Safety evaluation of large external fixation clamps and frames in a magnetic resonance environment.
Large orthopedic external fixation clamps and related components were evaluated for force, torque, and heating response when subjected to the strong electromagnetic fields of magnetic-resonance (MR) imaging devices. Forces induced by a 3-Tesla (T) MR scanner were compiled for newly designed nonmagnetic clamps and older clamps that contained ferromagnetic components. Heating trials were performed in a 1.5 and in a 3 T MR scanner with two assembled external fixation frames. Forces of the newly designed clamps were more than a factor 2 lower as the gravitational force on the device whereas, magnetic forces on the older devices showed over 10 times the force induced by earth acceleration of gravity. No torque effects could be found for the newly designed clamps. Temperature measurements at the tips of Schanz screws in the 1.5 T MR scanner showed a rise of 0.7 degrees C for a pelvic frame and of 2.1 degrees C for a diamond knee bridge frame when normalized to a specific absorption rate (SAR) of 2 W/kg. The normalized temperature increases in the 3 T MR scanner were 0.9 degrees C for the pelvic frame and 1.1 degrees C for the knee bridge frame. Large external fixation frames assembled with the newly designed clamps (390 Series Clamps), carbon fiber reinforced rods, and implant quality 316L stainless steel Schanz screws met prevailing force and torque limits when tested in a 3-T field, and demonstrated temperature increase that met IEC-60601 guidelines for extremities. The influence of frame-induced eddy currents on the risk of peripheral nerve stimulation was not investigated.


Child physical abuse: assessment of dental students' attitudes and knowledge in United Arab Emirates.
To investigate dental students' educational experience, attitudes and knowledge with regard to child physical abuse in all dental schools in United Arab Emirates. The data were collected by self-administered structured questionnaire completed by 578 under graduate dental students in four (all) dental schools in United Arab Emirates. Data were analysed using descriptive analyses for responses to each question. The results indicated that there was lack of knowledge of reporting procedure, signs of physical abuse and social indicators among all respondents. Over 80 % of the students agreed that dentists should be legally mandated to report abuse cases and a high percentage (94.3 %) of the participants believed they had an ethical duty to report child abuse. Most students indicated that their dental school was the main source of information on this topic. The majority of the respondents expressed a need for further training. Dental students were not sufficiently prepared to know what to look for when they suspect child abuse and what to actually do when they encounter this problem in a professional setting. To provide better care for these young domestic violence victims, dental schools' curriculum modifications should focus on providing students with concrete educational experiences regarding child abuse cases.


Pharmaco-morbidity linkage: a feasibility study comparing morbidity in two pharmacy based exposure cohorts.
The aims were (1) to compare discharge diagnoses and concurrent medication in a pharmacy based cohort of users of H2 receptor antagonists to those in a population of users of other drugs in the same period, who did not use H2 receptor antagonists; (2) to compare these results to those of a similar study performed with the Tayside record linkage scheme. The study was a retrospective cohort study. The morbidity data from the only hospital in one medium sized city (62,000 inhabitants) were linked to the dispensing data of all five community pharmacies on an individual basis (April 1, 1986-December 31, 1989). In the absence of a unique patient identification number, data from pharmacies and hospital were linked by the combination of date of birth, gender, and general practitioner code. For every user of H2 receptor antagonists two controls were obtained from all patients who had not used these drugs, and matched for age (within 5 years), gender, and general practitioner. All discharge diagnoses which followed this first prescription up to December 31, 1989, in a patient in the index cohort, and during the same period in his or her matched controls, were included in the study. In the index cohort (n = 2174) 341 persons were admitted (526 admissions) as against 398 persons (527 admissions) in the control cohort (n = 4348). There was increased morbidity in the index cohort, especially concerning the gastrointestinal system (peptic ulcers and malignancies, abdominal pain, gastrointestinal haemorrhage), but also concerning the musculoskeletal, respiratory, and circulatory systems. The morbidity in the last three groups corresponded with drugs used concomitantly by patients in the index cohort, so it was probably not causally related to the intake of H2 receptor antagonists but was rather an indicator of higher levels of morbidity in the index cohort. The figures were grossly comparable to those of the Tayside record linkage scheme. Probabilistic linking with the patient characteristics of gender, date of birth, and general practitioner code can facilitate the undertaking of postmarketing surveillance studies.


District specific correlates for hypertension in Kaoma and Kasama rural districts of Zambia.
Hypertension a major risk factor for cardiovascular disease and is the most widely recognized modifiable risk factor for this disease. There is little information on the prevalence and risk factors for hypertension in Zambia, and in particular in rural areas of the country. In order to contribute to the existing global literature on hypertension, particularly in rural Zambia, this study was conducted to determine the prevalence of hypertension and its correlates in two rural districts of Zambia, namely Kaoma and Kasama. A cross-sectional study using a modified World Health Organization (WHO) global non communicable diseases (NCD) surveillance initiative NCD-STEPwise approach was used. Proportions were compared using the Yates' corrected χ2 test, and a result yielding a p-value of less than 5% was considered significant. Bivariate and multivariate logistic regression analyses were conducted. Factors that were significantly associated with the outcome in bivariate analyses were considered in a multivariate logistic regression analysis using a backward variable selection method. Adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were reported. In total, 895 participants from Kaoma and 1198 participants from Kasama took part in the surveys. Overall, 25.8% participants (27.5% male, 24.6% female; p=0.373) in Kaoma and 30.3% (31.3% male, 29.5% female; p=0.531) in Kasama were hypertensive. In Kaoma, age and BMI were independently associated with hypertension. Compared with participants aged 45 years or older, participants aged 25-34 years were 60% (AOR=0.40, 95% CI [0.21, 0.56]) less likely to be hypertensive. Participants with BMI <18.5 and 18.5-24.9 were 54% (AOR=0.46, 95% CI [0.30, 0.69]) and 31% (AOR=0.69, 95% CI [0.49, 0.98]) less likely to be hypertensive compared with participants with BMI ≥30. In Kasama, age, smoking and heart rate were significantly associated with hypertension in multivariate analysis. Participants 25-34 years were 49% (AOR=0.51, 95% CI [0.41, 0.65]) less likely to be hypertensive compared with participants 45 years or older. Compared with participants who were non-smokers, smokers were 21% (AOR=1.21, 95% CI [1.02, 1.45]) more likely to be hypertensive. Participants who had heart rate >90 beats/min were 59% (AOR=1.59, 95% CI [1.17, 2.16]) more likely to be hypertensive compared with participants who had heart rate 60-90 beats/min. The findings reveal that hypertension is prevalent among rural residents in Kaoma and Kasama, Zambia. The disease is highly associated with age, BMI, smoking and heart rate. Efficient preventive strategies are needed to halt the growing trend of non-communicable diseases through the control of risk factors highlighted in this study.


Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.
Attention-deficit/hyperactivity disorder (ADHD) is 1 of the most common neurobehavioral disorders of childhood and can profoundly affect children's academic achievement, well-being, and social interactions. The American Academy of Pediatrics first published clinical recommendations for evaluation and diagnosis of pediatric ADHD in 2000; recommendations for treatment followed in 2001. The guidelines were revised in 2011 and published with an accompanying process of care algorithm (PoCA) providing discrete and manageable steps by which clinicians could fulfill the clinical guideline's recommendations. Since the release of the 2011 guideline, the Diagnostic and Statistical Manual of Mental Disorders has been revised to the fifth edition, and new ADHD-related research has been published. These publications do not support dramatic changes to the previous recommendations. Therefore, only incremental updates have been made in this guideline revision, including the addition of a key action statement related to diagnosis and treatment of comorbid conditions in children and adolescents with ADHD. The accompanying process of care algorithm has also been updated to assist in implementing the guideline recommendations. Throughout the process of revising the guideline and algorithm, numerous systemic barriers were identified that restrict and/or hamper pediatric clinicians' ability to adopt their recommendations. Therefore, the subcommittee created a companion article (available in the Supplemental Information) on systemic barriers to the care of children and adolescents with ADHD, which identifies the major systemic-level barriers and presents recommendations to address those barriers; in this article, we support the recommendations of the clinical practice guideline and accompanying process of care algorithm.


Management of Ontario children with acute lymphoblastic leukemia by the Dana-Farber Cancer Institute protocols.
There is ample evidence of the value of intensive therapeutic strategies in the management of acute lymphoblastic leukemia (ALL), the commonest form of malignant disease in children. Such a program, devised at the Dana-Farber Cancer Institute (DFCI), Boston, and incorporating high-dose L-asparaginase, was adopted in 1984 by the Children's Hospital at Chedoke-McMaster, Hamilton, Ont., and the Children's Hospital of Western Ontario, London. We describe the experience of these institutions in the treatment of 82 children with ALL, 19 of whom were switched to the DFCI protocols while in continuing first remission with other treatment programs to complete a minimum of 2 years of maintenance therapy; the remaining 63 children, who had recently diagnosed disease, were consecutively enrolled in the DFCI protocols. Each child was assigned at diagnosis to a category of risk for relapse and treated accordingly. There were no remission induction failures or deaths due to induction therapy among the patients with newly diagnosed disease. There were no differences in total or event-free survival rates between the patients in Hamilton and those in London or between those whose protocols were switched and those who were treated from the beginning with the DFCI protocols. With a median follow-up interval of 144 weeks the total survival rate was 95% and the event-free survival rate 88%. For patients at standard risk of relapse the event-free survival rate was 100%, for those at high risk the rate was 82%, and for those at very high risk the rate was 67%. If infants (all of whom suffered a relapse) are excluded from the last category the rate was 89%. These results were achieved with moderate toxic effects (except for two deaths, one of which was due to a therapeutic misadventure) and suggest that the prospect for cure in children with ALL. may now approximate 80%, a degree of success that demands that consideration be given to reducing total therapy, at least for children with standard-risk disease. Further follow-up will determine whether these high event-free survival rates will stabilize and meet the criteria for cure.


