection studies in U937 and murine lung macrophage (MALU) cells. Phorbol 12-myristate 13-acetate (PMA) and insulin, 2 known activators of AP-1, increased the binding of AP-1 to the MMP-12 promoter, with higher affinity for the A allele. In transfection experiments, both the A and the G alleles responded to insulin and PMA, the A allele showing higher promoter activity than the G allele. Furthermore, Western blot analysis demonstrated that insulin increased MMP-12 protein production. To analyze whether the -82 A/G polymorphism is associated with coronary artery disease, 367 consecutive patients who underwent percutaneous transluminal coronary angiography with stent implantation were genotyped. In patients (n=71) with diabetes, the A allele was associated with a smaller luminal diameter. In conclusion, a common functional polymorphism within the MMP-12 promoter influences coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.


Brazilian scientific journals in surgery. III: Analysis of the instructions for authors based on Vancouver uniform requirements.
To analyze the instructions for authors of Brazilian scientific journals in the surgery field, in order to describe the present situation, as well to make recommendations for editors and authors. Instruction for authors of 20 journals were analyzed and classified following Vancouver requirements. Instructions were taken from SciELO, from the journals homepage, or from the last printed issue available in BIREMEs collection. Results were descriptively analyzed, considering the frequency of each variable. 75% of the journals recommended ICMJE Uniform Requirements, although not always the newest version was indicated; 90% of the journals mentioned ethical research principles, 80% the peer-review process and 70% the conflict of interests and the author rights transfer agreement. Foreign languages frequently accepted were English (80%) and Spanish (30%). All journals publish original papers, followed by reviews (90%), case reports (80%), letters to the editor (70%), and clinical updates or continuing education (55%). The nomenclature for the sections varied among journals. Even though publishing freedom and independence of each publisher must be respected, there are internationally accepted criteria that must be observed. The current trends, towards the prioritization of open access electronic journals, will lead to important changes in the process of publishing scientific journals.


[Therapeutic drug monitoring of valproate].
Valproic acid is an anticonvulsant drug available in France since 1967. It is a broad spectrum molecule indicated in various forms of epilepsy of the adult and the child, but it is also prescribed in the treatment of different other pathologies of nervous system. The divalproate sodium is indicated in the treatment of bipolar disorders. The valproic acid is marketed under various pharmaceutical forms, with different corresponding tmax values. But, whatever the administered preparation, the circulating active molecule is the ion valproate. Elimination half-life is from 11 to 20 h. Metabolization of valproate is important and represents its main route of elimination. Valpromide is comparable to a prodrug which metabolizes in valproate. The inter and intraindividual variability of the plasma concentrations are important. Several studies show a concentration-effect relationship, but two interventional trials ended in the lack of interest of the Therapeutic Drug Monitoring (TDM), although it is of current practice. However, numerous drug interactions may modify the plasma concentrations of valproate. The therapeutic range is from 50 to 100 mg/L (346-693 micromol/L). The level of proof of the interest of the TDM for this molecule was estimated in: recommended.


Water stress enhances expression of genes encoding plastid terminal oxidase and key components of chlororespiration and alternative respiration in soybean seedlings.
Plastid terminal oxidase (PTOX) is a plastid-localized plastoquinone (PQ) oxidase in plants. It functions as the terminal oxidase of chlororespiration, and has the potential ability to regulate the redox state of the PQ pool. Expression of the PTOX gene was up-regulated in soybean seedlings after exposure to water deficit stress for 6 h. Concomitantly expression of the NDH-H gene, encoding a component of the NADPH dehydrogenase (NDH) complex which is a key component of both chlororespiration and NDH-dependent cyclic electron transfer (CET), was also up-regulated. Transcript levels of the proton gradient regulation (PGR5) gene, which encodes an essential component of the PGR5-dependent CET, were not affected by water stress, while the expression of the alternative oxidase (AOX1) gene, which encodes a terminal oxidase of alternative respiration in mitochondria, was also up-regulated under water stress. Therefore, our results indicate that water stress induced the up-regulation of genes encoding key components of chlororespiration and alternative respiration. Transcript levels of the AOX1 gene began to increase in response to water stress before those of PTOX suggesting that alternative respiration may react faster to water stress than chlororespiration.


Relapsing peritonitis with Bacillus cereus in a patient on continuous ambulatory peritoneal dialysis.
We present a case where Bacillus cereus was determined to be the causative agent of relapsing peritonitis in a patient on continuous ambulatory peritoneal dialysis (CAPD). The patient, a 70-year-old man from the Faroe Islands, was admitted with relapsing peritonitis four times over a 3-month period. Peritoneal cultures were positive for growth of B. cereus, a rare bacterial cause of peritonitis. The cultures demonstrated susceptibility to vancomycin, and therefore the patient was treated with intraperitoneal vancomycin, intraperitoneal gentamycin and oral ciprofloxacin. As a result of the relapsing B. cereus peritonitis diagnosis and a CT scan showing contraction of the peritoneum after longstanding inflammation, the peritoneal catheter was removed and the patient converted to haemodialysis. To date, the patient has not been readmitted due to peritonitis. A lack of proper hygiene when changing the dialysis bag was the suspected source of infection with B. cereus.


The impact of anthropometric parameters on colorectal cancer prognosis: A systematic review and meta-analysis.
Our study aims to clarify the relationship between weight parameters and colorectal cancer outcomes. NCBI, Embase, Cochrane, and Web of Science were searched from inception to December 2019. Studies reporting colorectal cancer (CRC) mortality, recurrence, disease-free survival, overall survival, overall mortality stratified by pre-diagnosis BMI or post-diagnosis weight change, were included in the analysis. Random effects analysis was performed for all outcomes, with heterogeneity assessed by the I2 statistic. Our meta-analysis included 45 studies encompassing 607,266 patients. Obesity was associated with increased odds of overall mortality and CRC-specific mortality compared to normal weight (p < 0.001). Patients with underweight BMI had increased odds of CRC-specific mortality compared to normal BMI but were not significantly different from obese BMI. Obese and underweight BMI are associated with increased CRC-specific and overall mortality compared to normal BMI. Long term prognosis was similar for patients with obese and underweight BMI.


[The peculiarities of intellectual development of boys and girls of 15-16 years old].
The structure of intelligence in senior adolescents was studied. The analysis of intelligence in adolescents of both sexes showed that there are no distinct differences in the structure of intellectual development in boys and girls of 15-16 years old. The significantly better results were marked only in girls memory development which can prove the fact that the specific character of cognitive development doesn't depend on sex at the last stages of puberty. Significant dispersion of individual intellectual characteristics can serve the evidence for the high variability of the psychophysiology structure of intelligence in adolescents at this ontogenetic stage of development.


From WOEST to AUGUSTUS: a review of safety and efficacy of triple versus dual antithrombotic regimens in patients with atrial fibrillation requiring percutaneous coronary intervention for acute coronary syndrome.
For patients with atrial fibrillation with concomitant acute coronary syndrome (ACS) requiring percutaneous coronary intervention (PCI), the increased risk of bleeding associated with the use triple therapy is well established. However, there is question whether it is a necessary risk for patients to prevent stroke and stent thrombosis. The purpose of this article is to highlight the findings of prior studies evaluating the comparative safety and efficacy of dual and triple antithrombotic regimens in the subgroup of atrial fibrillation patients requiring PCI for ACS. Trials that evaluated dual versus triple antithrombotic therapy demonstrated post-PCI treatment with a P2Y12 inhibitor alone was safer than aspirin plus a P2Y12 inhibitor in patients also taking an anticoagulant for atrial fibrillation. Data regarding ischemic outcomes have not suggested harm with the omission of aspirin, but these studies have not been powered to assess efficacy outcomes, especially in ACS patients. These studies also demonstrate a significant reduction in bleeding events when aspirin is excluded from the post-PCI regimen in the ACS subgroup of atrial fibrillation patients. Further studies, with added focus on the ACS subgroup, are needed to potentially confirm that dual therapy may be as efficacious as triple therapy in ACS patients with atrial fibrillation.


