The impact of high-intensity intermittent exercise on resting metabolic rate in healthy males.
High-intensity intermittent exercise training (HIT) may favourably alter body composition despite low training volumes and predicted energy expenditure (EE). To characterise the acute impact of two common HIT protocols on EE and post-exercise oxygen consumption (11 h EPOC). Oxygen consumption (l min(-1)), respiratory exchange ratio (RER) and EE were measured in nine healthy, lean males over 12 h under three conditions: control (CON), HIT1 (10 × 1 min high-intensity cycling bouts followed by 1 min rest) and HIT2 (10 × 4 min high-intensity cycling bouts followed by 2 min rest). Total exercise period EE during HIT1 (1,151 ± 205 kJ) (mean ± SD) was significantly lower than HIT2 (2,788 ± 322 kJ; p < 0.001). EE within the 60 min after exercise was significantly albeit marginally higher after HIT1 (388 ± 44 kJ; p = 0.02) and HIT2 (389 ± 39 kJ; p = 0.01) compared with CON (329 ± 39 kJ), with no difference between exercise conditions (p = 0.778). RER during this period was significantly lower in HIT1 (0.78 ± 0.06; p = 0.011) and HIT2 (0.76 ± 0.04; p = 0.004) compared with CON (0.87 ± 0.06). During the 'slow phase' of EPOC (1.25-9.75 h), there were no significant differences in EE (p = 0.07) or RER (p = 0.173) between trials. Single HIT sessions notably increases EE during exertion; however, the influence on metabolic rate post-exercise is transient and relatively minor.


Influence of educational level on test and treatment for incident hypothyroidism.
The incidence of hypothyroidism is not expected to differ by socioeconomic factors. However, the decision to test and initiate treatment may differ. We aimed to examine whether educational level influences the probability of thyroid stimulation hormone (TSH)-measurement and initiation of levothyroxine treatment. Citizens in the greater Copenhagen Area during 2001-2015 were included. Individual-level data on educational level, diagnoses, GP-contact, TSH-measurement and medication were derived from administrative and healthcare registers. The relative risks (RR) between educational levels of annual TSH-measurement and treatment initiation following a TSH-measurement were analysed in Poisson regression models with generalized estimation equations. A TSH-measurement was performed in 19% of 9,390,052 person years. The probability of TSH-measurement was higher with short (RR 1.16 [95% CI 1.15-1.16]) and medium (RR 1.11 [95% CI 1.06-1.12]) compared with long education. Treatment was initiated after 0.8% of 2,049,888 TSH-measurements. For TSH < 5 mIU/L, RR for treatment initiation ranged between 0.47 (95%CI 0.39-0.57) and 0.78 (95%CI 0.67-0.91) for short and medium compared with long education. For TSH 5-10 mIU/L, there was no statistically significant difference. For TSH > 10 mIU/L, RR was 1.07 (95% CI 1.02-1.12) for short and 1.08 (95% CI 1.03-1.13) for medium compared with long education. The probability of TSH-measurement was higher with shorter education, and the probability of treatment initiation with TSH > 10 mIU/L was marginally higher with short-medium education compared with long education. However, the probability of treatment initiation with TSH < 5 mIU/L, that is treatment incongruous with guidelines, was substantially higher in persons with long education.