Cardiomyocyte-specific overexpression of an active form of Rac predisposes the heart to increased myocardial stunning and ischemia-reperfusion injury.
The GTP-binding protein Rac regulates diverse cellular functions including activation of NADPH oxidase, a major source of superoxide production (O(2)(·-)). Rac1-mediated NADPH oxidase activation is increased after myocardial infarction (MI) and heart failure both in animals and humans; however, the impact of increased myocardial Rac on impending ischemia-reperfusion (I/R) is unknown. A novel transgenic mouse model with cardiac-specific overexpression of constitutively active mutant form of Zea maize Rac D (ZmRacD) gene has been reported with increased myocardial Rac-GTPase activity and O(2)(·-) generation. The goal of the present study was to determine signaling pathways related to increased myocardial ZmRacD and to what extent hearts with increased ZmRacD proteins are susceptible to I/R injury. The effect of myocardial I/R was examined in young adult wild-type (WT) and ZmRacD transgenic (TG) mice. In vitro reversible myocardial I/R for postischemic cardiac function and in vivo regional myocardial I/R for MI were performed. Following 20-min global ischemia and 45-min reperfusion, postischemic cardiac contractile function and heart rate were significantly reduced in TG hearts compared with WT hearts. Importantly, acute regional myocardial I/R (30-min ischemia and 24-h reperfusion) caused significantly larger MI in TG mice compared with WT mice. Western blot analysis of cardiac homogenates revealed that increased myocardial ZmRacD gene expression is associated with concomitant increased levels of NADPH oxidase subunit gp91(phox), O(2)(·-), and P(21)-activated kinase. Thus these findings provide direct evidence that increased levels of active myocardial Rac renders the heart susceptible to increased postischemic contractile dysfunction and MI following acute I/R.


Tunable terahertz coherent perfect absorption in a monolayer graphene.
Coherent perfect absorber (CPA) was proposed as the time-reversed counterpart to laser: a resonator containing lossy medium instead of gain medium can absorb the coherent optical fields completely. Here, we exploit a monolayer graphene to realize the CPA in a nonresonant manner. It is found that quasi-CPA point exists in the terahertz regime for suspending monolayer graphene, and the CPA can be implemented with the assistance of proper phase modulation among two incident beams at the quasi-CPA frequencies. The graphene-based CPA is found of broadband angular selectivity: CPA point splits into two frequency bands for the orthogonal s and p polarizations at oblique incidence, and the two bands cover a wide frequency range starting from zero frequency. Furthermore, the coherent absorption can be tuned substantially by varying the gate-controlled Fermi energy. The findings of CPA with nonresonant graphene sheet can be generalized for potential applications in terahertz/infrared detections and signal processing with two-dimensional optoelectronic materials.


Structure-function analysis and genetic interactions of the yeast branchpoint binding protein Msl5.
Saccharomyces cerevisiae Msl5 (branchpoint binding protein) orchestrates spliceosome assembly by binding the branchpoint sequence 5'-UACUAAC and establishing cross intron-bridging interactions with other components of the splicing machinery. Reciprocal tandem affinity purifications verify that Msl5 exists in vivo as a heterodimer with Mud2 and that the Msl5-Mud2 complex is associated with the U1 snRNP. By gauging the ability of mutants of Msl5 to complement msl5Δ, we find that the Mud2-binding (amino acids 35-54) and putative Prp40-binding (PPxY(100)) elements of the Msl5 N-terminal domain are inessential, as are the C-terminal proline-rich domain (amino acids 382-476) and two zinc-binding CxxCxxxxHxxxxC motifs (amino acids 273-286 and 299-312). A subset of conserved branchpoint RNA-binding amino acids in the central KH-QUA2 domain (amino acids 146-269) are essential pairwise (Ile198-Arg190; Leu256-Leu259) or in trios (Leu169-Arg172-Leu176), whereas other pairs of RNA-binding residues are dispensable. We used our collection of viable Msl5 mutants to interrogate synthetic genetic interactions, in cis between the inessential structural elements of the Msl5 polypeptide and in trans between Msl5 and yeast splicing factors (Mud2, Nam8 and Tgs1) that are optional for vegetative growth. The results suggest a network of important but functionally buffered protein-protein and protein-RNA interactions between the Mud2-Msl5 complex at the branchpoint and the U1 snRNP at the 5' splice site.


Quantitative dissection of clone-specific growth rates in cultured malaria parasites.
Measurement of parasite proliferation in cultured red blood cells underpins many facets of malaria research, from drug sensitivity assays to assessing the impact of experimentally altered genes on parasite growth, virulence and fitness. Pioneering efforts to grow Plasmodium falciparum in cultured red blood cells revolutionised malaria research and spurred the development of semi-high-throughput growth assays using radio-labelled hypoxanthine (Hx), an essential nucleic acid precursor, as a reporter of whole-cycle proliferation [Trager, W., Jensen, J.B., 1976. Human malaria parasites in continuous culture. Science 193, 673-675; Desjardins, R.E., Canfield, C.J., Haynes, J.D., Chulay, J.D., 1979. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob. Agents Chemother. 16, 710-718]. The isotopic Hx assay remains the standard quantitative growth assay with which newer non-radioactive procedures based on fluorescent DNA dyes or ELISA are compared. All of these readouts are surrogate reporters of changes in bulk parasitemias, reflecting proliferation over entire asexual reproductive cycles. While quantitatively robust and amenable to semi-high-throughput applications, these methods are blind to the underlying developmental and cellular events of growth in human red blood cells. Modern whole-genome tools including gene knockouts, mutagenesis and small molecule screens promise to reveal much about basic parasite biology; however methods to precisely quantify the within-cycle growth process are needed. Here we elaborate on the classical growth index, i.e. changes in parasitemia, by quantifying sub-phenotypes of a rapid proliferator, the multi-drug resistant clone Dd2, and a standard wild-type clone, HB3. These data illustrate differences in cycle duration, merozoite production, and invasion rate and efficiency that underpin Dd2's average 2-fold proliferation advantage over HB3 per erythrocytic cycle. The ability to refine growth phenotypes will inform the search for molecular determinants of differential parasite growth rates and broaden our understanding of killing mechanisms and cellular targets of antimalarial drugs.


Manganese superoxide dismutase and chemokine genes polymorphisms in chinese patients with anterior uveitis.
To investigate the association of single-nucleotide polymorphisms (SNPs) in the manganese superoxide dismutase (MnSOD) and two chemokine genes (CCL2 and CCL5) in patients with anterior uveitis (AU). Seventy-nine Chinese patients with acute AU were recruited, and genotyping of four SNPs including MnSOD 47, CCL2 -2518, CCL2 -2076, and CCL5 -403 alleles was performed with SNP genotyping assays. The genotype and allele frequencies were compared between patients with AU and 206 healthy control subjects. Analyses were also stratified according to the HLA-B27 status of the patients. There were significant increases in the frequency of the AA homozygosity in the MnSOD 47 SNP (P = 0.049) and in the CCL2 -2518G allele frequency and GG homozygosity in patients with AU compared with control subjects (P = 0.017 and P = 0.024, respectively). No significant association was found between AU with the CCL2 -2076 and CCL5 -403 SNPs. Subgroup analyses showed that the MnSOD 47A polymorphism was significantly associated with AU in HLA-B27-positive patients, but not in HLA-B27-negative patients, whereas the CCL2 -2518G polymorphism was significantly associated with AU in HLA-B27-negative patients, but not in HLA-B27-positive patients. The 47A polymorphism in the MnSOD gene and the -2518G polymorphism in the CCL2 gene are associated with the development of AU in HLA-B27-positive and -negative Chinese patients, respectively. Further studies to evaluate the interactions of the HLA-B27 status and these SNPs are warranted.


Infusions of artichoke and milk thistle represent a good source of phenolic acids and flavonoids.
Cynara scolymus L. (artichoke) and Silybum marianum (L.) Gaertn (milk thistle) are two herbs well-known for their efficiency in the prevention/treatment of liver injuries, among other chronic diseases. Therefore, the aim of this work was to characterize specific bioactive components, phenolic compounds, in hydromethanolic extracts but also in infusions (the most commonly used preparations) obtained from the whole plant of milk thistle and artichoke. The phenolic profiles were accessed using HPLC-DAD-MS/ESI. Infusions of both species presented higher phenolic contents than the hydromethanolic extracts. Milk thistle presented a similar phenolic composition between the two preparations, revealing only differences in the quantities obtained. Nevertheless, artichoke revealed a slightly different profile considering infusion and hydromethanolic extracts. Apigenin-7-O-glucuronide was the major flavonoid found in milk thistle, while luteolin-7-O-glucuronide was the most abundant in artichoke. Therefore, infusions of both artichoke and milk thistle represent a good source of bioactive compounds, especially phenolic acids and flavonoids.


[Protective effect of Liuweidihuang Pills against cellphone electromagnetic radiation-induced histomorphological abnormality, oxidative injury, and cell apoptosis in rat testes].
To observe the effect of Liuweidihuang Pills in relieving cellphone electromagnetic radiation-induced histomorphological abnormality, oxidative injury, and cell apoptosis in the rat testis. Thirty adult male SD rats were equally randomized into a normal, a radiated, and a Liuweidihuang group, the animals in the latter two groups exposed to electromagnetic radiation of 900 MHz cellphone frequency 4 hours a day for 18 days. Meanwhile, the rats in the Liuweidihuang group were treated with the suspension of Liuweidihuang Pills at 1 ml/100 g body weight and the other rats intragastrically with the equal volume of purified water. Then all the rats were killed for observation of testicular histomorphology by routine HE staining, measurement of testicular malondialdehyde (MDA) and glutathione (GSH) levels by colorimetry, and determination of the expressions of bax and bcl-2 proteins in the testis tissue by immunohistochemistry. Compared with the normal controls, the radiated rats showed obviously loose structure, reduced layers of spermatocytes, and cavitation in the seminiferous tubules. Significant increases were observed in the MDA level (P < 0.01) and bax expression (P < 0.01) but decreases in the GSH level (P < 0.01) and bcl-2 expression (P < 0.01) in the testis issue of the radiated rats. In comparison with the radiated rats, those of the Liuweidihuang group exhibited nearly normal testicular structure, significantly lower MDA level (P < 0.05), bax expression (P < 0.01), and bcl-2 expression (P < 0.01). Liuweidihuang Pills can improve cellphone electromagnetic radiation-induced histomorphological abnormality of the testis tissue and reduce its oxidative damage and cell apoptosis.