Chondrocyte dedifferentiation increases cell stiffness by strengthening membrane-actin adhesion.
Chondrocyte dedifferentiation is known to influence cell mechanics leading to alterations in cell function. This study examined the influence of chondrocyte dedifferentiation in monolayer on cell viscoelastic properties and associated changes in actin organisation, bleb formation and membrane-actin cortex interaction. Micropipette aspiration was used to estimate the viscoelastic properties of freshly isolated articular chondrocytes and the same cells after passage in monolayer. Studies quantified the cell membrane-actin cortex adhesion by measuring the critical pressure required for membrane detachment and bleb formation. We then examined the expression of ezrin, radixin and moesin (ERM) proteins which are involved in linking the membrane and actin cortex and combined this with theoretical modelling of bleb dynamics. Dedifferentiated chondrocytes at passage 1 (P1) were found to be stiffer compared to freshly isolated chondrocytes (P0), with equilibrium modulus values of 0.40 and 0.16 kPa respectively. The critical pressure increased from 0.59 kPa at P0 to 0.74 kPa at P1. Dedifferentiated cells at P1 exhibited increased cortical F-actin organisation and increased expression of total and phosphorylated ERM proteins compared to cells at P0. Theoretical modelling confirmed the importance of membrane-actin cortex adhesion in regulating bleb formation and effective cellular elastic modulus. This study demonstrates that chondrocyte dedifferentiation in monolayer strengthens membrane-actin cortex adhesion associated with increased F-actin organisation and up-regulation of ERM protein expression. Thus dedifferentiated cells have reduced susceptibility to bleb formation which increases cell modulus and may also regulate other fundamental aspects of cell function such as mechanotransduction and migration.


Self-management: is it time for a new direction in rehabilitation and post stroke care?
Stroke is traditionally thought of as an acute condition and most rehabilitation is provided in the first six months poststroke. To date there has been minimal focus on strategies which could support people in the longer term and manage the transition towards successful adjustment and self-management. Stroke self-management programs whilst rare are now starting to emerge but while the feasibility and acceptability of delivering stroke self-management programs looks to be promising, there are minimal findings beyond phase II trials. A self-management program is a complex intervention and a carefully staged approach to research is required, one which addresses the issues around implementation and the skills required by those delivering the intervention. In addition there are a number of questions relating to maintenance of self-management skills beyond attendance at programs or after rehabilitation. Currently the sustainability of any impact from these programs is uncertain and it is unclear which are the best methods to enhance self-management skills over a longer time period. More work is required in order to develop and test different forms of support which could range from a simple goal setting interventions to more structured self-management programs delivered either as a group or individualized intervention.


Association of postural control with muscle strength, proprioception, self-reported knee instability and activity limitations in patients with knee osteoarthritis.
To determine the association of postural control with muscle strength, proprioception, self-reported knee instability and activity limitations in patients with knee osteoarthritis. A total of 284 patients with knee osteoarthritis from the Amsterdam Osteoarthritis cohort were included. Postural control was assessed using the One-Leg Stand Test (OLST), in which the patients were asked to stand on one leg for 30 s. Muscle strength (isokinetic dynamometer), proprioception (joint motion detection threshold) and self-reported knee instability (episodes of buckling, shifting or giving way) were also assessed. Activity limitations were assessed using the Get Up and Go (GUG) test, the walking up-down stairs test, and Western Ontario and McMaster University Osteoarthritis Index - Physical Function subscale. Regression analyses were used to assess the associations. Muscle weakness (p = 0.02) and proprioceptive inaccuracy (p < 0.001) were associated with decreased postural control. Decreased postural control was associated with less time performing the GUG test (p < 0.001) and the walking up-down stairs test (p < 0.001). These associations were found after adjustment for relevant confounders. In patients with knee osteoarthritis, decreased postural control is associated with muscle weakness, proprioceptive inaccuracy and performance-based activity limitations. These results highlight the importance of including assessment and training of postural control in this group of patients.


Fit-For-Purpose PD-L1 Biomarker Testing For Patient Selection in Immuno-Oncology: Guidelines For Clinical Laboratories From the Canadian Association of Pathologists-Association Canadienne Des Pathologistes (CAP-ACP).
Since 2014, programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors have been approved by various regulatory agencies for the treatment of multiple cancers including melanoma, lung cancer, urothelial carcinoma, renal cell carcinoma, head and neck cancer, classical Hodgkin lymphoma, colorectal cancer, gastroesophageal cancer, hepatocellular cancer, and other solid tumors. Of these approved drug/disease combinations, a subset also has regulatory agency-approved, commercially available companion/complementary diagnostic assays that were clinically validated using data from their corresponding clinical trials. The objective of this document is to provide evidence-based guidance to assist clinical laboratories in establishing fit-for-purpose PD-L1 biomarker assays that can accurately identify patients with specific tumor types who may respond to specific approved immuno-oncology therapies targeting the PD-1/PD-L1 checkpoint. These recommendations are issued as 38 Guideline Statements that address (i) assay development for surgical pathology and cytopathology specimens, (ii) reporting elements, and (iii) quality assurance (including validation/verification, internal quality assurance, and external quality assurance). The intent of this work is to provide recommendations that are relevant to any tumor type, are universally applicable and can be implemented by any clinical immunohistochemistry laboratory performing predictive PD-L1 immunohistochemistry testing.


The DNA sequences of the long repeat region and adjoining parts of the long unique region in the genome of herpes simplex virus type 1.
We have determined the DNA sequence of the long repeat region (RL) in the genome of herpes simplex virus type 1 (HSV-1) strain 17, as 9215 bp of composition 71.6% G + C. In addition, the sequences of parts of the long unique region (UL) adjacent to the terminal (TRL) and internal (IRL) copies of RL were determined (2611 and 3836 bp, respectively). Gene organization in these regions of UL was deduced from the sequences and other available data. It was proposed that the region of UL sequenced, adjacent to TRL, contains three complete genes, none with significant previous characterization, and that the region of UL adjacent to IRL also contains three genes, one encoding the immediate early protein IE63. The RL sequence contains one well characterized gene, for the protein IE110, whose organization we have described previously. Between the downstream end of the IE110 gene and UL there is a 3500 bp segment of RL in which we did not find convincing protein-coding sequences, and which thus remains of obscure functionality. Upstream of the IE110 gene is a region previously proposed by others to contain a gene. However, our sequence data are not compatible with their interpretation. We do consider it possible that the region is protein-coding, but regard gene organization here as still unresolved.


Physical distress, emotional status, and quality of life in patients with nasopharyngeal cancer complicated by post-radiotherapy endocrinopathy.
To explore factors affecting quality of life (QOL) among patients with nasopharyngeal cancer (NPC) complicated by post-radiotherapy endocrinopathy. This cross-sectional study was conducted in a tertiary medical center and involved a total of 43 post-radiotherapy, recurrence-free NPC patients with endocrinopathy. They performed self-assessment of their emotional status using the Beck Anxiety Inventory and Beck Depression Inventory-II, and their QoL with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) questionnaire and the H&N35 cancer module. Emotional and cognitive functioning of EORTC QLQ-C30 were the most affected. Fatigue, insomnia, and pain were the main concerns. Of the patients, 22 (51.2%) had anxiety and 19 (44.2%) had depression. Both depression and anxiety were negatively correlated with functional scales and global QoL but positively correlated with symptom scales. Multiple linear regression analysis revealed that physical distress symptoms of QLQ-C30 and physical functioning were the significant predictors of global QoL. Emotional and social functioning could predict depression, whereas emotional and physical functioning were significant predictors of anxiety. NPC patients with post-radiotherapy endocrinopathy exhibit impaired cognitive function and negative emotions. Symptoms of physical distress play an important role in QoL perception. Measurement of EORTC QLQ-C30 can be a useful instrument for the early detection of patients' impaired cognitive function and psychological morbidity. The high psychological distress related to the endocrine disturbances or the impact of NPC itself needs further study.