Empirical Antimicrobial Therapy of Neonates with Necrotizing Enterocolitis: A Systematic Review.
Necrotizing enterocolitis (NEC) is an inflammatory disease of the gastrointestinal tract characterized by ischemic necrosis of the intestinal mucosa, mostly affecting premature neonates. Management of NEC includes medical care and surgical approaches, with supportive care and empirical antibiotic therapy recommended to avoid any disease progression. However, there is still no clear evidence-based consensus on empiric antibiotic strategies or surgical timing. This study was aimed to review the available evidence on the effectiveness and safety of different antibiotic regimens for NEC. MEDLINE, EMBASE, Cochrane CENTRAL, and CINAHL databases were systematically searched through May 31, 2020. Randomized controlled trials (RCTs) and nonrandomized interventions reporting data on predefined outcomes related to NEC treatments were included. Clinical trials were assessed using the criteria and standard methods of the Cochrane risk of bias tool for randomized trials, while the risk of bias in nonrandomized studies of interventions was evaluated using the ROBINS-I tool. The certainty in evidence of each outcome's effects was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. Five studies were included in this review, two RCTs and three observational studies, for a total amount of 3,161 patients. One RCT compared the outcomes of parenteral (ampicillin plus gentamicin) and oral (gentamicin) treatment with parenteral only. Three studies (one RCT and two observational) evaluated adding anaerobic coverage to different parenteral regimens. The last observational study compared two different parenteral antibiotic combinations (ampicillin and gentamicin vs. cefotaxime and vancomycin). No antimicrobial regimen has been shown to be superior to ampicillin and gentamicin in decreasing mortality and preventing clinical deterioration in NEC. The use of additional antibiotics providing anaerobic coverage, typically metronidazole, or use of other broad-spectrum regimens as first-line empiric therapy is not supported by the very limited current evidence. Well-conducted, appropriately sized comparative trials are needed to make evidence-based recommendations. · Ampicillin and gentamicin are effective in decreasing mortality and preventing clinical deterioration in NEC.. · Metronidazole could be added in patients with surgical NEC.. · No study with high-quality evidence was found..


Observation of a topologically non-trivial surface state in half-Heusler PtLuSb (001) thin films.
The discovery of topological insulators, materials with bulk band gaps and protected cross-gap surface states in compounds such as Bi2Se3, has generated much interest in identifying topological surface states (TSSs) in other classes of materials. In particular, recent theoretical calculations suggest that TSSs may be found in half-Heusler ternary compounds. If experimentally realizable, this would provide a materials platform for entirely new heterostructure spintronic devices that make use of the structurally identical but electronically varied nature of Heusler compounds. Here we show the presence of a TSS in epitaxially grown thin films of the half-Heusler compound PtLuSb. Spin- and angle-resolved photoemission spectroscopy, complemented by theoretical calculations, reveals a surface state with linear dispersion and a helical tangential spin texture consistent with previous predictions. This experimental verification of topological behaviour is a significant step forward in establishing half-Heusler compounds as a viable material system for future spintronic devices.


Regulation causes nitrogen cycling discontinuities in Mediterranean rivers.
River regulation has fundamentally altered large sections of the world's river networks. The effects of dams on the structural properties of downstream reaches are well documented, but less is known about their effect on river ecosystem processes. We investigated the effect of dams on river nutrient cycling by comparing net uptake of total dissolved nitrogen (TDN), phosphorus (TDP) and organic carbon (DOC) in river reaches located upstream and downstream from three reservoir systems in the Ebro River basin (NE Iberian Peninsula). Increased hydromorphological stability, organic matter standing stocks and ecosystem metabolism below dams enhanced the whole-reach net uptake of TDN, but not that of TDP or DOC. Upstream from dams, river reaches tended to be at biogeochemical equilibrium (uptake≈release) for all nutrients, whereas river reaches below dams acted as net sinks of TDN. Overall, our results suggest that flow regulation by dams may cause relevant N cycling discontinuities in rivers. Higher net N uptake capacity below dams could lead to reduced N export to downstream ecosystems. Incorporating these discontinuities could significantly improve predictive models of N cycling and transport in complex river networks.


Optical shuttle pulse measurements of gas lenses.
To study the distortion of a gaussian light beam in a long gas lens beam waveguide, a light pulse was shuttled back and forth more than 200 times in a 25-m optical cavity containing a gas lens. From the decay of the pulse train, a conservative upper limit of the optical loss of the gas lens was found to be 0.1%. By scanning the intensity of the beam on various round trips, the beam distortion could be measured. When the center of the beam remained near the optic axis of the lens, no appreciable beam distortion was measured after more than 400 trips through the lens. If the beam center did not hit the lens at the same transverse point on each pass but undulated, some distortion was observed. The largest distortions occurred when the beam undulated in the lower part of the lens where the lens has the greatest aberration caused by gravity. The larger the undulation amplitude, the faster the beam broke up. The largest distortion was observed when the lens with the greatest aberration due to gravity was used.