Performance of an automated Q-beta replicase amplification assay for Mycobacterium tuberculosis in a clinical trial.
We present data from a clinical trial study in which an automated version (Galileo) of a previously described Q-Beta replicase-amplified probe assay (J. S. Shah et al., J. Clin. Microbiol. 33:1435-1441, 1995) was used for the direct detection of Mycobacterium tuberculosis complex in sputum. The assay was designed to target specific regions of 23S rRNA found in M. tuberculosis, Mycobacterium bovis, Mycobacterium africanum, and Mycobacterium microti and had a sensitivity ranging from approximately <10 to 300 CFU. The assay was tested for cross-hybridization by using large numbers (e.g., 10(5)to 10(10) CFU/assay) of 133 other organisms commonly found in respiratory tract samples, including non-M. tuberculosis Mycobacterium spp., other bacteria, fungi, and viruses. All of these competitors tested negative by the assay. Automated assay results for 780 respiratory tract samples (sputum or bronchoalveolar lavage specimens) collected and tested at three trial sites in the United States) were compared with the results of culture and acid-fast microscopy. Aliquots of conventionally digested and decontaminated sputum pellets were heated at 100 degrees C and mechanically disrupted prior to hybridization and background reduction, amplification, and detection in a closed disposable test pack. Pertinent elements of individual patient histories relating to tuberculosis exposure, previous active disease, antituberculosis therapy status, etc., were considered in the resolution of discrepant results for 48 (assay false-positive) samples. Seventy-one of 90 (78.9%) culture-positive samples were positive when tested in the Galileo assay, while 7% of culture-negative samples were assay positive, corresponding to a sensitivity of 79% and a specificity of 93%. Following resolution of discrepant results by chart review, the sensitivity and specificity for the Q-Beta replicase amplification assay with the Galileo analyzer were 84 and 97%, respectively. A total of 69.2% of smear-negative (culture positive) samples were detected by the assay. Ten test packs at a time were automatically processed by the Galileo analyzer without operator intervention following loading of samples. The first result was reported in approximately 3 h, and the last result was available in 6.5 h. To our knowledge, this is the first report of a clinical study with a fully automated amplification probe hybridization assay for the detection of pathogens directly from a clinical specimen.


The measured effect of delay in completing operative performance ratings on clarity and detail of ratings assigned.
Operative performance ratings (OPRs) need adequate clarity and detail to support self-directed learning and valid progress decisions. This study was designed to determine (1) the elapsed time between observing operative performances and completing performance ratings under field conditions and (2) the effect of increased elapsed time on rating clarity and detail. Overall, 895 OPRs by 19 faculty members for 37 general surgery residents were the focus of this study. The elapsed time between observing the performance and completing the evaluation was recorded. No-delay comparison data included 45 additional ratings of 8 performances collected under controlled conditions immediately following the performance by 17 surgeons whose sole responsibility was to observe and rate the performances. Item-to-item OPR variation and the presence and nature of comments were indicators of evaluation clarity, detail, and quality. Elapsed time between observing and evaluating performances under field conditions were as follows: 1 day or less, 116 performances (13%); 2 to 3 days, 178 performances (20%); 4 to 14 days, 377 performances (42%); and more than 14 days, 224 performances (25%). Overall, 87% of performances rated more than 14 days after observation had no item-to-item ratings variation compared with 62% rated with a delay of 4 to 14 days, 41% rated with a delay of 2 to 3 days, 42% rated within 1 day, and 2% rated immediately. In addition, 70% of ratings completed more than 14 days after observation had no written comments, compared with 49% for those completed with a delay of 4 to 14 days, 45% for those completed in 2 to 3 days, and 46% for those completed within 1 day. Moreover, 47% of comments submitted after more than 14 days were exclusively global comments (less instructionally useful) compared with 7% for those completed with a delay of 4 to 14 days and 5% for those completed in 1 to 3 days. The elapsed time between observation and rating of operative performances should be recorded. Immediate ratings should be encouraged. Ratings completed more than 3 days after observation should be discouraged and discounted, as they lack clarity and detail about the performance.


Repeated high-intensity exercise modulates Ca(2+) sensitivity of human skeletal muscle fibers.
The effects of short-term high-intensity exercise on single fiber contractile function in humans are unknown. Therefore, the purposes of this study were: (a) to access the acute effects of repeated high-intensity exercise on human single muscle fiber contractile function; and (b) to examine whether contractile function was affected by alterations in the redox balance. Eleven elite cross-country skiers performed four maximal bouts of 1300 m treadmill skiing with 45 min recovery. Contractile function of chemically skinned single fibers from triceps brachii was examined before the first and following the fourth sprint with respect to Ca(2+) sensitivity and maximal Ca(2+) -activated force. To investigate the oxidative effects of exercise on single fiber contractile function, a subset of fibers was incubated with dithiothreitol (DTT) before analysis. Ca(2+) sensitivity was enhanced by exercise in both MHC I (17%, P < 0.05) and MHC II (15%, P < 0.05) fibers. This potentiation was not present after incubation of fibers with DTT. Specific force of both MHC I and MHC II fibers was unaffected by exercise. In conclusion, repeated high-intensity exercise increased Ca(2+) sensitivity in both MHC I and MHC II fibers. This effect was not observed in a reducing environment indicative of an exercise-induced oxidation of the human contractile apparatus.


Asymptotic evolution of transient pulses undergoing stimulated Raman scattering.
Propagation of short, transient pulses undergoing stimulated Raman scattering over long length scales is considered. It is shown that under common experimental circumstances the evolution has two different regimes: an I regime, at short lengths, where the pump changes little and the Stokes rapidly grows, and a J regime, at long lengths, where the Stokes intensity is close to saturation and the pump intensity decreases slowly as the square root of distance. The distance at which the J regime is reached is determined numerically.


Variant fractional Fourier transformer for optical pulses.
We demonstrate that it is possible to perform a fractional Fourier transform of an incident pulse with a continuously variable degree of fractionality, using a dispersive and nonlinear Kerr medium. This medium acts as a linear waveguide for the optical pulse if its intensity is small and if the refractive index is nonlinearly time-dependently modified by a simultaneously launched bright soliton. For optical pulses the dispersive and nonlinear medium is perfectly equivalent to a graded-index refractive medium for optical beams.


Dual Simian Foamy Virus/Human Immunodeficiency Virus Type 1 Infections in Persons from Côte d'Ivoire.
Zoonotic transmission of simian retroviruses in West-Central Africa occurring in primate hunters has resulted in pandemic spread of human immunodeficiency viruses (HIVs) and human T-lymphotropic viruses (HTLVs). While simian foamy virus (SFV) and simian T- lymphotropic virus (STLV)-like infection were reported in healthy persons exposed to nonhuman primates (NHPs) in West-Central Africa, less is known about the distribution of these viruses in Western Africa and in hospitalized populations. We serologically screened for SFV and STLV infection using 1,529 specimens collected between 1985 and 1997 from Côte d'Ivoire patients with high HIV prevalence. PCR amplification and analysis of SFV, STLV, and HIV/SIV sequences from PBMCs was used to investigate possible simian origin of infection. We confirmed SFV antibodies in three persons (0.2%), two of whom were HIV-1-infected. SFV polymerase (pol) and LTR sequences were detected in PBMC DNA available for one HIV-infected person. Phylogenetic comparisons with new SFV sequences from African guenons showed infection likely originated from a Chlorocebus sabaeus monkey endemic to Côte d'Ivoire. 4.6% of persons were HTLV seropositive and PCR testing of PBMCs from 15 HTLV seroreactive persons identified nine with HTLV-1 and one with HTLV-2 LTR sequences. Phylogenetic analysis showed that two persons had STLV-1-like infections, seven were HTLV-1, and one was an HTLV-2 infection. 310/858 (53%), 8/858 (0.93%), and 18/858 (2.1%) were HIV-1, HIV-2, and HIV-positive but undifferentiated by serology, respectively. No SIV sequences were found in persons with HIV-2 antibodies (n = 1) or with undifferentiated HIV results (n = 7). We document SFV, STLV-1-like, and dual SFV/HIV infection in Côte d'Ivoire expanding the geographic range for zoonotic simian retrovirus transmission to West Africa. These findings highlight the need to define the public health consequences of these infections. Studying dual HIV-1/SFV infections in immunocompromised populations may provide a new opportunity to better understand SFV pathogenicity and transmissibility in humans.


Effects of β-Adrenoceptor and Catechol-O-Methyl-Transferase (COMT) Polymorphism on Postoperative Outcome in Cardiac Surgery Patients.
BACKGROUND There is a long-standing debate about the role of beta-adrenoceptor polymorphisms in the cardiovascular system. We wanted to elucidate whether β1-adrenoceptor-polymorphisms affects the postoperative catecholamine consumption and the length of intermediate care unit stay in patients undergoing cardiac surgery, and whether this might be enhanced or attenuated by catechol-O-methyl-transferase (COMT) polymorphism. MATERIAL AND METHODS We included 116 patients (63±1.2 years; 34% females; 81±1 kg) undergoing cardiac surgery. We assessed Arg389Gly and Ser49Gly-β1-adrenoceptor (B1AR) polymorphism together with Val158Met-COMT polymorphism by real-time PCR using fluorescence resonance energy transfer (PCR-FRET). The preoperative risk was assessed by EuroSCORE. In addition, we measured the endogenous preoperative epinephrine and norepinephrine plasma concentrations using an electrochemical HPLC method. RESULTS 84.6% were homozygous for Ser49Ser, 52.1% homozygous for Arg389Arg B1AR, and 32.5% for Val158Val-COMT, while 15.4% showed Ser49Gly B1AR, 38.5% Arg389Gly-B1AR, and 35.6% Val158Met-COMT. We found that the Gly49-variant, the Gly389-variant, and the Val158-COMT-variant were associated with higher postoperative norepinephrine consumption. All patients carrying the Val158-COMT allele exhibited higher preoperative norepinephrine concentrations. Moreover, we found that both β1-adrenoceptor polymorphisms were associated with a longer stay in hospital, which was modulated by the COMT polymorphism. CONCLUSIONS These data show that the β1-adrenoceptor polymorphisms, together with the COMT polymorphism, affect norepinephrine consumption and stay in hospital in a situation of enhanced cardiovascular stress, reflected here by the postoperative period after cardiac surgery. Moreover, we conclude that patients with the Val158-COMT genotype exhibit higher endogenous resting plasma norepinephrine levels.