Cannabinoid CB1 Receptor Antagonist Rimonabant Decreases Levels of Markers of Organ Dysfunction and Alters Vascular Reactivity in Aortic Vessels in Late Sepsis in Rats.
Sepsis is a life-threatening condition with high mortality rates that is caused by dysregulation of the host response to infection. We previously showed that treatment with the cannabinoid CB1 receptor antagonist rimonabant reduced mortality rates in animals with sepsis that was induced by cecal ligation and puncture (CLP). This improvement in the survival rate appeared to be related to an increase in arginine vasopressin (AVP) levels 12 h after CLP. The present study investigated the effects of rimonabant on organ dysfunction, hematologic parameters, and vascular reactivity in male Wistar rats with sepsis induced by CLP. Intraperitoneal treatment with rimonabant (10 mg/kg, 4 h after CLP) abolished the increase in the plasma levels of lactate, lactate dehydrogenase, glucose, and creatinine kinase MB without altering hematological parameters (i.e., leukopenia and a reduction of platelet counts). CLP increased plasma levels of nitrate/nitrite (NOx) and induced vasoconstriction in the tail artery. The treatment of CLP rats with rimonabant did not alter NOx production but reduced the vasoconstriction. Rimonabant also attenuated the hyperreactivity to AVP induced by CLP without affecting hyporesponsiveness to phenylephrine in aortic rings. These results suggest that rimonabant reduces organ dysfunction during sepsis, and this effect may be related to AVP signaling in blood vessels. This effect may have contributed to the higher survival rate in rimonabant-treated septic animals.


Time-sequential change in immune-related gene expression after irradiation in glioblastoma: next-generation sequencing analysis.
The time-sequential change in immune-related gene expression of the glioblastoma cell line after irradiation was evaluated to speculate the effect of combined immunotherapy with radiotherapy. The U373 MG glioblastoma cell line was irradiated with 6 Gy single dose. Next-generation sequencing (NGS) transcriptome data was generated before irradiation (control), and at 6, 24, and 48 h post-irradiation. Immune-related pathways were analyzed at each time period. The same analyses were also performed for A549 lung cancer and U87 MG glioblastoma cell lines. Western blotting confirmed the programmed death-ligand 1 (PD-L1) expression levels over time. In the U373 MG cell line, neutrophil-mediated immunity, type I interferon signaling, antigen cross-presentation to T cell, and interferon-γ signals began to increase significantly at 24 h and were upregulated until 48 h after irradiation. The results were similar to those of the A549 and U87 MG cell lines. Without T cell infiltration, PD-L1 did not increase even with upregulated interferon-γ signaling in cancer cells. In conclusions, in the glioblastoma cell line, immune-related signals were significantly upregulated at 24 and 48 h after irradiation. Therefore, the time interval between daily radiotherapy might not be enough to expect full immune responses by combined immune checkpoint inhibitors and newly infiltrating immune cells after irradiation.


[Primary care management of hematuria: is it obvious?].
Hematuria is frequent and its diagnostic array is wide, ranging from benign pathologies such as infections or stones to neoplasia, sometimes also including some nephropathies. Twenty per cent of patients presenting with macro-hematuria harbour a urologic tumor. This validates an in-depth evaluation, classicaly associating contrast studies and cystoscopy. The occurrence of hematuria in patients on anticoagulants and/or antithrombotics should never be overlooked, since post work-up etiologies are as significant as these outlined in patients not under such prescriptions. Microhematuria also requires a distinct work-up, especially when there are risk factors for a urothelial neoplasia.


A successful case of repeat thrombolysis in acute prosthetic valve thrombosis.
Acute heart failure is an important presentation in the Acute Medical Unit. We describe a case of successful repeat thrombolysis in an elderly woman presenting as an emergency with severe pulmonary oedema, due to acute prosthetic mitral valve thrombosis. The diagnostic imaging and therapeutic modalities available are also described.This case highlights the need for acute physicians to consider prosthetic valve thrombosis in the differential for patients with metallic heart valves who present with acute heart failure or cardiogenic shock.


Ultraviolet vision in larval Neogonodactylus oerstedii.
Stomatopod crustaceans have among the most complex eyes in the animal kingdom, with up to 12 different color detection channels. The capabilities of these unique eyes include photoreception of ultraviolet (UV) wavelengths (<400 nm). UV vision has been well characterized in adult stomatopods but has not been previously demonstrated in the comparatively simpler larval eye. Larval stomatopod eyes are developmentally distinct from their adult counterpart and have been described as lacking the visual pigment diversity and morphological specializations found in adult eyes. However, recent studies have provided evidence that larval stomatopod eyes are more complex than previously thought and warrant closer investigation. Using electroretinogram recordings in live animals we found physiological evidence of blue- and UV-sensitive photoreceptors in larvae of the Caribbean stomatopod species Neogonodactylus oerstedii. Transcriptomes of individual larvae were used to identify the expression of three distinct UV opsin mRNA transcripts, which may indicate the presence of multiple UV spectral channels. This is the first paper to document UV vision in any larval stomatopod, expanding our understanding of the importance of UV sensitivity in plankton. Larval stomatopod eyes are more complex and more similar to adult eyes than expected, showing previously uncharacterized molecular diversity and physiological functions.


Role of hematopoietic growth factors in transfusion medicine.
Recombinant human growth factors are expected to have a significant impact on the use of allogeneic blood components. For example, recombinant human erythropoietin has had a significant impact on blood transfusion in renal dialysis patients. Likewise, myeloid growth factors have reduced infections and hospital stay by promoting hematologic recovery after high-dose ablative chemotherapy. The high costs of these agents mandate that their use be limited to settings where they are clinically indicated. This review discusses the emerging clinical data to help establish guidelines for the use of hematopoietic growth factors. Comments regarding the myeloid growth factors are restricted to their emerging role in stem cell transplantation, because this clinical setting is anticipated to have the greatest impact in the use of allogeneic blood components in oncology.


Recycling of end-of-life reverse osmosis membranes by oxidative treatment: a technical evaluation.
The adverse impacts caused by the disposal of thousands of tonnes per annum of reverse osmosis (RO) membranes modules have grown dramatically around the world. The objective of this study was to evaluate the technical feasibility of recycling by chemical oxidation of end-of-life RO membranes for applications in other separation processes with specifications less rigorous. The recycling technique consisted in to cause a membrane exposition with oxidant solutions in order to remove its aromatic polyamide layer and subsequent conversion to a porous membrane. The recycling technique was evaluated by water permeability and salt rejection tests before and after the oxidative treatments. Initially, membranes' chemical cleaning and pretreatment procedures were assessed. Among factors evaluated, the oxidizing agent, its concentration and pH, associated with the oxidative treatment time, showed important influence on the oxidation of the membranes. Results showed that sodium hypochlorite and potassium permanganate are efficient agents for the membrane recycling. The great increased permeability and decreased salt rejection indicated changes on membranes' selective properties. Scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), atomic force microscopy (AFM), and contact angle characterization techniques revealed marked changes on the main membranes' physical-chemical properties, such as morphology, roughness and hydrophobicity. Reuse of produced effluents and fouling tendency of recycled membranes were also evaluated.