Chick myotendinous antigen. I. A monoclonal antibody as a marker for tendon and muscle morphogenesis.
Extracellular matrix components are likely to be involved in the interaction of muscle with nonmuscle cells during morphogenesis and in adult skeletal muscle. With the aim of identifying relevant molecules, we generated monoclonal antibodies that react with the endomysium, i.e., the extracellular matrix on the surface of single muscle fibers. Antibody M1, which is described here, specifically labeled the endomysium of chick anterior latissimus dorsi muscle (but neither the perimysium nor, with the exception of blood vessels and perineurium, the epimysium ). Endomysium labeling was restricted to proximal and distal portions of muscle fibers near their insertion points to tendon, but absent from medial regions of the muscle. Myotendinous junctions and tendon fascicles were intensely labeled by M1 antibody. In chick embryos, " myotendinous antigen" (as we tentatively call the epitope recognized by M1 antibody) appeared first in the perichondrium of vertebrae and limb cartilage elements, from where it gradually extended to the premuscle masses. Around day 6, tendon primordia were clearly labeled. The other structures labeled by M1 antibody in chick embryos were developing smooth muscle tissues, especially aorta, gizzard, and lung buds. In general, tissues labeled with M1 antibody appeared to be a subset of the ones accumulating fibronectin. In cell cultures, M1 antibody binds to fuzzy, fibrillar material on the substrate and cell surfaces of living fibroblast and myogenic cells, which confirms an extracellular location of the antigenic site. The appearance of myotendinous antigen during limb morphogenesis and its distribution in adult muscle and tendon are compatible with the idea that it might be involved in attaching muscle fibers to tendon fascicles. Its biochemical characterization is described in the accompanying paper ( Chiquet , M., and D. Fambrough , 1984, J. Cell Biol. 98:1937-1946).


Bone morphogenetic proteins in the nervous system.
Bone morphogenetic proteins (BMPs) are a rapidly expanding subclass of the transforming growth factor superfamily. BMP ligands and receptor subunits are present throughout neural development within discrete regions of the embryonic brain and within neural crest-derived pre- and post-migratory zones. BMPs initially inhibit the formation of neuroectoderm during gastrulation while, within the neural tube, they act as gradient morphogens to promote the differentiation of dorsal cell types and intermediate cell types throughout co-operative signaling. In the peripheral nervous system, BMPs act as instructive signals for neuronal lineage commitment and promote graded stages of neuronal differentiation. By contrast, within the CNS, these same factors promote astroglial lineage elaboration from embryonic subventricular zone progenitor cells, with concurrent suppression of the neuronal or oligodendroglial lineages, or both. In addition, BMPs act on more lineage-restricted embryonic CNS progenitor cells to promote regional neuronal survival and cellular differentiation. Furthermore, these versatile cytokines induce selective apoptosis of discrete rhombencephalic neural crest-associated cellular populations. These observations suggest that the BMPs exhibit a broad range of cellular and context-specific effects during multiple stages of neural development.


Indoleacetic acid production and plant growth promoting potential of bacterial endophytes isolated from rice (Oryza sativa L.) seeds.
Bacterial endophytes from the phyllosphere and rhizosphere have been used to produce bioactive metabolites and to promote plant growth. However, little is known about the endophytes residing in seeds. This study aimed to isolate and identify seed-borne bacterial endophytes from rice and elucidate their potential for phytohormone production and growth enhancement. The isolated endophytes included Micrococcus yunnanensis RWL-2, Micrococcus luteus RWL-3, Enterobacter soli RWL-4, Leclercia adecarboxylata RWL-5, Pantoea dispersa RWL-6, and Staphylococcus epidermidis RWL-7, which were identified using 16S rRNA sequencing and phylogenetic analysis. These strains were analyzed for indoleacetic acid (IAA) production by using GC-MS and IAA was found in the range of 11.50 ± 0.77 μg ml-1 to 38.80 ± 1.35 μg ml-1. We also assessed the strains for plant growth promoting potential because these isolates were able to produce IAA in pure culture. Most of the growth attributes of rice plants (shoot and root length, fresh and dry biomass, and chlorophyll content) were significantly increased by bacterial endophytes compared to the controls. These results show that IAA producing bacterial endophytes can improve hostplant growth traits and can be used as bio-fertilizers.