Use of an excision reporter plasmid to study the intracellular mobility of the conjugative transposon Tn916 in gram-positive bacteria.
An excision reporter plasmid was constructed to characterize the intracellular mobility of Tn916 in various Gram-positive bacteria. The reporter component of this plasmid is a chloramphenicol-resistance gene which has been insertionally inactivated with the integrative vector pAT112 containing the attachment site of Tn916. Tn916-mediated excision of pAT112, to produce clones resistant to chloramphenicol, was detected in Enterococcus faecalis BM4110, Listeria monocytogenes L028-Str and Streptococcus gordonii BM120, but not in Lactococcus lactis MG1363-RF or in Streptococcus pneumoniae BM124, and always depended upon the ability of the bacterial host to generate circular forms of the transposon. The results suggest that (i) the excision event, although required, is not sufficient for conjugal transfer to occur and (ii) there is no linear relationship between the donor potential of E. faecalis strains and either the excision frequency of pAT112 or the copy number of Tn916 circular intermediates per cell in these hosts. Excision of pAT112 occurred mainly during the late exponential phase of growth of E. faecalis and L. monocytogenes and this recombination event was not stimulated by heat shock, salt and alcohol stresses or by the presence of tetracycline in the medium.


Development of the Microbiota and Associations With Birth Mode, Diet, and Atopic Disorders in a Longitudinal Analysis of Stool Samples, Collected From Infancy Through Early Childhood.
Establishment of the gastrointestinal microbiota during infancy affects immune system development and oral tolerance induction. Perturbations in the microbiome during this period can contribute to development of immune-mediated diseases. We monitored microbiota maturation and associations with subsequent development of allergies in infants and children. We collected 1453 stool samples, at 5, 13, 21, and 31 weeks postpartum (infants), and once at school age (6-11 years), from 440 children (49.3% girls, 24.8% born by cesarean delivery; all children except for 6 were breastfed for varying durations; median 40 weeks; interquartile range, 30-53 weeks). Microbiota were analyzed by amplicon sequencing. Children were followed through 3 years of age for development of atopic dermatitis; data on allergic sensitization and asthma were collected when children were school age. Diversity of fecal microbiota, assessed by Shannon index, did not differ significantly among children from 5 through 13 weeks after birth, but thereafter gradually increased to 21 and 31 weeks. Most bacteria within the Bacteroidetes and Proteobacteria phyla were already present at 5 weeks after birth, whereas many bacteria of the Firmicutes phylum were acquired at later times in infancy. At school age, many new Actinobacteria, Firmicutes, and Bacteroidetes bacterial taxa emerged. The largest increase in microbial diversity occurred after 31 weeks. Vaginal, compared with cesarean delivery, was most strongly associated with an enrichment of Bacteroides species at 5 weeks through 31 weeks. From 13 weeks onward, diet became the most important determinant of microbiota composition; cessation of breastfeeding, rather than solid food introduction, was associated with changes. For example, Bifidobacteria, staphylococci, and streptococci significantly decreased on cessation of breastfeeding, whereas bacteria within the Lachnospiraceae family (Pseudobutyrivibrio, Lachnobacterium, Roseburia, and Blautia) increased. When we adjusted for confounding factors, we found fecal microbiota composition to be associated with development of atopic dermatitis, allergic sensitization, and asthma. Members of the Lachnospiraceae family, as well as the genera Faecalibacterium and Dialister, were associated with a reduced risk of atopy. In a longitudinal study of fecal microbiota of children from 5 weeks through 6 to 11 years, we tracked changes in diversity and composition associated with the development of allergies and asthma.


Porphyromonas Gingivalis Infection Induces Synaptic Failure via Increased IL-1β Production in Leptomeningeal Cells.
Studies have reported that synaptic failure occurs before the Alzheimer's disease (AD) onset. The systemic Porphyromonas gingivalis (P. gingivalis) infection is involved in memory decline. We previously showed that leptomeningeal cells, covering the brain, activate glial cells by releasing IL-1β in response to systemic inflammation. In the present study, we focused on the impact of leptomeningeal cells on neurons during systemic P. gingivalis infection. The responses of leptomeningeal cells and cortical neurons to systemic P. gingivalis infection were examined in 15-month-old mice. The mechanism of IL-1β production by P. gingivalis infected leptomeningeal cells was examined, and primary cortical neurons were treated with P. gingivalis infected leptomeningeal cells condition medium (Pg LCM). Systemic P. gingivalis infection increased the expression of IL-1β in leptomeninges and reduced the synaptophysin (SYP) expression in leptomeninges proximity cortex in mice. Leptomeningeal cells phagocytosed P. gingivalis resulting in lysosomal rupture and cathepsin B (CatB) leakage. Leaked CatB mediated NLRP3 inflammasome activation inducing IL-1β secretion in leptomeningeal cells. Pg LCM decreased the expression of synaptic molecules, including SYP, which was inhibited by an IL-1 receptor antagonist pre-treatment. These observations demonstrate that P. gingivalis infection is involved in synaptic failure by inducing CatB/NLRP3 inflammasome-mediated IL-1β production in leptomeningeal cells. The periodontal bacteria-induced synaptic damage may accelerate the onset and cognitive decline of AD.


Mobile phone use among patients and health workers to enhance primary healthcare: A qualitative study in rural South Africa.
Mobile phones have the potential to improve access to healthcare information and services in low-resourced settings. This study investigated the use of mobile phones among patients with chronic diseases, pregnant women, and health workers to enhance primary healthcare in rural South Africa. Qualitative research was undertaken in Mpumalanga in 2014. Semi structured in-depth interviews were conducted with 113 patients and 43 health workers from seven primary healthcare clinics and one district hospital. Data were thematically analysed. We found that some health workers and patients used their own mobile phones for healthcare, bearing the cost themselves. Patients used their mobile phones to remind themselves to take medication or attend their clinic visits, and they appreciated receiving voice call reminders. Some patients and health workers accessed websites and used social media to gather health information, but lacked web search strategies. The use of the websites and social media was intermittent due to lack of financial ability to afford airtime among these patients and health workers. Many did not know what to search for and where to search. Doctors have developed their own informal mobile health solutions in response to their work needs and lack of resources due to their rurality. Physical and social factors influence the usability of mobile phones for healthcare, and this can shape communication patterns such as poor eyesight. The bottom-up use of mobile phones has been evolving to fill the gaps to augment primary care services in South Africa; however, barriers to access remain, such as poor digital infrastructure and low digital literacy.


Antibodies to human papillomavirus 16 and subsequent in situ or invasive cancer of the cervix.
Our objective was to examine whether past infection with human papillomavirus (HPV)-16, as determined by an antibody assay, is a risk factor for subsequent cervical cancer. Incident cases of in situ or invasive cervical cancer occurring between 1975 and 1990 in a cohort of over 11,000 healthy women in Washington County, MD, were identified. The baseline sera of cases and of matched controls, collected in 1974, were examined for IgG antibodies reactive with virus-like particles of HPV-16, a cancer-associated HPV, and HPV-6, a low-risk HPV. Postdiagnosis sera of 11 cases were also assessed similarly. Fourteen cases of invasive and 28 cases of in situ cervical cancer and 83 matched controls were evaluated. The main outcome measure was the risk of cervical cancer in women who had HPV-16 or HPV-6 antibodies in prediagnostic sera. Antibodies to HPV-16 but not to HPV-6 were a marker for subsequent occurrence of cervical cancer. Case sera were reactive more often and more strongly with HPV-16 virus-like particles than were sera of matched controls. The presence of antibodies to HPV-16 was significantly associated with an increased risk of cervical cancer (odds ratio, 3.9; 95% confidence limits, 1.4, 10.7); high antibody levels to HPV-16 were associated with an even greater risk of cervical cancer (odds ratio = 7.5, 95% confidence limits 1.5, 36.3). The association with cervical cancer was strengthened after adjustment for smoking and years of education. In tests of 11 pairs of pre- and postdiagnostic sera, HPV-16 antibodies did not decline markedly over a 7-13-year time period, and seroconversion to HPV-16 appeared to have occurred in 2 cases. The serological data indicate that HPV-16 infection is associated with future risk of cervical cancer and strengthen the evidence for the etiological role of HPVs in cervical cancer.


Effect of Training Pediatric Clinicians in Human Papillomavirus Communication Strategies on Human Papillomavirus Vaccination Rates: A Cluster Randomized Clinical Trial.
Missed opportunities for human papillomavirus (HPV) vaccination during pediatric health care visits are common. To evaluate the effect of online communication training for clinicians on missed opportunities for HPV vaccination rates overall and at well-child care (WCC) visits and visits for acute or chronic illness (hereafter referred to as acute or chronic visits) and on adolescent HPV vaccination rates. From December 26, 2018, to July 30, 2019, a longitudinal cluster randomized clinical trial allocated practices to communication training vs standard of care in staggered 6-month periods. A total of 48 primary care pediatric practices in 19 states were recruited from the American Academy of Pediatrics Pediatric Research in Office Settings network. Participants were clinicians in intervention practices. Outcomes were evaluated for all 11- to 17-year-old adolescents attending 24 intervention practices (188 clinicians) and 24 control practices (177 clinicians). Analyses were as randomized and performed on an intent-to-treat basis, accounting for clustering by practice. Three sequential online educational modules were developed to help participating clinicians communicate with parents about the HPV vaccine. Weekly text messages were sent to participating clinicians to reinforce learning. Statisticians were blinded to group assignment. Main outcomes were missed opportunities for HPV vaccination overall and for HPV vaccine initiation and subsequent doses at WCC and acute or chronic visits (visit-level outcome). Secondary outcomes were HPV vaccination rates (person-level outcome). Outcomes were compared during the intervention vs baseline. Altogether, 122 of 188 clinicians in intervention practices participated; of these, 120, 119, and 116 clinicians completed training modules 1, 2, and 3, respectively. During the intervention period, 29 206 adolescents (14 664 girls [50.2%]; mean [SD] age, 14.2 [2.0] years) made 15 888 WCC and 28 123 acute or chronic visits to intervention practices; 33 914 adolescents (17 069 girls [50.3%]; mean [SD] age, 14.2 [2.0] years) made 17 910 WCC and 35 281 acute or chronic visits to control practices. Intervention practices reduced missed opportunities overall by 2.4 percentage points (-2.4%; 95% CI, -3.5% to -1.2%) more than controls. Intervention practices reduced missed opportunities for vaccine initiation during WCC visits by 6.8 percentage points (-6.8%; 95% CI, -9.7% to -3.9%) more than controls. The intervention had no effect on missed opportunities for subsequent doses of the HPV vaccine or at acute or chronic visits. Adolescents in intervention practices had a 3.4-percentage point (95% CI, 0.6%-6.2%) greater improvement in HPV vaccine initiation compared with adolescents in control practices. This scalable, online communication training increased HPV vaccination, particularly HPV vaccine initiation at WCC visits. Results support dissemination of this intervention. ClinicalTrials.gov Identifier: NCT03599557.