A Tiled Ultrasound Matrix Transducer for Volumetric Imaging of the Carotid Artery.
High frame rate three-dimensional (3D) ultrasound imaging would offer excellent possibilities for the accurate assessment of carotid artery diseases. This calls for a matrix transducer with a large aperture and a vast number of elements. Such a matrix transducer should be interfaced with an application-specific integrated circuit (ASIC) for channel reduction. However, the fabrication of such a transducer integrated with one very large ASIC is very challenging and expensive. In this study, we develop a prototype matrix transducer mounted on top of multiple identical ASICs in a tiled configuration. The matrix was designed to have 7680 piezoelectric elements with a pitch of 300 μm × 150 μm integrated with an array of 8 × 1 tiled ASICs. The performance of the prototype is characterized by a series of measurements. The transducer exhibits a uniform behavior with the majority of the elements working within the -6 dB sensitivity range. In transmit, the individual elements show a center frequency of 7.5 MHz, a -6 dB bandwidth of 45%, and a transmit efficiency of 30 Pa/V at 200 mm. In receive, the dynamic range is 81 dB, and the minimum detectable pressure is 60 Pa per element. To demonstrate the imaging capabilities, we acquired 3D images using a commercial wire phantom.


A specific role for phosphoinositide 3-kinase and AKT in osteoblasts?
The phosphoinositide 3-kinase and AKT (protein kinase B) signaling pathway (PI3K/AKT) plays a central role in the control of cell survival, growth, and proliferation throughout the body. With regard to bone, and particularly in osteoblasts, there is an increasing amount of evidence that the many signaling molecules exert some of their bone-specific effects in part via selectively activating some of the generic effects of the PI3K/AKT pathway in osteoblasts. There is further data demonstrating that PI3K/AKT has the capacity to specifically cross-talk with other signaling pathways and transcriptional networks controlling bone cells' development in order to fine-tune the osteoblast phenotype. There is also evidence that perturbations in the PI3K/AKT pathway may well be responsible for certain bone pathologies. In this review, we discuss some of these findings and suggest that the PI3K/AKT pathway is a central nexus in the extensive network of extracellular signaling pathways that control the osteoblast.


Theoretical study on geometric, electronic and catalytic performances of Fe dopant pairs in graphene.
The formation geometries, electronic structures and catalytic properties of monovacancy and divacancy graphene sheets with two embedded Fe dopants (2Fe-MG and 2Fe-DG) have been systematically investigated using the first-principles calculations. It was found that the configuration of 2Fe-DG is slightly more stable than that of 2Fe-MG sheets and the two doped Fe atoms in graphene (2Fe-graphene) as active sites could regulate the stability of gas molecules. In addition, the adsorption of O2 and CO molecules could modulate the electronic and magnetic properties of 2Fe-graphene systems. Moreover, the adsorption behaviors of reactants could determine the reaction pathway and energy barrier of the catalytic oxidation of CO. On the 2Fe-graphene substrates, the adsorptive decomposition of O2 molecules (<0.20 eV) and the subsequent Eley-Rideal (ER) reaction (2Oads + 2CO → CO2) (<0.60 eV) have low energy barriers. In comparison, the CO3 complex is quite stable and its formation needs to overcome a higher energy barrier (>0.90 eV). Hence, the dissociation of O2 as an initial step is an energetically more favored process. These results provide valuable guidance for the design of functionalized graphene-based devices.


[A model of the interaction of chemical synapses].
The simple quasi-static model for convergence of afferent impulse fluxes on the neuron membrane is presented in this paper. Interaction of activation effects in basic types of chemical synapses is considered. It is shown that the character of this interaction differs from the algebraic summation of single effects. This phenomenon is based on the mechanism of the internal negative feedbacks' action.


The opsoclonus-myoclonus syndrome. A review of the literature.
There have been many reports in the literature of an association of the opsoclonus-myoclonus syndrome and occult neuroblastoma in children. This syndrome is of interest due to the fact that it appears to be a neurological manifestation of an occult carcinoma (without a metastasis to the CNS). This paper examines pathologic, diagnostic, and etiologic issues concerning this syndrome as well as discussing the functional implications of cerebellar lesions associated with it and how those lesions may produce the symptoms observed.


Musculoskeletal pain in other body sites is associated with new-onset low back pain: a longitudinal study among survivors of the great East Japan earthquake.
Low back pain (LBP) is a common health problem experienced after natural disasters. LBP is often concurrent with other musculoskeletal pain; however, the effects of preexisting musculoskeletal pain on the development of LBP are not clear. The purpose of this study was to elucidate the association of musculoskeletal pain in other body sites with new-onset LBP among survivors of the Great East Japan Earthquake (GEJE). A longitudinal study was conducted with survivors of the GEJE. The survivors who did not have LBP at the 3 year time period after the GEJE were followed up 1 year later (n = 1782). Musculoskeletal pain, such as low back, hand and/or foot, knee, shoulder, and neck pain, were assessed with self-reported questionnaires. The outcome of interest was new-onset LBP, which was defined as LBP absent at 3 years but present at 4 years after the disaster. The main predictor was musculoskeletal pain in other body sites 3 years after the GEJE, which was categorized according to the number of pain sites (0, 1, ≥ 2). Multiple regression analyses were performed to calculate the odds ratio (OR) and 95% confidence interval (CI) for new-onset LBP due to musculoskeletal pain in other body sites. The incidence of new-onset LBP was 14.1% (251/1782). Musculoskeletal pain in other body sites was significantly associated with new-onset LBP. Including people without other musculoskeletal pain as a reference, the adjusted OR and 95% CI for new-onset LBP were 1.73 (1.16-2.57) for people with one musculoskeletal pain site and 3.20 (2.01-5.09) for people with ≥ 2 sites (p < 0.001). Preexisting musculoskeletal pain in other body sites was associated with new-onset LBP among survivors in the recovery period after the GEJE.


Normalization of hematocrit in hemodialysis patients with cardiac disease does not increase blood pressure.
Since the earliest reports of the use of Epoetin alfa in hemodialysis patients, it has been described that Epoetin alfa may exacerbate preexisting hypertension or induce hypertension in End Stage Renal Disease (ESRD) patients not previously hypertensive. We undertook this study to determine if the correction of anemia in ESRD patients with cardiac disease from a hematocrit of 30+/-3% to 42+/-3% with the use of Epoetin alfa would result in increased blood pressure. This study was a substudy of the "Normal hematocrit Study". Thirty-one patients were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoetin alfa to 42+/-3% and patients in Group B were maintained with a hematocrit of 30+/-3% throughout the course of the study. All patients had their blood pressure recorded with a 24 hour ambulatory BP device at study entry and at 28 weeks following randomization when they had achieved their target hematocrit. Pre-dialysis systolic and diastolic BP was also recorded. The mean hematocrit increased in Group A from 29.1+/-2.4% to 40.8+/-5.2% after 30 weeks. The hematocrit in Group B remained stable at 30+/-3% throughout the course of the study. There was no difference in mean daytime, mean nighttime or 24 hour systolic or diastolic blood pressure between Groups A and B at either baseline or follow-up. Neither was there a difference in mean pre-dialysis systolic or diastolic BP between Groups A or B at baseline or Follow-up. Four patients in Group A and 4 patients in Group B required an increase in their antihypertensive medication during the course of the study. It is possible to increase hematocrit to normal levels in hemodialysis with the administration of Epoetin alfa. The increase in hematocrit from 30+/-3% to 42+/-3% is not associated with increased blood pressure.