Trend of antibiotics usage for acute pyelonephritis in Korea based on national health insurance data 2010-2014.
The objective of this study is to describe the changes in prescribing practices of antibiotics to treat acute pyelonephritis (APN) in Korea. The claim data base of the Health Insurance Review and Assessment Service in Korea was used to select patients with ICD-10 codes N10 (acute tubulo-interstitial nephritis) or N12 (tubulo-interstitial nephritis, not specified as acute nor chronic) as the primary discharge diagnosis during 2010-2014. Consumption of each class of antibiotics was converted to Defined Daily Dose (DDD)/event. Throughout the five-year period, the average antibiotic consumption were 11.3 DDD per inpatient event and 6.0 DDD per outpatient event. The annual average antibiotic consumption increased for inpatients (P = 0.002), but remained stable for outpatients (P = 0.066). The use of parenteral antibiotics increased for inpatients (P < 0.001), but decreased for outpatients (P = 0.017). As for the the antibiotic classes, 3rd generation cephalosporins (3rd CEPs) was the most commonly prescribed (41.4%) for inpatients, followed by fluoroquinolones (FQs) (28.5%); for outpatient, FQs (54.8%) was the most commonly prescribed, followed by 3rd CEPs (13.1%). The use of 3rd CEPs (P < 0.001), beta-lactam/beta-lactamase inhibitors (P = 0.007), and carbapenems (P < 0.001) increased substantially for the treatment of hospitalized APN patients. In particular, carbapenems use increased 3.1-fold over the 5 years. Prescription of broad-spectrum antibiotics increased much for the treatment of APN in Korea during 2010-2014.


Psychiatric morbidity in hypertensives attending a cardiology outpatient clinic in West Africa.
To determine kinds of psychiatric morbidity among a sample of stable hypertensive outpatients in a teaching hospital. A cross-sectional study of 260 enrolled outpatients. Psychiatric morbidity was assessed using a 2-stage evaluation method with the General Health Questionnaire Version 12 (GHQ-12) and Structured Clinical Interview for DSM-IV (SCID) to assess for psychiatric diagnosis. 28 (10.8%) of the 260 patients endorsed some psychological distress, with a mean GHQ-12 score of ≥ 2. At the second stage, 16.1% (N=13 of 81) interviewed had one or more psychiatric disorder on the SCID. The commonest psychiatric diagnosis made were mood disorders, with current major depressive disorder occurring at a rate of 6.2%. Other disorders found were past major depressive episode (2.5%), organic mood syndrome (3.7%), and somatoform disorder (3.7%). The relationship between hypertension and mood disorders should inform a higher index of suspicion among physicians and general practitioners in order to give patients appropriate treatments or referrals where necessary. It is recommended that collaboration with mental health service providers be encouraged.


Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation.
The study of the chronological life span of Saccharomyces cerevisiae, which measures the survival of populations of non-dividing yeast, has resulted in the identification of homologous genes and pathways that promote aging in organisms ranging from yeast to mammals. Using a competitive genome-wide approach, we performed a screen of a complete set of approximately 4,800 viable deletion mutants to identify genes that either increase or decrease chronological life span. Half of the putative short-/long-lived mutants retested from the primary screen were confirmed, demonstrating the utility of our approach. Deletion of genes involved in vacuolar protein sorting, autophagy, and mitochondrial function shortened life span, confirming that respiration and degradation processes are essential for long-term survival. Among the genes whose deletion significantly extended life span are ACB1, CKA2, and TRM9, implicated in fatty acid transport and biosynthesis, cell signaling, and tRNA methylation, respectively. Deletion of these genes conferred heat-shock resistance, supporting the link between life span extension and cellular protection observed in several model organisms. The high degree of conservation of these novel yeast longevity determinants in other species raises the possibility that their role in senescence might be conserved.


Macrophage scavenger receptors and host-derived ligands.
The scavenger receptors are a large family of molecules that are structurally diverse and have been implicated in a range of functions. They are expressed by myeloid cells, selected endothelial cells and some epithelial cells and recognise many different ligands, including microbial pathogens as well as endogenous and modified host-derived molecules. This review will focus on the eight classes of scavenger receptors (class A-H) in terms of their structure, expression and recognition of host-derived ligands. Scavenger receptors have been implicated in a range of physiological and pathological processes, such as atherosclerosis and Alzheimer's disease, and function in adhesion and tissue maintenance. More recently, some of the scavenger receptors have been shown to mediate binding and endocytosis of chaperone proteins, such as the heat shock proteins, thereby playing an important role in antigen cross-presentation.


Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells.
The cytotoxicity of NK cells has been thought to be mediated mainly by the perforin-dependent pathway. We investigated the involvement of Fas-mediated pathway in the killing activity of purified human CD3-, CD16+ NK cells. Fas ligand mRNA was expressed in freshly isolated NK cells. Apoptosis, which was identified by the fragmented chromatin in individual cells, was induced in the cells that expressed high levels of Fas via direct NK-to-target cell interaction or Ab-dependent cell-mediated cytotoxicity, even in Ca(2+)-free medium, in which perforin pores are known not to be formed. Apoptosis in both the presence and absence of external Ca2+ was inhibited by Fab of an anti-Fas mAb. Transfection of the Fas gene in target cells facilitated the induction of apoptosis, compared with the parental cell line. The function of the Fas-mediated pathway in the coexistence of the perforin-dependent pathway was examined in 10 cell lines expressing different levels of Fas by Ca2+ imaging and morphologic observation of single cells. With a certain boundary level, low or high levels of Fas expression in target cells were correlated to a great degree with either acute necrosis due to severe membrane damage after NK-target cell contact or apoptosis at a later period, respectively. We concluded that Fas ligand/Fas interaction is present and plays a significant role in the human NK cell-induced apoptosis.


Prostate-Specific Antigen Density and Gleason Score Predict Adverse Pathologic Features in Patients with Clinically Localized Prostate Cancer.
According to recent studies, prostate cancer is the second most common cancer among Iranian men. Radical prostatectomy has been considered the gold standard treatment in patients with clinically localized prostate cancer. Gleason score, PSA density, and PSA velocity are some of the parameters used to predict adverse pathologic features. The aim of this study was to evaluate the prognostic value of PSA density and Gleason score in predicting adverse pathologic features in patients with localized prostate cancer who undergo radical prostatectomy. We conducted a cross-sectional study of 105 patients with localized prostate cancer who underwent radical prostatectomy between 2006 and 2013. We recorded Gleason scores and PSA levels, in addition to the results of pathological evaluations after radical prostatectomy, including prostate volume, stage, LNI (lymph node involvement), SVI (seminal vesicle invasion), and extraprostatic extension (EPE). Data were analyzed using SPSS version 21. Mean PSA density was 0.27 (0.17 SD). The frequencies of EPE, SVI, and LNI were 21.9, 16.2, and 2.9, respectively. The Mann-Whitney U-test demonstrated a significant correlation between PSA density and adverse pathologic features (EPE, SVI, and LNI). PSA, PSA density, and Gleason score should be considered together in order to more accurately predict the adverse pathologic features of prostate cancer.


Suppression of intestinal carcinogenesis in Apc-mutant mice by limonin.
Limonoids in citrus fruits are known to possess multiple biological functions, such as anti-proliferative functions in human cancer cell lines. Therefore, we aimed to investigate the suppressive effect of limonin on intestinal polyp development in Apc-mutant Min mice. Five-week-old female Min mice were fed a basal diet or a diet containing 250 or 500 ppm limonin for 8 weeks. The total number of polyps in mice treated with 500 ppm limonin decreased to 74% of the untreated control value. Neoplastic cell proliferation in the polyp parts was assessed by counting PCNA positive cells, and a tendency of reduction was obtained by limonin treatment. Moreover, expression levels of c-Myc and MCP-1 mRNA in the polyp part were reduced by administration of limonin. We finally confirmed the effects of limonin on β-catenin signaling, and found limonin significantly inhibited T-cell factor/lymphocyte enhancer factor-dependent transcriptional activity in a dose-dependent manner in the Caco-2 human colon cancer cell line. Our results suggest that limonin might be a candidate chemopreventive agent against intestinal carcinogenesis.