Effect of intentional bias on agency attribution of animated motion: an event-related fMRI study.
Animated movements of simple geometric shapes can readily be interpreted as depicting social events in which animate agents are engaged in intentional activity. However, the brain regions associated with such intention have not been clearly elucidated. In this study, intentional bias was manipulated using shape and pattern animations while measuring associated brain activity using event-related functional magnetic resonance imaging (fMRI). Twenty-five higher-intention involved and twenty-five lower-intention involved animations were presented to participants. Behavioral results showed that the degree of agency attribution of the mental state increased as intentional involvement increased. fMRI results revealed that the posterior superior temporal sulcus (STS), inferior temporal gyrus (ITG), inferior frontal gyrus (IFG), premotor, temporal pole, supramarginal gyrus, and superior parietal lobule (SPL) were activated while participants viewed the high-intention animations. In contrast, occipital, lingual, and middle frontal gyri were activated while the participants viewed the low-intention animations. These findings suggest that as agent attribution increases, the visual brain changes its functional role to the intentional brain and becomes a flexible network for processing information about social interaction.


Effects of using four baskets during simulated youth basketball games.
This study aimed to identify how playing basketball with two additional baskets influences the players' technical, physiological, physical and especially, positional performance. Fourteen youth players performed eight 5vs.5 simulated basketball games, four with the two official baskets and four with two-extra official baskets, each one placed in the court restricted area. The variables collected were technical (field-goals made and missed, offensive and defensive rebounds, steals, passes, dribble-drive, give-and-go and ball possessions), physiological (heart rate monotony and sample entropy), workload (total distance covered and distance covered at different velocities) and positioning-related (distance to the nearest opponent, distance to the nearest teammate, stretch-index and distance between centroids). The results showed that the four-baskets games favoured the emergence of individual behaviours, increasing the game' physical demands and promoting a collective dispersion, which might impair team playing. Conversely, when playing with two-baskets, there was less distance between teammates. In conclusion, this study has clear implications for practice as it emphasizes that coaches can manipulate the number of baskets to modulate training workload and promote different individual and team behaviours.


The combined effect of clothianidin and environmental stress on the behavioral and reproductive function in male mice.
Neonicotinoids, some of the most widely used pesticides in the world, act as agonists to the nicotinic acetylcholine receptors (nAChRs) of insects, resulting in death from abnormal excitability. Neonicotinoids unexpectedly became a major topic as a compelling cause of honeybee colony collapse disorder, which is damaging crop production that requires pollination worldwide. Mammal nAChRs appear to have a certain affinity for neonicotinoids with lower levels than those of insects; there is thus rising concern about unpredictable adverse effects of neonicotinoids on vertebrates. We hypothesized that the effects of neonicotinoids would be enhanced under a chronic stressed condition, which is known to alter the expression of targets of neonicotinoids, i.e., neuronal nAChRs. We performed immunohistochemical and behavioral analyses in male mice actively administered a neonicotinoid, clothianidin (CTD; 0, 10, 50 and 250 mg/kg/day), for 4 weeks under an unpredictable chronic stress procedure. Vacuolated seminiferous epithelia and a decrease in the immunoreactivity of the antioxidant enzyme glutathione peroxidase 4 were observed in the testes of the CTD+stress mice. In an open field test, although the locomotor activities were not affected, the anxiety-like behaviors of the mice were elevated by both CTD and stress. The present study demonstrates that the behavioral and reproductive effects of CTD become more serious in combination with environmental stress, which may reflect our actual situation of multiple exposure.


Enabling the participation of marginalized populations: case studies from a health service organization in Ontario, Canada.
We examined efforts to engage marginalized populations in Ontario Community Health Centers (CHCs), which are primary health care organizations serving 74 high-risk communities. Qualitative case studies of community participation in four Ontario CHCs were carried out through key informant interviews with CHC staff to identify: (i) the approaches, strategies and methods used in participation initiatives aimed specifically at engaging marginalized populations in the planning of and decision making for health services; and (ii) the challenges and enablers for engaging these populations. The marginalized populations involved in the community participation initiatives studied included Low-German Speaking Mennonites in a rural town, newcomer immigrants and refugees in an urban downtown city, immigrant and francophone seniors in an inner city and refugee women in an inner city. Our analysis revealed that enabling the participation of marginalized populations requires CHCs to attend to the barriers experienced by marginalized populations that constrain their participation. Key informants outlined the features of a 'community development approach' that they rely on to address the barriers to marginalized peoples' involvement by strengthening their skills, abilities and leadership in capacity-building activities. The community development approach also shaped the participation methods that were used in the engagement process of CHCs. However, key informants also described the challenges of applying this approach, influenced by the cultural values of some groups, which shaped their willingness and motivation to participate. This study provides further insight into the approach, strategies and methods used in the engagement process to enable the participation of marginalized populations, which may be transferable to other health services settings.


Risk of preterm birth after the excisional surgery for cervical lesions: a propensity-score matching study in Japan.
There is a paucity of data on the risk of preterm birth subcategorized by gestational age in pregnancies after the pre-pregnancy excisional treatment for cervical lesions. In addition, little is known about the effect of prophylactic cerclage on the risk of preterm birth. The aim of this study was to investigate the risk of preterm birth stratified by gestational period and its reduction by the prophylactic cerclage in women with prior excisional surgery. We retrospectively analyzed a cohort of singleton pregnancies in the Japan Perinatal Registry Network Database (2013-2014, n = 307,001). Cases included pregnancies after the surgery (i.e. conization and loop electrosurgical excision procedure). Controls comprised the propensity-score matched pregnancies without pre-pregnancy surgery. The main outcome was the occurrence of preterm birth. The effect of prophylactic cervical cerclage on the risk of preterm birth after the excisional surgery was also examined using cases. In the propensity-score matched population (cases, n = 1389; controls, n = 1389), cases exhibited a higher risk of preterm birth and preterm prelabor rupture of membranes (PROM), compared with controls (preterm birth: 25.3 versus 10.6%; preterm PROM: 14.0 versus 3.5%: both p < .0001). Odds ratios (OR; 95% confidence interval [CI]) for preterm birth at 22-27 weeks, 28-31 weeks, 32-33 weeks, and 34-36 weeks were 3.4 [1.8-6.5], 4.6 [2.7-7.7], 2.2 [1.4-3.5], and 2.1 [1.6-2.7], respectively. The association was stronger for preterm PROM at earlier gestational age (22-27 weeks, 28-31 weeks, 32-33 weeks, and 34-36 weeks: 5.2 [2.3-11.8], 7.1 [3.4-15.0], 3.8 [1.7-8.3], and 3.9 [1.8-4.6], respectively). In cases, 171 underwent the prophylactic cervical cerclage. The occurrence of preterm birth and preterm PROM was comparable between those with and without the cerclage (28.7 versus 24.2, and 12.9 versus 13.3%, respectively). Pre-pregnancy excisional cervical surgery was associated with the increased risk of preterm birth, especially before 32 weeks of gestation. The prophylactic cerclage did not reduce the risk of preterm birth.


Incidence of surgical site infection in dogs undergoing soft tissue surgery: risk factors and economic impact.
To determine (1) the incidence of surgical site infection (SSI) in patients undergoing soft tissue surgery at a veterinary teaching hospital and to study (2) and describe the main risk factors associated with SSI and (3) assess the economic impact of SSI. Prospective cohort study. Veterinary teaching hospital. 184 dogs undergoing soft tissue surgery during a 12-month period (October 2013 to September 2014). Surgical site infection. Out of the 184 patients analysed, SSI was diagnosed in 16 (8.7 per cent) patients, 13 (81.3 per cent) were classified as superficial incisional infection, 2 (12.5 per cent) as deep incisional infection and 1 (6.3 per cent) as organ/space infection. The administration of steroidal anti-inflammatory drugs (P=0.028), preoperative hyperglycaemia (P=0.015), surgical times longer than 60 minutes (P=0.013), urinary catheterisation (P=0.037) and wrong use of the Elizabethan collar (P=0.025) were identified as risk factors. Total costs increased 74.4 per cent, with an increase in postsurgical costs of 142.2 per cent. The incidence of SSI was higher than the incidence reported in other published studies, although they were within expected ranges when a surveillance system was implemented. This incidence correlated with an increase in costs. Additionally new important risk factors for its development were detected.


Ion pairs in non-redundant protein structures.
Ion pairs contribute to several functions including the activity of catalytic triads, fusion of viral membranes, stability in thermophilic proteins and solvent-protein interactions. Furthermore, they have the ability to affect the stability of protein structures and are also a part of the forces that act to hold monomers together. This paper deals with the possible ion pair combinations and networks in 25% and 90% non-redundant protein chains. Different types of ion pairs present in various secondary structural elements are analysed. The ion pairs existing between different subunits of multisubunit protein structures are also computed and the results of various analyses are presented in detail. The protein structures used in the analysis are solved using X-ray crystallography, whose resolution is better than or equal to 1.5 A and R-factor better than or equal to 20%. This study can, therefore, be useful for analyses of many protein functions. It also provides insights into the better understanding of the architecture of protein structure.


Atomic quantum simulation of dynamical gauge fields coupled to fermionic matter: from string breaking to evolution after a quench.
Using a Fermi-Bose mixture of ultracold atoms in an optical lattice, we construct a quantum simulator for a U(1) gauge theory coupled to fermionic matter. The construction is based on quantum links which realize continuous gauge symmetry with discrete quantum variables. At low energies, quantum link models with staggered fermions emerge from a Hubbard-type model which can be quantum simulated. This allows us to investigate string breaking as well as the real-time evolution after a quench in gauge theories, which are inaccessible to classical simulation methods.