Effects of mitogen-activated protein kinase pathway and co-activator CREP-binding protein on peroxisome proliferator-activated receptor-gamma-mediated transcription suppression of angiotensin II type 1 receptor gene.
Peroxisome proliferator-activated receptor (PPAR)-gamma and its ligands suppress several genes related to atherogenesis. We previously reported that ligand-activated PPAR-gamma suppressed angiotensin II type 1 receptor (AT1R) gene transcription in vascular smooth muscle cells (VSMCs) by the inhibition of Sp1 binding to the --58/--34 GC-box related element in the AT1R gene promoter region via a protein-protein interaction. It has been reported that the mitogen-activated protein (MAP) kinase pathway inhibits PPAR-gamma function through its phosphorylation, and co-activator CREB-binding protein (CBP)/p300 interacts with PPAR-gamma and modulates its activity. Since both the MAP kinase pathway and CBP have recently been reported to be atherogenic, we examined their effects on PPAR-gamma-mediated AT1R gene transcription suppression. We observed that 1) PPAR-gamma-mediated AT1R gene transcription suppression was augmented by treatment with the MAP kinase kinase inhibitor PD98059, while treatment with the p38 kinase inhibitor SB203580 showed no effect; 2) the PPAR-gamma-mediated AT1R mRNA decrease was also augmented by PD98059 treatment; 3) CBP overexpression partially, but significantly, abrogated PPAR-gamma-mediated AT1R gene transcription suppression; and 4) the CBP effect was eliminated when the --58/--34 GC-box related element was disrupted. It is therefore speculated that: 1) PPAR-gamma phosphorylation by the MAP kinase pathway may attenuate PPAR-gamma-mediated AT1R gene transcription suppression through the inhibition of PPAR-gamma activity; and 2) CBP may enhance the activity of the remaining Sp1 on the --58/--34 GC-box related element, resulting in a reduction in PPAR-gamma-mediated AT1R gene transcription suppression. The MAP kinase pathway and CBP may thus antagonize against PPAR-gamma in AT1R gene transcription, probably leading to the progression of atherosclerosis.


4,4',5,5'-Tetracarboxy-2,2'-bipyridine Ru(II) sensitizers for dye-sensitized solar cells.
Two Ru(II) sensitizers TCR-1 and TCR-2 bearing four carboxy anchoring groups were prepared using 4,4',5,5'-tetraethoxycarbonyl-2,2'-bipyridine chelate and 4-(5-hexylthien-2-yl)-2-(3-trifluoromethyl-1H-pyrazol-5-yl)pyridine and 6-t-butyl-1-(3-trifluoromethyl-1H-pyrazol-5-yl)isoquinoline, respectively. Dissolution of these sensitizers in DMF solution afforded a light green solution up to 10(-5) M, for which their color gradually turned red upon further dilution and deposition on the surface of a TiO2 photoanode due to the spontaneous deprotonation of carboxylic acid groups. These sensitizers were characterized using electrochemical means and structural analysis time-dependent density functional theory (TDDFT) simulation and were also subjected to actual device fabrication. The as-fabricated DSC devices showed overall efficiencies η = 6.16% and 6.23% versus their 4,4'-dicarboxy counterparts TFRS-2 and TFRS-52 with higher efficiencies of 7.57% and 8.09%, using electrolyte with 0.2 M LiI additive. Their inferior efficiencies are possibly caused by the combination of blue-shifted absorption on TiO2, inadequate dye loading, and the perpendicularly oriented central carboxy groups.


cAmp regulation of arylalkylamine N-acetyltransferase (AANAT, EC 126.96.36.199): a new cell line (1E7) provides evidence of intracellular AANAT activation.
Arylalkylamine N-acetyltransferase (serotonin N-acetyltransferase, AANAT, EC ) is the penultimate enzyme in melatonin synthesis. As described here, a cell line (1E7) expressing human AANAT (hAANAT) has been developed to study the human enzyme. 1E7 hAANAT is detectable in immunoblots as a 23-kDa band and is immunocytochemically visualized in the cytoplasm. The specific concentration of hAANAT in homogenates is comparable to that of the night rat pineal gland. Kinetics of AANAT extracted from 1E7 cells are the same as those of bacterially expressed hAANAT; both preparations of hAANAT are equally sensitive to the inhibitor CoA-S-N-acetyltryptamine. Studies of cAMP regulation indicate that treatment with forskolin, dibutyryl cAMP, isobutylmethylxanthine, or isoproterenol activate cellular hAANAT within intact 1E7 cells approximately 8-fold without markedly increasing the abundance of AANAT protein or the activity of AANAT in broken cell preparations; and, that forskolin, isobutylmethylxanthine and isoproterenol elevate cyclic AMP production. These observations extend our understanding of cAMP regulation of AANAT activity, because it is currently thought that this only involves changes in the steady-state levels of AANAT protein. This previously unrecognized switching mechanism could function physiologically to control melatonin production without changing AANAT protein levels.


Comparing Estimates of Multiple and Concurrent Partnerships Across Population Based Surveys: Implications for Combination HIV Prevention.
We compare estimates of multiple and concurrent sexual partnerships from Demographic and Health Surveys (DHS) with comparable Population Services International (PSI) surveys in four African countries (Kenya, Lesotho, Uganda, Zambia). DHS data produce significantly lower estimates of all indicators for both sexes in all countries. PSI estimates of multiple partnerships are 1.7 times higher [1.4 for men (M), 3.0 for women (W)], cumulative prevalence of concurrency is 2.4 times higher (2.2 M, 2.7 W), the point prevalence of concurrency is 3.5 times higher (3.5 M, 3.3 W), and the fraction of multi-partnered persons who report concurrency last year is 1.4 times higher (1.6 M, 0.9 W). These findings provide strong empirical evidence that DHS surveys systematically underestimate levels of multiple and concurrent partnerships. The underestimates will contaminate both empirical analyses of the link between sexual behavior and HIV infection, and theoretical models for combination prevention that use these data for inputs.


Nucleotide sequence and deduced amino acid sequence of Escherichia coli pyruvate oxidase, a lipid-activated flavoprotein.
The entire nucleotide sequence of the poxB (pyruvate oxidase) gene of Escherichia coli K-12 has been determined by the dideoxynucleotide (Sanger) sequencing of fragments of the gene cloned into a phage M13 vector. The gene is 1716 nucleotides in length and has an open reading frame which encodes a protein of Mr 62,018. This open reading frame was shown to encode pyruvate oxidase by alignment of the amino acid sequences deduced for the amino and carboxy termini and several internal segments of the mature protein with sequences obtained by amino acid sequence analysis. The deduced amino acid sequence of the oxidase was not unusually rich in hydrophobic sequences despite the peripheral membrane location and lipid binding properties of the protein. The codon usage of the oxidase gene was typical of a moderately expressed protein. The deduced amino acid sequence shares homology with the large subunits of the acetohydroxy acid synthase isozymes I, II, and III, encoded by the ilvB, ilvG, and ilvI genes of E. coli.


Child Abuse and Neglect: Screening for Risks During the Perinatal Period.
Purpose: Currently, there is a claim for earlier interventions for families in order to prevent child maltreatment. Here, a screening instrument to assess risk indicators for child abuse and neglect already in the context of maternity clinics is introduced. The present study is the first report on the psychometric properties of this instrument, the "short questionnaire for risk indices around birth" (RIAB). Material and Methods: Data were collected in the context of three different studies conducted at Ulm University Hospital. To examine interrater reliability eight case vignettes were rated by n = 90 study participants (50 students and 40 experts working at a maternity clinic). Criterion validity was examined in two studies applying the German version of the child abuse potential inventory CAPI (n = 96 families at risk and n = 160 additional families). Results: Both laymen and experts were able to understand and use the screening instrument correctly, leading to a high agreement with the sample solutions given. A high concordance was found between parents' and experts' ratings: In case of no reported risk factors applying the screening instrument RIAB, parents themselves reported significantly less stressors and burdens, compared to those parents with an indication for a thorough examination as pointed out in the RIAB. Conclusion: In the context of maternity clinics the RIAB is a useful, broadly applicable instrument, screening for existing risk factors at the earliest and thus allowing for the initiation of specific interventions when needed.