G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder.
The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16INK4a, are commonly altered in human malignancies, abrogating cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16INK4a protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16INK4a, which occurred in 15/79 cases (19%). One biphenotypic case, with Rb+p16- and Rb-p16+ areas, was identified as well. Cyclin D1 was overexpressed in 21/79 carcinomas (27%), all of which retained Rb protein. Fifty of 79 tumours (63%) showed aberrant accumulation of p53 protein; p53 staining did not correlate with Rb, p16INK4a, or cyclin D1 status. Overall, 70% of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16INK4a and cyclin D1). Only 15% of all bladder carcinomas (12/79) showed a normal phenotype for all four proteins. In a multivariate survival analysis, cyclin D1 overexpression was linked to less aggressive disease and relatively favourable outcome. In our series, Rb, p16INK4a and p53 status did not reach statistical significance as prognostic factors. In conclusion, G1 restriction point defects can be identified in the majority of bladder carcinomas. Our findings support the hypothesis that cyclin D1 and p16INK4a can cooperate to dysregulate the cell cycle, but that loss of Rb protein abolishes the G1 checkpoint completely, removing any selective advantage for cells that alter additional cell cycle proteins.


A validation of the pain interference index in adults with long-standing pain.
Chronic pain is a major health problem and more knowledge is needed regarding the interference of pain on behaviors in different life domains. Clinically useful and statistically sound pain interference measures are highly important. Studies on youths have shown that the Pain Interference Index (PII) is a reliable and valid instrument that is sensitive to change following behavioral treatment. This measure may also have utility for adults, but no study has so far evaluated the statistical properties of the PII for long-standing pain in adults. Data were collected from 239 consecutive adults with non-specific chronic pain referred to a tertiary pain clinic. We investigated the factor structure of items using a principal component analysis. Cronbach's alpha was calculated to assess internal consistency. The questionnaire's ability to predict levels of, e.g., disability was analyzed by means of regression analyses. Analyses illustrated the adequacy of a one-factor solution with six items. Cronbach's alpha (0.85) suggested a satisfactory internal consistency among items. The PII explained significant amounts of variance in pain disability, physical, and mental health-related quality of life and depression, suggesting concurrent criteria validity. The PII is a brief questionnaire with reliable and valid statistical properties to assess pain interference in adults. Other studies support the reliability and validity of PII for use with youths, and now the PII can be used to analyze the influence of pain on behaviors across age groups. Potentially, the PII can also be used as an outcome measure in clinical trials.


National survey of clinical communication assessment in medical education in the United Kingdom (UK).
All medical schools in the UK are required to be able to provide evidence of competence in clinical communication in their graduates. This is usually provided by summative assessment of clinical communication, but there is considerable variation in how this is carried out. This study aimed to gain insight into the current assessment of clinical communication in UK medical schools. The survey was sent via e-mail to communication leads who then were asked to consult with all staff within their medical school involved in the assessment of communication. Results were obtained from 27 out of 33 schools (response rate 82%) and a total of 34 courses. The average number of assessments per year was 2.4 (minimum 0, maximum 10). The Objective Structured Clinical Exam (OSCE) was the most commonly used method of assessment (53%). Other assessments included MCQ and workplace based assessments. Only nine courses used a single method of assessment. Issues raised included, logistics and costs of assessing mainly by OSCE, the robustness and reliability of such exams and integration with other clinical skills. It is encouraging that a variety of assessment methods are being used within UK medical schools and that these methods target different components of clinical communication skills acquisition.


DY determinants, possibly associated with novel class II molecules, stimulate autoreactive CD4+ T cells with suppressive activity.
A set of T cell clones (TCC) isolated from HLA-DR-, Dw-, DQ-matched allogeneic MLCs was found to proliferate autonomously when stimulated with cells carrying a wide range of class I or II specificities. This apparently unrestricted proliferation was relatively weak, and only low levels of IL-2 were present in the supernatants of stimulated cells. Autologous as well as allogeneic PBMC and B lymphoblastoid cell lines (B-LCL) were capable of stimulating such clones, which were also restimulated by suppressive, but not by helper, TCC. Moreover, such clones displayed the unusual property of autostimulation. mAb inhibition experiments suggested that class II- or class II-restricted antigens were involved in stimulation. Thus, certain "broad" mAbs (TU39, SG520) reacting with multiple locus products inhibited activation of these reagents, but none of those reacting more specifically with DR (TU34, TU37, L243, Q2/70, SG157), DQ (TU22, SPV-L3, Leu 10), or DP (B7/21), or mixtures of these mAbs, were able to do so. Evidence from sequential immunoprecipitation experiments suggested that mAb TU39 bound class II-like molecules other than DR, DQ, and DP on TCC and B-LCL, and it is therefore proposed that such putative novel class II-like molecules may carry the stimulating determinants for these autoreactive clones. DY-reactive clones lacked helper activity for B cells but mediated potent suppressive activity on T cell proliferative responses that was not restricted by the HLA type of the responding cells. Suppressive activity was induced in normal PBMC by such clones, as well as by independent suppressive clones, which was also inhibited only by mAb TU39. These findings lead to the proposal that DY-reactive autostimulatory cells may constitute a self-maintaining suppressive circuit, the level of activity of which would be regulated primarily by the availability of IL-2 in the microenvironment.