Detection of hydrogen peroxide-producing Lactobacillus species in the vagina: a comparison of culture and quantitative PCR among HIV-1 seropositive women.
The presence of hydrogen peroxide (H(2)O(2)) producing Lactobacillus in the vagina may play a role in controlling genital HIV-1 shedding. Sensitive molecular methods improve our ability to characterize the vaginal microbiota; however, they cannot characterize phenotype. We assessed the concordance of H(2)O(2)-producing Lactobacillus detected by culture with quantitative PCR (qPCR) detection of Lactobacillus species commonly assumed to be H(2)O(2)-producers. Samples were collected as part of a prospective cohort study of HIV-1 seropositive US women. Cervicovaginal lavage specimens were tested for L. crispatus and L. jensenii using 16S rRNA gene qPCR assays. Vaginal swabs were cultured for Lactobacillus and tested for H(2)O(2)-production. We calculated a kappa statistic to assess concordance between culture and qPCR. Culture and qPCR results were available for 376 visits from 57 women. Lactobacilli were detected by culture at 308 (82%) visits, of which 233 of 308 (76%) produced H(2)O(2). L. crispatus and/or L. jensenii were detected at 215 (57%) visits. Concordance between detection of L. crispatus and/or L. jensenii by qPCR and H(2)O(2)-producing Lactobacillus by culture was 75% (kappa = 0.45). Among HIV-1 seropositive women, there was a moderate level of concordance between H(2)O(2)-producing Lactobacillus detected by culture and the presence of L. crispatus and/or L. jensenii by qPCR. However, one-quarter of samples with growth of H(2)O(2)-producing lactobacilli did not have L. crispatus or L. jensenii detected by qPCR. This discordance may be due to the presence of other H(2)O(2)-producing Lactobacillus species.


Thyroid Autoimmunity: An Interplay of Factors.
The literature on thyroid autoimmunity has identified many potential factors at play for the initiation and progression of autoimmune thyroid diseases. These factors include genetic susceptibility, environmental factors, some drugs, iodine and selenium, infection, molecular mimics, and immune system defects. The sheer number of feasible factors makes sorting out the necessary agents from the fellow travelers difficult. In addition, many of these factors have the capability to interact-further confusing the picture. Another difficulty in interpreting these data is that most proposed mechanisms are not able to accomplish the triggering event in which the tolerance to self-antigens is actually overcome. In addition, some findings may be describing the conditions present after a disease is diagnosed and may be consequences of the disease rather than a cause. Recent description of the role of adipokines, which include leptin, tumor necrosis factor-alpha, and interleukin-6, in contributing to the inflammatory environment of the thyroid, along with the presence of thyroid Toll-like receptors for pathogen-associated patterns have the potential to deliver that necessary adjuvant signal to break tolerance, seen as necessary in animal autoimmune models. An additional factor, vitamin D3, due to its interaction both with white adipose tissue (WAT) and the immune system, has a complicated and somewhat controversial story with respect to thyroid autoimmunity. Conflicting results can result when not all factors are considered together. To describe the many factors at play in thyroid autoimmunity and how they interact. Thyroid autoimmunity is the result of an interplay of factors, with adipokines produced by WAT and vitamin D providing immune modulating signals external to the thyroid, while thyrocyte innate responses to environmental conditions provide the necessary adjuvant signal. Shaping the response to be reactive to particular self-antigens and likelihood of a response are due to genetics and molecular mimics.


Coffee consumption and risk of type 2 diabetes: a systematic review.
Emerging epidemiological evidence suggests that higher coffee consumption may reduce the risk of type 2 diabetes. To examine the association between habitual coffee consumption and risk of type 2 diabetes and related outcomes. We searched MEDLINE through January 2005 and examined the reference lists of the retrieved articles. Because this review focuses on studies of habitual coffee consumption and risk of type 2 diabetes, we excluded studies of type 1 diabetes, animal studies, and studies of short-term exposure to coffee or caffeine, leaving 15 epidemiological studies (cohort or cross-sectional). Information on study design, participant characteristics, measurement of coffee consumption and outcomes, adjustment for potential confounders, and estimates of associations was abstracted independently by 2 investigators. We identified 9 cohort studies of coffee consumption and risk of type 2 diabetes, including 193 473 participants and 8394 incident cases of type 2 diabetes, and calculated summary relative risks (RRs) using a random-effects model. The RR of type 2 diabetes was 0.65 (95% confidence interval [CI], 0.54-0.78) for the highest (>or=6 or >or=7 cups per day) and 0.72 (95% CI, 0.62-0.83) for the second highest (4-6 cups per day) category of coffee consumption compared with the lowest consumption category (0 or <or=2 cups per day). These associations did not differ substantially by sex, obesity, or region (United States and Europe). In the cross-sectional studies conducted in northern Europe, southern Europe, and Japan, higher coffee consumption was consistently associated with a lower prevalence of newly detected hyperglycemia, particularly postprandial hyperglycemia. This systematic review supports the hypothesis that habitual coffee consumption is associated with a substantially lower risk of type 2 diabetes. Longer-term intervention studies of coffee consumption and glucose metabolism are warranted to examine the mechanisms underlying the relationship between coffee consumption and type 2 diabetes.


Feasibility of Left Atrial Appendage Occlusion for Left Atrial Appendage Thrombus in Patients With Persistent Atrial Fibrillation.
This study sought to investigate the safety of percutaneous left atrial appendage (LAA) occlusion for stroke prevention in patients with nonvalvular atrial fibrillation who have LAA thrombus. From October 2010 to October 2016, LAA occlusions were performed in facilities within a Korean multicenter registry in patients without (n = 132) or with (n = 10) LAA thrombus (detected during preprocedural assessments). The incidences of periprocedural complications, including stroke, pericardial tamponade, major bleeding, and device embolization, were assessed and compared between the groups. The incidence of periprocedural complications was not significantly different between patients with and without LAA thrombus (0% vs 5% [6 of 132]; p = 0.49). During the mean 23.2 ± 17.5-month follow-up duration, 7 major adverse cardiac events occurred (1 cardiovascular death, 6 ischemic strokes), but overall event rates were not significantly different between the groups (14% vs 9%; p = 0.47). In conclusion, percutaneous LAA occlusion in nonvalvular atrial fibrillation patients with LAA thrombus may be a safe and feasible alternative to anticoagulation in select patients at a high risk of bleeding or contraindication to anticoagulation, or in whom anticoagulation failed to prevent stroke.


Evaluation of NCI-7 Cell Line Panel as a Reference Material for Clinical Proteomics.
Reference materials are vital to benchmarking the reproducibility of clinical tests and essential for monitoring laboratory performance for clinical proteomics. The reference material utilized for mass spectrometric analysis of the human proteome would ideally contain enough proteins to be suitably representative of the human proteome, as well as exhibit a stable protein composition in different batches of sample regeneration. Previously, The Clinical Proteomic Tumor Analysis Consortium (CPTAC) utilized a PDX-derived comparative reference (CompRef) materials for the longitudinal assessment of proteomic performance; however, inherent drawbacks of PDX-derived material, including extended time needed to grow tumors and high level of expertise needed, have resulted in efforts to identify a new source of CompRef material. In this study, we examined the utility of using a panel of seven cancer cell lines, NCI-7 Cell Line Panel, as a reference material for mass spectrometric analysis of human proteome. Our results showed that not only is the NCI-7 material suitable for benchmarking laboratory sample preparation methods, but also NCI-7 sample generation is highly reproducible at both the global and phosphoprotein levels. In addition, the predicted genomic and experimental coverage of the NCI-7 proteome suggests the NCI-7 material may also have applications as a universal standard proteomic reference.


Low haemoglobin predicts early mortality among adults starting antiretroviral therapy in an HIV care programme in South Africa: a cohort study.
Antiretroviral therapy (ART) has dramatically reduced morbidity and mortality among people with HIV infection; however, mortality after the start of ART is high in resource-limited settings. We investigated risk factors for mortality among adults starting ART in a multi-clinic community programme in South Africa. Cohort of adults starting ART at 27 clinics between February 2005 and June 2006, followed to 31st March 2007. Kaplan-Meier survival estimates were used to describe overall mortality. Shared frailty Cox regression was used to identify baseline risk factors for early mortality. Among 1350 participants (median age 35.5 years, 60% female, median CD4 count 83/microL [interquartile range (27-147)], median follow-up 13.4 months), there were 185 deaths, overall mortality rate 13/100 pyrs; for 0-3, 3-9 and >9 months from ART start mortality rates were 24, 13 and 6/100 pyrs respectively. 43% of the deaths were in the first 3 months of treatment. Risk factors for mortality in univariable analysis were baseline CD4 count, viral load, haemoglobin and body mass index, in multivariable analysis adjusting for age and gender, only CD4 count and haemoglobin remained independently associated with proportional hazards not being satisfied for haemoglobin. Adjusted hazard ratios (aHR) for participants with haemoglobin <8, 8.1-9.9, >11.9(f)/12.9 (m) g/mL were 4.99, 3.05 and 0.12 respectively comparing to 10-11.9 (f)/12.9 (m)g/mL in the first 3 months of ART. aHRs for CD4 counts were 0.40, 0.38 and 0.34 for 50-99, 100-200 and >200/microL comparing to <50/microL. The high mortality rate in the first 3 months underlines the need for earlier HIV diagnosis so that ART can be initiated earlier. Low haemoglobin and low CD4 count are both strong predictors of mortality, and could be used to identify individuals at high risk who might benefit from intensive case management.


Motion sensing superpixels (MOSES) is a systematic computational framework to quantify and discover cellular motion phenotypes.
Correct cell/cell interactions and motion dynamics are fundamental in tissue homeostasis, and defects in these cellular processes cause diseases. Therefore, there is strong interest in identifying factors, including drug candidates that affect cell/cell interactions and motion dynamics. However, existing quantitative tools for systematically interrogating complex motion phenotypes in timelapse datasets are limited. We present Motion Sensing Superpixels (MOSES), a computational framework that measures and characterises biological motion with a unique superpixel 'mesh' formulation. Using published datasets, MOSES demonstrates single-cell tracking capability and more advanced population quantification than Particle Image Velocimetry approaches. From > 190 co-culture videos, MOSES motion-mapped the interactions between human esophageal squamous epithelial and columnar cells mimicking the esophageal squamous-columnar junction, a site where Barrett's esophagus and esophageal adenocarcinoma often arise clinically. MOSES is a powerful tool that will facilitate unbiased, systematic analysis of cellular dynamics from high-content time-lapse imaging screens with little prior knowledge and few assumptions.