Interlaboratory evaluations of a standardized quantitative test method for determining the bactericidal and tuberculocidal efficacy of antimicrobial substances on hard non-porous surfaces.
The development, validation, and use of new quantitative methodologies for testing the effectiveness of antimicrobial products are necessary to meet the regulatory challenges associated with an ever-changing marketplace, novel product claims, new infection control practices, and the emergence of new clinical pathogens. A series of four interlaboratory studies were conducted in a standardized manner on an interim quantitative method for testing liquid treatments against bacteria to assess its statistical performance. The Quantitative Method, a derivative of ASTM E2197, is designed to enumerate the number of viable microbes remaining on a test carrier following exposure to a liquid antimicrobial treatment; a log10 reduction (LR) in viable bacteria is calculated based on the difference between the mean log10 density values of the untreated control and treated carriers. The Quantitative Method uses 1 cm diameter disks (carriers) of brushed stainless steel as the material to represent a hard, non-porous surface. The LR value is used as the measure of product effectiveness, where higher LR values are indicative of greater microbial kill. The test microbes were Staphylococcus aureus, Pseudomonas aeruginosa, and Mycobacterium terrae. The liquid antimicrobial treatments used in these studies were highly relevant to those in the marketplace and provided a wide range of mean LR outcomes. The focus of the statistical assessment was on the repeatability of the LRs across experiments within a lab (Sr) and the reproducibility of the LRs across labs (SR). Due to the additional sources of variability, the SR is expected to be higher than the variability within a laboratory (Sr); this was observed in the studies reported here. Across the studies, the Sr values for LR were small (i.e., less than 0.84), most notably for treatments generating high mean LRs (5 or above) where the Sr was as small as 0.12. Overall, the SR values ranged from 0.227 to 1.217. Only three of the twenty-four treatment combinations over the study period resulted in SR values above 1.0 - the associated LRs for the three treatments ranged from 2.22 to 3.26. Antimicrobial treatments with a LR of 4.5 or higher exhibited SR of 0.561 or less. The statistical attributes reported here for the draft Quantitative Method when used to test P. aeruginosa, S. aureus, and M. terrae provide information for decision makers when considering the method as a candidate regulatory procedure. The data and statistical analyses contained in this report are historical in nature and provide useful baseline information for individuals conducting additional technical review of the method. Based on the data, the Quantitative Method displays a statistical profile consistent with other standard methods approved by standard-setting organizations where method performance data are available.


|SE|S|AM|E| Barcode: NGS-oriented software for amplicon characterization--application to species and environmental barcoding.
Progress in NGS technologies has opened up new opportunities for characterizing biodiversity, both for individual specimen identification and for environmental barcoding. Although the amount of data available to biologist is increasing, user-friendly tools to facilitate data analysis have yet to be developed. Our aim, with |SE|S|AM|E| Barcode, is to provide such support through a unified platform. The sequences are analysed through a pipeline that (i) processes NGS amplicon runs, filtering markers and samples, (ii) builds reference libraries and finally (iii) identifies (barcodes) the sequences in each amplicon from the reference library. We use a simulated data set for specimen identification and a recently published data set for environmental barcoding to validate the method. The results obtained are consistent with the expected characterizations (in silico and previously published, respectively). |SE|S|AM|E| Barcode and its documentation are freely available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported Licence for Windows and Linux from http://www1.montpellier.inra.fr/CBGP/NGS/.


Cytotoxic Compounds from Brucea mollis.
Ten compounds, including soulameanone (1), isobruceine B (2), 9-methoxy-canthin-6-one (3), bruceolline F (4), niloticine (5), octatriacontan-1-ol (6), bombiprenone (7), α-tocopherol (8), inosine (9), and apigenin 7-O-β-D-glucopyranoside (10), were isolated from the leaves, stems, and roots of Brucea mollis Wall. ex Kurz. Their structures were determined using one-and two-dimensional NMR spectroscopy and mass spectrometry. All compounds were evaluated for their cytotoxic activity against KB (human carcinoma of the mouth), LU-1 (human lung adenocarcinoma), LNCaP (human prostate adeno-carcinoma), and HL-60 (human promyelocytic leukemia) cancer cell lines. Compound 2 showed significant cytotoxic activity against KB, LU-1, LNCaP, and HL-60 cancer cells with IC50 values of 0.39, 0.40, 0.34, and 0.23 μg/mL, respectively. In addition, compounds 3 and 5 showed significant cytotoxic activity against KB, LU-1, LNCaP, and HL-60 cancer cells with IC50 values around 1-4 μg/mL. Compounds 9-methoxycanthin-6-one (3) and niloticine (5) have been discovered for the first time from the Brucea genus.


On the Validity of Single Regression Strategy for Granger Causality Assessment in Cardiovascular and Cardiorespiratory Control Studies.
Granger causality (GC) analysis is based on the comparison between prediction error variances computed over the full and restricted models after identifying the coefficients of appropriate vector regressions. GC markers can be computed via a double regression (DR) approach identifying two separate, independent models and a single regression (SR) strategy optimizing the description of the dynamics of the target over the full model and, then, reusing some parts of it in the restricted model. The present study compares the SR and DR strategies over heart period (HP), systolic arterial pressure (SAP) and respiration (R) beat-to-beat series collected during a graded orthostatic challenge induced by head-up tilt in 17 healthy individuals (age: 21-36 yrs; median: 29 yrs; 9 females and 8 males). We found that the DR approach was more powerful than the SR one in detecting the expected stronger involvement of the baroreflex during the challenge, while the expected weaker cardiorespiratory coupling was identified by both SR and DR strategies. The less powerful ability of the SR approach was the result of the greater variance of GC markers compared to the DR strategy. We conclude that, contrary to the suggestions present in literature, the SR approach is not necessarily associated with a smaller dispersion of GC markers. Moreover, we suggest that additional factors, such as the strategy utilized to build embedding spaces and metric utilized to compare prediction error variances, might play an important role in differentiating SR and DR approaches.


Force-activated reactivity switch in a bimolecular chemical reaction.
The effect of mechanical force on the free-energy surface that governs a chemical reaction is largely unknown. The combination of protein engineering with single-molecule force-clamp spectroscopy allows us to study the influence of mechanical force on the rate at which a protein disulfide bond is reduced by nucleophiles in a bimolecular substitution reaction (S(N)2). We found that cleavage of a protein disulfide bond by hydroxide anions exhibits an abrupt reactivity 'switch' at ∼500 pN, after which the accelerating effect of force on the rate of an S(N)2 chemical reaction greatly diminishes. We propose that an abrupt force-induced conformational change of the protein disulfide bond shifts its ground state, drastically changing its reactivity in S(N)2 chemical reactions. Our experiments directly demonstrate the action of a force-activated switch in the chemical reactivity of a single molecule.


[Integrity of the death records and problems of information transcription in 8 states of the Mexican Republic].
This paper states some of the main problems associated with the collection and processing of the information about deaths in Mexico. The results reported are in relation to the integrity and transcription problems found in 23 municipalities of eight states of the Republic of Mexico. The main results were: lack of continuity in the flow of information; different criteria in the handling of the several existing formats; incomplete documentation (medical death certificates, official registration and special concentration forms 823-824) in 39 percent, with a variation range of 2 to 72 percent depending of the particular degree of development in each state or county; the forms used to make up the national death statistics (forms 823-824) were not found in 21.5 percent of the cases, and transcription problems of the main variables (age, sex and cause of death), using as common denominator (total deaths) those registered at least in 2 documents, occurred in 26 percent of the age registers, 22.4 percent in the case of sex, and 51.6 percent in the cause of death variable.