Vascular ring presenting as dysphagia in an adult woman: a case report.
A 48-year-old woman was seen in a surgical outpatient clinic with a 2 year history of progressive dysphagia with occasional regurgitation, partially controlled with a proton pump inhibitor. Primary investigations of pH testing and gastroscopy were normal, although a barium swallow study revealed significant hold-up at the aortic arch impression and a posterior right-sided oesophageal impression suggestive of a right-sided aortic arch. A follow-up computed tomography angiogram discovered a vascular ring encircling the trachea and oesophagus, formed by a right-sided aortic arch with aberrant aortic branches, and a Kommerell's diverticulum. It was deemed that the patient's symptoms were related to this vascular ring. The patient underwent stage-one surgery - an extra-anatomic bypass of the double aortic arch and right subclavian artery - and 4 months later a stent graft insertion over the origin of the diverticulum with the aim of complete symptomatic relief. This case presents a common symptom familiar to any clinician (dysphagia), which has been caused by a rare pathology. It is even more unusual that this should present itself in adulthood.


Recovering 3D images of polymeric nanofibers in solution through theoretical analysis and Monte-Carlo simulations of their 2D TEM images.
Nanofibers are well-known nanomaterials that are promising for many important applications. Since sample preparation for the applications usually starts from a nanofiber solution, characterization of the original conformation of nanofibers in the solution is significant because the conformation affects remarkably the behavior of nanofibers in the samples. However, the characterization is very difficult by existing methods: light scattering can only roughly evaluate the conformation in solution; cryo-TEM is laborious, time-consuming, and challenging technically, and thus difficult to study a system statistically. Herein we report a novel and reliable method to recover the 3D original image of nanofibers in solution through theoretical analysis and Monte-Carlo simulations of TEM images of the nanofibers. Firstly, six kinds of monodisperse nanofibers with the same composition and inner structure but different contour lengths were prepared by the method developed in our laboratory. Then, each kind of nanofiber deposited on the substrate of the TEM sample was measured by TEM and meanwhile simulated by the Monte Carlo method. By matching the simulation results with the TEM results, we determined information about the nanofibers including their rigidity and the interaction between the nanofibers and the substrate. Furthermore, for each kind of nanofiber, based on the information, 3D images of the nanofibers in solution can be re-constructed, and then the average gyration radius and hydrodynamic radius can be calculated, which were compared with the corresponding values measured experimentally to demonstrate the reliability of this method.


Evidence-based standards for cancer pain management.
High-quality management of cancer pain depends on evidence-based standards for screening, assessment, treatment, and follow-up for general cancer pain and specific pain syndromes. We developed a set of standards through an iterative process of structured literature review and development and refinement of topic areas and standards and subjected recommendations to rating by a multidisciplinary expert panel. Providers should routinely screen for the presence or absence and intensity of pain and should perform descriptive pain assessment for patients with a positive screen, including assessment for likely etiology and functional impairment. For treatment, providers should provide pain education, offer breakthrough opioids in patients receiving long-acting formulations, offer bowel regimens in patients receiving opioids chronically, and ensure continuity of opioid doses across health care settings. Providers should also follow up on patients after treatment for pain. For metastatic bone pain, providers should offer single-fraction radiotherapy as an option when offering radiation, unless there is a contraindication. When spinal cord compression is suspected, providers should treat with corticosteroids and evaluate with whole-spine magnetic resonance imaging scan or myelography as soon as possible but within 24 hours. Providers should initiate definitive treatment (radiotherapy or surgical decompression) within 24 hours for diagnosed cord compression and should follow up on patients after treatment. These standards provide an initial framework for high-quality evidence-based management of general cancer pain and pain syndromes.