Neuroanatomical correlates of prion disease progression - a 3T longitudinal voxel-based morphometry study.
MRI has become an essential tool for prion disease diagnosis. However there exist only a few serial MRI studies of prion patients, and these mostly used whole brain summary measures or region of interest based approaches. We present here the first longitudinal voxel-based morphometry (VBM) study in prion disease. The aim of this study was to systematically characterise progressive atrophy in patients with prion disease and identify whether atrophy in specific brain structures correlates with clinical assessment. Twenty-four prion disease patients with early stage disease (3 sporadic, 2 iatrogenic, 1 variant and 18 inherited CJD) and 25 controls were examined at 3T with a T1-weighted 3D MPRAGE sequence at multiple time-points (2-6 examinations per subject, interval range 0.1-3.2 years). Longitudinal VBM provided intra-subject and inter-subject image alignment, allowing voxel-wise comparison of progressive structural change. Clinical disease progression was assessed using the MRC Prion Disease Rating Scale. Firstly, in patients, we determined the brain regions where grey and white matter volume change between baseline and final examination correlated with the corresponding change in MRC Scale score. Secondly, in the 21/24 patients with interscan interval longer than 3 months, we identified regions where annualised rates of regional volume change in patients were different from rates in age-matched controls. Given the heterogeneity of the cohort, the regions identified reflect the common features of the different prion sub-types studied. In the patients there were multiple regions where volume loss significantly correlated with decreased MRC scale, partially overlapping with anatomical regions where yearly rates of volume loss were significantly greater than controls. The key anatomical areas involved included: the basal ganglia and thalamus, pons and medulla, the hippocampal formation and the superior parietal lobules. There were no areas demonstrating volume loss significantly higher in controls than patients or negative correlation between volume and MRC Scale score. Using 3T MRI and longitudinal VBM we have identified key anatomical regions of progressive volume loss which correlate with an established clinical disease severity index and are relevant to clinical deterioration. Localisation of the regions of progressive brain atrophy correlating most strongly with clinical decline may help to provide more targeted imaging endpoints for future clinical trials.


Differential expression of connexin 43 in mouse mammary cells.
In this study we have employed suppressive subtractive hybridization (SSH) analysis to investigate differential gene expression in primary mouse mammary epithelial cells (PMMEC) cultured under mildly apoptotic/quiescent and differentiating conditions. Among a small group of genes whose expression was differentially regulated was connexin 43. In vitro, connexin 43 mRNA and protein were detectable in PMMEC cultured under proliferative or mildly apoptotic conditions. The level of connexin 43 mRNA expression in vivo was also investigated. High levels of expression were found to be associated with the periods of greatest glandular plasticity (pubertal expansion of the mammary tree, early pregnancy and during early involution). Thus, terminally differentiated cells in vivo and in vitro did not express connexin 43 mRNA suggesting that connexin 43 expression, and perhaps facilitated gap junction communication, is associated with undifferentiated progenitor cell populations.


Analytical asymptotic solutions of nA+mB-->C reaction-diffusion equations in two-layer systems: a general study.
Large time evolution of concentration profiles is studied analytically for reaction-diffusion systems where the reactants A and B are each initially separately contained in two immiscible solutions and react upon contact and transfer across the interface according to a general nA+mB-->C reaction scheme. This study generalizes to immiscible two-layer systems the large time analytical asymptotic limits of concentrations derived by Koza [J. Stat. Phys. 85, 179 (1996)] for miscible fluids and for reaction rates of the form A;{n}B;{m} with arbitrary diffusion coefficients and homogeneous initial concentrations. In addition to a dependence on the parameters already characterizing the miscible case, the asymptotic concentration profiles in immiscible systems depend now also on the partition coefficients of the chemical species between the two solution layers and on the ratio of diffusion coefficients of a given species in the two fluids. The miscible time scalings are found to remain valid for the immiscible fluids case. However, for immiscible systems, the reaction front speed is enhanced by increasing the stoichiometry of the invading species over that of the species being invaded. The direction of the front propagation is found to depend on the diffusion coefficient of the invading species in its initial fluid but not on its value in the invading fluid. Hence, a reaction front in immiscible fluids can travel in the opposite direction to the reaction front formed in miscible fluids for a range of parameter values. The value of the invading species partition coefficient affects the magnitude of the front speed but it cannot alter the direction of the front. For sufficiently large times, the total amount of product produced in time is independent of the rate of the reaction. The centre of mass of the product can move in the opposite direction to the center of mass of the reaction rate.


Vaterite: a mineralization product of the hard tissues of a marine organism (Ascidiacea).
X-ray diffraction and infrared absorption spectra show that the spicules of the common tropical ascidian, Herdmania momus, are mineralized with vaterite. These are the first strictly marine organisms known to normally precipitate vaterite. The biomineralization of vaterite may constitute another link between the urochordates and vertebrates. The vaterite of ascidian spicules immersed in natural seawater remains mineralogically unchanged for 1 year, which indicates that vaterite may be preserved transiently in marine sediments.


Misalignment aberrations calibration in testing of high-numerical-aperture spherical surfaces.
The calibration of misalignment aberrations is a key issue in the testing of high-numerical-aperture spherical surfaces, and it is hard to separate the high-order aberrations introduced by misalignment from the measured data. The traditional calibration method is still applicable in the case of only wavefront tilt, but no longer effective in the existence of defocus. A calibration technique based on the wavefront difference is proposed to calibrate the misalignment aberrations in the presence of wavefront defocus, and it can be carried out without foreknowledge of the spherical surface under test. With the wavefront difference method, the calibration needs two separate measurements to separate the high-order aberrations. Both the computer simulation and experiments with the ZYGO interferometer have been carried out to validate the proposed calibration technique, with the accuracies better than 0.0005λ RMS and 0.0010λ RMS achieved, respectively. The proposed calibration method provides a feasible way to lower the requirement on the adjustment in the measurement, while retaining good accuracy.


A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle characterized by otherwise unexplained thickening of the left ventricle. Left ventricular outflow tract (LVOT) obstruction is present in approximately two-thirds of patients and substantially increases the risk of disease complications. Invasive treatment with septal myectomy or alcohol septal ablation can improve symptoms and functional status, but currently available drugs for reducing obstruction have pleiotropic effects and variable therapeutic responses. New medical treatments with more targeted pharmacology are needed, but the lack of preclinical animal models for HCM with LVOT obstruction has limited their development. HCM is a common cause of heart failure in cats, and a subset exhibit systolic anterior motion of the mitral valve leading to LVOT obstruction. MYK-461 is a recently-described, mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve LVOT obstruction in feline HCM. We evaluated mixed-breed cats in a research colony derived from a Maine Coon/mixed-breed founder with naturally-occurring HCM. By echocardiography, we identified five cats that developed systolic anterior motion of the mitral valve and LVOT obstruction both at rest and under anesthesia when provoked with an adrenergic agonist. An IV MYK-461 infusion and echocardiography protocol was developed to serially assess contractility and LVOT gradient at multiple MYK-461 concentrations. Treatment with MYK-461 reduced contractility, eliminated systolic anterior motion of the mitral valve and relieved LVOT pressure gradients in an exposure-dependent manner. Our findings provide proof of principle that acute reduction in contractility with MYK-461 is sufficient to relieve LVOT obstruction. Further, these studies suggest that feline HCM will be a valuable translational model for the study of disease pathology, particularly LVOT obstruction.


Late outgrowth endothelial progenitor cells in patients with age-related macular degeneration.
To evaluate the feasibility of isolating and expanding endothelial progenitor cells (EPCs), in the form of late outgrowth endothelial progenitor cells (OECs), from the peripheral blood of an aged population, particularly patients affected by different forms of AMD. Peripheral blood mononuclear cells were collected from young control subjects (n = 18) and from elderly subjects with non-AMD/low-risk dry AMD (n = 15), high-risk dry AMD (n = 6), or neovascular AMD (nvAMD; n = 32); cultured in established conditions; and observed for appearance of OEC clusters and growth characteristics on expansion. Expression of VEGF receptor-2 (KDR) in OECs after expansion was determined by Western blot. Plasma samples of study subjects were analyzed for CRP and VEGF levels. OEC cultures were successfully generated from a similar number of subjects in each group. After adjustment for all other variables, subjects with high-risk dry AMD had a 5.6-fold higher number of OEC clusters per 20 mL blood, and subjects with nvAMD had a 5.1-fold high number than did subjects with non-AMD/low-risk dry AMD (P < 0.05). High-risk dry AMD generated 63 times more (NS) and nvAMD 32-times more (P < 0.05) OECs on expansion of clusters than did non-AMD/low-risk dry AMD. Population doubling occurred significantly faster in cultures from nvAMD eyes compared to non-AMD/low-risk dry AMD eyes. In addition, a significant correlation between the number of OEC clusters, expanded OECs and levels of KDR was demonstrated. An OEC population was isolated and expanded from the blood of elderly control and AMD-affected patients and demonstrated significantly higher number of initial OEC clusters and expansion potential of OECs in patients at risk for or already affected by nvAMD. OECs may be used for further phenotypic, genetic, and functional analyses in patients with nvAMD.


The quality of reports of randomised trials in 2000 and 2006: comparative study of articles indexed in PubMed.
To examine the reporting characteristics and methodological details of randomised trials indexed in PubMed in 2000 and 2006 and assess whether the quality of reporting has improved after publication of the Consolidated Standards of Reporting Trials (CONSORT) Statement in 2001. Comparison of two cross sectional investigations. Study sample All primary reports of randomised trials indexed in PubMed in December 2000 (n=519) and December 2006 (n=616), including parallel group, crossover, cluster, factorial, and split body study designs. The proportion of general and methodological items reported, stratified by year and study design. Risk ratios with 95% confidence intervals were calculated to represent changes in reporting between 2000 and 2006. The majority of trials were two arm (379/519 (73%) in 2000 v 468/616 (76%) in 2006) parallel group studies (383/519 (74%) v 477/616 (78%)) published in specialty journals (482/519 (93%) v 555/616 (90%)). In both 2000 and 2006, a median of 80 participants were recruited per trial for parallel group trials. The proportion of articles that reported drug trials decreased between 2000 and 2006 (from 393/519 (76%) to 356/616 (58%)), whereas the proportion of surgery trials increased (51/519 (10%) v 128/616 (21%)). There was an increase between 2000 and 2006 in the proportion of trial reports that included details of the primary outcome (risk ratio (RR) 1.18, 95% CI 1.04 to 1.33), sample size calculation (RR 1.66, 95% CI 1.40 to 1.95), and the methods of random sequence generation (RR 1.62, 95% CI 1.32 to 1.97) and allocation concealment (RR 1.40, 95% CI 1.11 to 1.76). There was no difference in the proportion of trials that provided specific details on who was blinded (RR 0.91, 95% CI 0.75 to 1.10). Reporting of several important aspects of trial methods improved between 2000 and 2006; however, the quality of reporting remains well below an acceptable level. Without complete and transparent reporting of how a trial was designed and conducted, it is difficult for readers to assess its conduct and validity.