IEEE 802.15.4 MAC with GTS transmission for heterogeneous devices with application to wheelchair body-area sensor networks.
In wireless personal area networks, such as wireless body-area sensor networks, stations or devices have different bandwidth requirements and, thus, create heterogeneous traffics. For such networks, the IEEE 802.15.4 medium access control (MAC) can be used in the beacon-enabled mode, which supports guaranteed time slot (GTS) allocation for time-critical data transmissions. This paper presents a general discrete-time Markov chain model for the IEEE 802.15.4-based networks taking into account the slotted carrier sense multiple access with collision avoidance and GTS transmission phenomena together in the heterogeneous traffic scenario and under nonsaturated condition. For this purpose, the standard GTS allocation scheme is modified. For each non-identical device, the Markov model is solved and the average service time and the service utilization factor are analyzed in the non-saturated mode. The analysis is validated by simulations using network simulator version 2.33. Also, the model is enhanced with a wireless propagation model and the performance of the MAC is evaluated in a wheelchair body-area sensor network scenario.


Using compensation to improve primary care.
Progressive primary care networks are now placing significant portions of physician salaries at risk by linking compensation to quantifiable measures such as net medical revenue (collections), reduced practice expenses, cost and utilization, quality of care and patient satisfaction. For most networks, a combination of productivity increases and expense reductions are critical to ensure financial survival. This case study illustrates how one network's unique incentive compensation program targeted higher productivity levels by incentivizing desirable behaviors.


Synchrony-dependent autocorrelation in eighth-nerve-fiber response to rippled noise.
Autocorrelograms and interval and delay histograms of the eighth-nerve-fiber response in cats to cosine noise were recorded. A good detectability level for the delay oscillations in the autocorrelograms was always found, when the fiber had a high value of the synchronization index at characteristic frequency (CF). In order to study their relationship, autocorrelograms for cosine noise stimulation were computed by the substitution of synchronization indices in the Poisson distribution formulas for higher-order intervals. The approach was made possible through a further exploration of Johnson's synchronization theory [D. H. Johnson, "The response of single auditory-nerve fibers in the cat to single tones: synchrony and average discharge rate," Ph. D. thesis, MIT, Cambridge, MA (1974)]. It was shown that computed autocorrelograms somewhat resembled experimental ones. The differences between them concerned the envelopes of the "onset" and "delay" oscillations, viz., in their constrictions and amplitudes. These constrictions were shown to be significant only in recordings at delays greater than or equal to 4/CF, corresponding to the dominant region for human repetition pitch.


Kinematics and dynamic stability of the locomotion of post-polio patients.
The study reported in this article was conducted to propose a set graphical and analytical tools and assess their clinical utility by analyzing gait kinematics and dynamics of polio survivors. Phase-plane portraits and first return maps were used as graphical tools to detect abnormal patterns in the sagittal kinematics of post-polio gait. Two new scalar measures were introduced to assess the bilateral kinematic symmetry and dynamic stability of human locomotion. Nine healthy subjects and seventeen post-polio patients were involved in the project. Significant increases in the knee extension and ankle plantar flexion of post-polio patients were observed during the weight acceptance phases of their gait. Polio patients also exhibited highly noticeable excessive hip flexion during the swing phase of their ambulation. Using the proposed symmetry measure, we concluded that post-polio patients walked less symmetrically than normals. Our conclusion, however, was based on the bilateral symmetry in the sagittal plane only. Finally, we observed that post-polio patients walked significantly less stably than normals. In addition, weaknesses in lower extremity muscles of polio patients were found to be an important factor that affected stable ambulation.


Functional determination of the differentiation potential of ventral mesencephalic neural precursor cells during dopaminergic neurogenesis.
The ventral mesencephalic neural precursor cells (vmNPCs) that give rise to dopaminergic (DA) neurons have been identified by the expression of distinct genes (e.g., Lmx1a, Foxa2, Msx1/2). However, the commitment of these NPCs to the mesencephalic DA neuronal fate has not been functionally determined. Evaluation of the plasticity of vmNPCs suggests that their commitment occurs after E10.5. Here we show that E9.5 vmNPCs implanted in an ectopic area of E10.5 mesencephalic explants, retained their specification marker Lmx1a and efficiently differentiated into neurons but did not express the gene encoding tyrosine hydroxylase (Th), the limiting enzyme for dopamine synthesis. A proportion of E10.5-E11.5 implanted vmNPCs behaved as committed, deriving into Th+ neurons in ectopic sites. Interestingly, implanted cells from E12.5 embryos were unable to give rise to a significant number of Th+ neurons. Concomitantly, differentiation assays in culture and in mesencephalic explants treated with Fgf2+LIF detected vmNPCs with astrogenic potential since E11.5. Despite this, a full suspension of E12.5 vmNPCs give rise to DA neurons in a similar proportion as those of E10.5 when they were transplanted into adult brain, but astrocytes were only detected with the former population. These data suggest that the subventricular postmitotic progenitors present in E12.5 ventral mesencephalon are unable to implant in embryonic explants and are the source of DA neurons in the transplanted adult brain. Based on our findings we propose that during DA differentiation committed vmNPCs emerge at E10.5 and they exhaust their neurogenic capacity with the rise of NPCs with astrogenic potential.


Association between timing of introducing solid foods and obesity in infancy and childhood: a systematic review.
Determining early-life risk factors for obesity in later life is essential in order to effectively target preventative interventions to reduce obesity. The aim of this systematic review was to investigate current evidence to determine whether the timing of introducing solid foods is associated with obesity in infancy and childhood. Relevant randomized and observational studies from developed countries were identified by searching the following six bio-medical databases (Medline, Embase, British Nursing Index, CINAHL, Maternity and Infant Care, and PsycINFO) and hand-searching reference lists. Studies of pre-term or low birthweight infants were excluded. Twenty-four studies met the inclusion criteria for the systematic review. Data from over 34,000 participants were available for interpretative analysis. No clear association between the age of introduction of solid foods and obesity was found. It is likely that a whole family approach to obesity prevention will be most effective and health professionals should continue to promote healthy infant feeding in line with national recommendations.


ACTIVITY OF AMPICILLIN IN VITRO COMPARED WITH OTHER ANTIBIOTICS.
Comparative tests in vitro for antibacterial activity were carried out with ampicillin, tetracycline, and chloramphenicol using 673 clinical isolates of Gram-negative bacilli and Streptococcus faecalis. Further comparative tests were also carried out with ampicillin, chloramphenicol, colistin sulphate, colistin methane sulphonate, cycloserine, kanamycin, nitrofurantoin, polymyxin, streptomycin, and tetracycline, using groups of 20 strains of each of the main species selected at random from the total number of isolates. Of the total number of isolates a higher percentage was inhibited by ampicillin than by tetracycline or chloramphenicol. Ampicillin showed particularly high activity against certain species of bacteria and displayed an antibacterial spectrum not shown by any of the other antibiotics tested.


Drug therapies for tardive dyskinesia: Part 1.
Blocking dopamine (DA) receptors in the basal ganglia can cause parkinsonian symptoms, acute dystonia, akathisia, tardive dyskinesia (TD), and neuroleptic malignant syndrome. TD is characterized by abnormal, involuntary, irregular motor movements involving muscles of the head, limbs, or trunk. Many drug therapies have been tried for TD, but none are approved by the U.S. Food and Drug Administration. The second-generation antipsychotic drugs should be considered as a treatment of first choice for clinically significant TD, because they will also be potentially effective as a primary treatment for the underlying disorder. Dopamine-depleting drugs are effective for TD, but their practical use is severely limited because of tolerability and safety concerns. Various DA-modulating drugs have been tried; clinical evidence of efficacy suggests that amantadine (Symmetrel®) and naloxone (Narcan®) are worthwhile to try. Although efficacy evidence for buspirone (Buspar®) in TD is limited, this drug is safe and well tolerated and would be reasonable to try. Bromocriptine (Parlodel®), selegiline (Deprenyl®), and cholinergic-modulating drugs are not considered effective for TD.