[Second Clinical Consensus of the Ibero-American Society of Neonatology: hemodynamic management of newborns].
This study reports on the process and results of the Second Clinical Consensus of the Ibero-American Society of Neonatology. Eighty neonatologists from 23 countries were invited to collaborate and participate in the event. Several questions of clinical-physiological importance in the hemodynamic management of newborns were addressed. Participants were divided into groups to facilitate interaction and teamwork, with instructions to respond to three to five questions by analyzing the literature and local factors. Meeting in Mar del Plata, Argentina, the Consensus Group served as a form for various presentations and discussions. In all, 54 neonatologists from 21 countries attended, with the objective of reaching a consensus on such matters as concepts and definitions of hemodynamic instability, the physiopathology of hemodynamic compromise, recommended therapy strategies, and hemodynamic monitoring. It is hoped that this international experience will serve as a useful initiative for future consensus building and reduction of the existing disparities among the countries of the Region in terms of treatment and outcomes.


One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer.
Accumulating evidence from epidemiologic studies suggests that risk of breast cancer is reduced in relation to increased consumption of folate and related B vitamins. We investigated independent and joint effects of B vitamin intake as well as two polymorphisms of a key one-carbon metabolizing gene [i.e., methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C] on breast cancer risk. The study uses the resources of a population-based case-control study, which includes 1,481 cases and 1,518 controls. Significant inverse associations between B vitamin intake and breast cancer risk were observed among non-supplement users. The greatest reduction in breast cancer risk was observed among non-supplement users in the highest quintile of dietary folate intake [odds ratio (OR), 0.61; 95% confidence interval (95% CI), 0.41-0.93] as compared with non-supplement users in the lowest quintile of dietary folate intake (high-risk individuals). The MTHFR 677T variant allele was associated with increased risk of breast cancer (P, trend = 0.03) with a multivariate-adjusted OR of 1.37 (95% CI, 1.06-1.78) for the 677TT genotype. The 1298C variant allele was inversely associated with breast cancer risk (P, trend = 0.03), and was likely due to the linkage of this allele to the low-risk allele of 677C. The MTHFR-breast cancer associations were more prominent among women who did not use multivitamin supplements. Compared with 677CC individuals with high folate intake, elevation of breast cancer risk was most pronounced among 677TT women who consumed the lowest levels of dietary folate (OR, 1.83; 95% CI, 1.13-2.96) or total folate intake (OR, 1.71; 95% CI, 1.08-2.71). From a public heath perspective, it is important to identify risk factors, such as low B vitamin consumption, that may guide an effective prevention strategy against the disease.


Simulation in perfusion: evaluating the efficacy of a specific training with eye-tracking.
With the aim of integrating simulation training into the training of perfusionists, we examined whether the participants were able to transfer a specific learning content to the same and different situations and assessed their feedback on the simulation training. Eye-tracking was tested as a measure and supplemented by additional measures. A 2 × 2 mixed design was used, with test time (pre- and post-test) and training group (same and different content training) as factors. In the pre- and post-test, the participant had to handle a critical situation on the cardiopulmonary bypass, namely, a drop in arterial partial oxygen pressure. Between the two test times, the participant practised under guidance the handling of either the same critical situation (Group 1) or a different one, that is, impaired venous return (Group 2). Dependent measures were fixations of the eyes on specific areas of interest on the heart-lung machine, measures of latency and subjective assessments. Moreover, participants gave feedback on the simulation training. Fixation analyses showed that the training led to an increased gaze on areas of interest relevant to the drop in arterial partial oxygen pressure in both groups, with a significant increase only for Group 1. The surveys revealed a great interest in the integration of simulation training into education. In combination with other measures, eye-tracking is suitable for the evaluation of simulation training. Due to the positive training effects and positive participant feedback, the integration of simulation into the training of perfusionists is advocated. Concerning transfer of learning content, more research is needed.


Molecular simulations minimally restrained by experimental data.
One popular approach to incorporating experimental data into molecular simulations is to restrain the ensemble average of observables to their experimental values. Here, I derive equations for the equilibrium distributions generated by restrained ensemble simulations and the corresponding expected values of observables. My results suggest a method to restrain simulations so that they generate distributions that are minimally perturbed from the unbiased distributions while reproducing the experimental values of the observables within their measurement uncertainties.


Complementary and alternative medicine contacts by persons with mental disorders in 25 countries: results from the World Mental Health Surveys.
A substantial proportion of persons with mental disorders seek treatment from complementary and alternative medicine (CAM) professionals. However, data on how CAM contacts vary across countries, mental disorders and their severity, and health care settings is largely lacking. The aim was therefore to investigate the prevalence of contacts with CAM providers in a large cross-national sample of persons with 12-month mental disorders. In the World Mental Health Surveys, the Composite International Diagnostic Interview was administered to determine the presence of past 12 month mental disorders in 138 801 participants aged 18-100 derived from representative general population samples. Participants were recruited between 2001 and 2012. Rates of self-reported CAM contacts for each of the 28 surveys across 25 countries and 12 mental disorder groups were calculated for all persons with past 12-month mental disorders. Mental disorders were grouped into mood disorders, anxiety disorders or behavioural disorders, and further divided by severity levels. Satisfaction with conventional care was also compared with CAM contact satisfaction. An estimated 3.6% (standard error 0.2%) of persons with a past 12-month mental disorder reported a CAM contact, which was two times higher in high-income countries (4.6%; standard error 0.3%) than in low- and middle-income countries (2.3%; standard error 0.2%). CAM contacts were largely comparable for different disorder types, but particularly high in persons receiving conventional care (8.6-17.8%). CAM contacts increased with increasing mental disorder severity. Among persons receiving specialist mental health care, CAM contacts were reported by 14.0% for severe mood disorders, 16.2% for severe anxiety disorders and 22.5% for severe behavioural disorders. Satisfaction with care was comparable with respect to CAM contacts (78.3%) and conventional care (75.6%) in persons that received both. CAM contacts are common in persons with severe mental disorders, in high-income countries, and in persons receiving conventional care. Our findings support the notion of CAM as largely complementary but are in contrast to suggestions that this concerns person with only mild, transient complaints. There was no indication that persons were less satisfied by CAM visits than by receiving conventional care. We encourage health care professionals in conventional settings to openly discuss the care patients are receiving, whether conventional or not, and their reasons for doing so.


Protein translocation across the yeast microsomal membrane is stimulated by a soluble factor.
We have found that a soluble activity present in the postribosomal supernatant fraction of Saccharomyces cerevisiae stimulates posttranslational translocation of yeast prepro-alpha-factor across yeast microsomal membranes. Stimulation of translocation is not due to a nonspecific affect on ATP levels. The activity is likely to be due to protein(s) as it is destroyed by N-ethylmaleimide, protease, or heat treatment but not by incubation with RNase. Its apparent sedimentation coefficient is approximately 9.6 S.


Synthetic deoxynojirimycin derivatives bearing a thiolated, fluorinated or unsaturated N-alkyl chain: identification of potent α-glucosidase and trehalase inhibitors as well as F508del-CFTR correctors.
The synthesis of eleven 1-deoxynojirimycin (DNJ) derivatives presenting either a monofluoro, difluoro, thiolated or unsaturated N-alkyl chain of various length is described. Exploiting the unsaturated moiety on the nitrogen, fluorine has been introduced through a HF/SbF5 superacid catalysed hydrofluorination and thiol-ene click chemistry allowed introduction of sulfur. The synthetic derivatives have been tested for their ability to inhibit glycosidases and correct F508del-CFTR. Two of the unsaturated iminosugars exhibited potency similar to Miglustat as F508del-CFTR correctors. The thioalkyl iminosugars as well as the corresponding alkyl iminosugars demonstrated low micromolar α-glucosidases and trehalases inhibition. Introduction of fluorine abolished F508del-CFTR correction and trehalase inhibition.


Ginkgo biloba extract suppresses endotoxin-mediated monocyte activation by inhibiting nitric oxide- and tristetraprolin-mediated toll-like receptor 4 expression.
Monocytes expressing toll-like receptor 4 (TLR4) play a major role in regulating the innate immune response and are involved in systemic inflammation. Previous studies have shown that Ginkgo biloba extract (GBE) may act as a therapeutic agent for some cardiovascular and neurological disorders. The objective of this study was to determine whether GBE could modulate immunity in human cells. The monocytic cell line THP-1 was used. Enzyme-linked immunosorbent assay results showed that lipopolysaccharide (LPS) induces the expression of monocyte chemotactic protein-1 (MIP-1), tumor necrosis factor-α, stromal cell-derived factor-1, and MIP-1α, and this induction may be repressed by GBE treatment due to TLR4 blockade. The Griess reagent assay and western blot analysis showed that GBE-mediated inhibition of TLR4 expression was associated with the activation of mitogen-activated protein kinase and production of nitric oxide (NO). Actinomycin D chase experiments demonstrated that GBE decreased the TLR4 mRNA stability in cells. Confocal microscopy and real-time polymerase chain reaction showed that GBE induced the expression of intracellular tristetraprolin (TTP). Transfection with TTP siRNA reversed the effects of GBE in naïve or TLR4-overexpressing cells. Treatment with SNAP (an NO donor) may increase intracellular TTP expression in cells. Immunoprecipitation analysis showed that GBE mediates TTP activation and increases the interaction of TTP with the 3' untranslated region (UTR) of TLR4 mRNA by regulating NO production. Our findings indicate that GBE could decrease the sensitivity of monocytes to LPS. Utilizing TTP to control TLR4 expression may be a promising approach for controlling systemic inflammation, and GBE may have potential applications in the clinical treatment of immune diseases.