Suicide first aid guidelines for Sri Lanka: a Delphi consensus study.
Sri Lanka has one of the highest suicide rates in the world. Gatekeeper programs aimed at specific target groups could be a promising suicide prevention strategy in the country. The aim of this study was to develop guidelines that help members of the public to provide first aid to persons in Sri Lanka who are at risk of suicide. The Delphi method was used to elicit consensus on potential helping statements to include in the guidelines. These statements describe information members of the public should have and actions they can take to help a person who is experiencing suicidal thoughts. An expert panel, comprised of mental health and suicide experts in Sri Lanka, rated each statement. The panellists were encouraged to suggest any additional action that was not included in the original questionnaire and, in particular, to include items that were culturally appropriate or gender specific. Responses to open-ended questions were used to generate new items. These items were included in the subsequent Delphi rounds. Three Delphi rounds were carried out. Statements were accepted for inclusion in the guidelines if they were endorsed (rated as essential or important) by at least 80 % of the panel. Statements endorsed by 70-79 % of the panel were re-rated in the following round. Statements with less than 70 % endorsement, or re-rated items that did not receive 80 % or higher endorsement were rejected. The output from the Delphi process was a set of endorsed statements. In the first round questionnaire 473 statements were presented to the panel and 58 new items were generated from responses to the open-ended questions. Of the total 531 statements presented, 304 were endorsed. These statements were used to develop the suicide first aid guidelines for Sri Lanka. By engaging Sri Lankans who are experts in the field of mental health or suicide this research developed culturally appropriate guidelines for providing mental health first aid to a person at risk of suicide in Sri Lanka. The guidelines may serve as a basis for developing training for members of the public to provide mental health first aid to persons at risk of suicide as part of Sri Lanka's suicide prevention strategy.


Magnesium lithospermate B improves the gut microbiome and bile acid metabolic profiles in a mouse model of diabetic nephropathy.
Magnesium lithospermate B (MLB) is a new drug marketed in China to treat angina, but its low oral bioavailability limits its clinical application to the intravenous route. Paradoxically, orally administered low-dose MLB was found to alleviate kidney injury in diabetic nephropathy (DN) rats, but its mechanism of action remains unknown. In recent years, the kidney-gut axis has been suspected to be involved in kidney damage pathogenesis, potentially representing a non-classical pathway for pharmacologic intervention. To ascertain whether MLB targets the kidney-gut axis, streptozotocin (STZ)-treated mice were prepared as a mouse model of DN. The STZ mice were treated with MLB (50 mg kg-1 d-1, p.o.) for 8 weeks. Twenty-four-hour urinary albumin was detected to mirror kidney function. At week 4, 6, 8, feces were collected; bile acids (BAs) were quantified to examine the alterations in the BA metabolic profiles, and bacterial 16S rRNA gene fragments were sequenced to identify alterations in gut microbial composition. In STZ mice, 24-h urinary albumin levels and total fecal BAs, especially cholic acids (CAs) and deoxycholic acids (DCAs) were greatly increased, and the gut microbiome was dramatically shifted compared with control mice. Oral administration of MLB significantly decreased 24-h urinary albumin levels and total BAs, CAs and DCAs, and reversed CA:TCA (taurocholic acid) and DCA:CA ratios. It also changed the microbiome composition in STZ mice based on operational units. Thus the therapeutic effect of MLB on kidney injury might be attributed (at least partially) to its ability to modulate the disordered gut microbiome and BA metabolism.


Effect of the hope FT-B1 allele on wheat heading time and yield components.
Precise regulation of flowering time is critical for plant reproductive success and, in cereals, to maximize grain yields. Seasonal cues including temperature and day length are integrated to regulate the timing of flowering. In temperate cereals, extended periods of cold (vernalization) release the repression of FLOWERING LOCUS T1 (FT1), which is upregulated in the leaves in response to inductive long-day photoperiods. FT1 is a homolog of rice HD3a, which encodes a protein transported from leaves to the shoot apical meristem to induce flowering. A rare FT-B1 allele from the wheat variety "Hope" has been previously shown to be associated with an early flowering phenotype under long-day photoperiods. Here, we demonstrate that the Hope FT-B1 allele accelerates flowering even under short days, and that it is epistatic to the VERNALIZATION 1 (VRN1) gene. On average, the introgression of Hope FT-B1 into 6 genetic backgrounds resulted in 2.6 days acceleration of flowering (P<0.0001) and 4.1% increase in spike weight (P=0.0093), although in one variety, it was associated with a decrease in spike weight. These results suggest that the Hope FT-B1 allele could be useful in wheat breeding programs to subtly accelerate floral development and increase adaptation to changing environments.


The Physician-Investigator Workforce: Looking Ahead.
Support of the U.S. health professions investigator workforce is critically important to the continued advancement of health care nationally. Physician-investigators comprise one segment of this health professions investigator workforce, which also includes investigators in the nursing, pharmacy, and dentistry professions, and others. Among physician health professionals in particular, the term "physician-investigator" has been described as encompassing physicians engaged in research in various ways including "clinical researchers" (physicians with clinical duties who do clinical, patient-centered research), "clinician-scientists" (physicians with clinical roles who perform research in laboratories or using computational tools), and "physician-scientists" (physicians focused on research with little or no clinical activity). Broadly defined, physician-investigators are included in various groups of researchers described in several articles recently published in Academic Medicine; these articles provide details on a range of approaches, with supporting outcomes data, being taken to train, support, and retain physicians in the health professions investigator workforce. The authors of this commentary examine selected literature, including several articles in this issue among others, along with Association of American Medical Colleges data, to offer observations about programs that train physician-investigators. Evidence-informed single-program approaches for early-career researchers can sustain continued research interest and foster the career development of the emerging physician-investigator workforce. Collaborative multi-institutional approaches offer the benefit of multisite work to power outcomes studies and to increase generalizability beyond a specific institutional program. System-wide institutional approaches may be particularly critical in supporting physician-investigators across all career stages. Although the articles discussed in this commentary are largely (although not exclusively) focused on various initiatives and programs designed to develop and sustain the physician-investigator workforce, such initiatives and programs may have value in addressing shared challenges of developing, supporting, and retaining the broader investigator workforce across all health professions.


Expression of CD11c Is Associated with Unconventional Activated T Cell Subsets with High Migratory Potential.
CD11c is an α integrin classically employed to define myeloid dendritic cells. Although there is little information about CD11c expression on human T cells, mouse models have shown an association of CD11c expression with functionally relevant T cell subsets. In the context of genital tract infection, we have previously observed increased expression of CD11c in circulating T cells from mice and women. Microarray analyses of activated effector T cells expressing CD11c derived from naïve mice demonstrated enrichment for natural killer (NK) associated genes. Here we find that murine CD11c+ T cells analyzed by flow cytometry display markers associated with non-conventional T cell subsets, including γδ T cells and invariant natural killer T (iNKT) cells. However, in women, only γδ T cells and CD8+ T cells were enriched within the CD11c fraction of blood and cervical tissue. These CD11c+ cells were highly activated and had greater interferon (IFN)-γ secretory capacity than CD11c- T cells. Furthermore, circulating CD11c+ T cells were associated with the expression of multiple adhesion molecules in women, suggesting that these cells have high tissue homing potential. These data suggest that CD11c expression distinguishes a population of circulating T cells during bacterial infection with innate capacity and mucosal homing potential.