The Vitiligo Working Group recommendations for narrowband ultraviolet B light phototherapy treatment of vitiligo.
Treatment of vitiligo with narrowband ultraviolet B light (NBUVB) is an important component of the current standard of care. However, there are no consistent guidelines regarding the dosing and administration of NBUVB in vitiligo, reflected by varied treatment practices around the world. To create phototherapy recommendations to facilitate clinical management and identify areas requiring future research. The Vitiligo Working Group (VWG) Phototherapy Committee addressed 19 questions regarding the administration of phototherapy over 3 conference calls. Members of the Photomedicine Society and a group of phototherapy experts were surveyed regarding their phototherapy practices. Based on comparison and analysis of survey results, expert opinion, and discussion held during conference calls, expert recommendations for the administration of NBUVB phototherapy in vitiligo were created. There were several areas that required further research before final recommendations could be made. In addition, no standardized methodology was used during literature review and to assess the strength of evidence during the development of these recommendations. This set of expert recommendations by the VWG is based on the prescribing practices of phototherapy experts from around the world to create a unified, broadly applicable set of recommendations on the use of NBUVB in vitiligo.


Sjgrens syndrome: pathogenesis.
Sjgrens syndrome is a chronic inflammatory disease of the lacrimal and salivary gland with subsequent keratoconjunctivitis sicca and xerostomia. Histopathologic findings include damaged acini of the lacrimal and salivary glands with mononuclear cell infiltrates of lymphocytic and plasma cell type. The cause of the damage is cell-mediated cytotoxicity. The pathogenesis of Sjgrens syndrome is still unknown. The role of viral infections failed to show a causative effect. On the other hand, tissue destruction was shown to be mediated by activated T cells of CD4+ type that home into the lacrimal gland. This process is signal-mediated through the T-cell receptor that interacts with class II antigen on the epithelial cells of exocrine glands. This, in turn, induces the expression of Fas/APO-1 and Fas-mediated apoptosis of acinar cells. Granzyme A and perforin are cytolytic enzymes secreted by activated T lymphocytes that seem to participate in acinar cell destruction. (Eur J Ophthalmol 1999; 9: 1-7).


Oncolytic Herpes Virus Armed with Vasculostatin in Combination with Bevacizumab Abrogates Glioma Invasion via the CCN1 and AKT Signaling Pathways.
Anti-VEGF treatments such as bevacizumab have demonstrated convincing therapeutic advantage in patients with glioblastoma. However, bevacizumab has also been reported to induce invasiveness of glioma. In this study, we examined the effects of rapid antiangiogenesis mediated by oncolytic virus (RAMBO), an oncolytic herpes simplex virus-1 expressing vasculostatin, on bevacizumab-induced glioma invasion. The effect of the combination of RAMBO and bevacizumab in vitro was assessed by cytotoxicity, migration, and invasion assays. For in vivo experiments, glioma cells were stereotactically inoculated into the brain of mice. RAMBO was intratumorally injected 7 days after tumor inoculation, and bevacizumab was administered intraperitoneally twice a week. RAMBO significantly decreased both the migration and invasion of glioma cells treated with bevacizumab. In mice treated with bevacizumab and RAMBO combination, the survival time was significantly longer and the depth of tumor invasion was significantly smaller than those treated with bevacizumab monotherapy. Interestingly, RAMBO decreased the expression of cysteine-rich protein 61 and phosphorylation of AKT, which were increased by bevacizumab. These results suggest that RAMBO suppresses bevacizumab-induced glioma invasion, which could be a promising approach to glioma therapy.


BIAS: Transparent reporting of biomedical image analysis challenges.
The number of biomedical image analysis challenges organized per year is steadily increasing. These international competitions have the purpose of benchmarking algorithms on common data sets, typically to identify the best method for a given problem. Recent research, however, revealed that common practice related to challenge reporting does not allow for adequate interpretation and reproducibility of results. To address the discrepancy between the impact of challenges and the quality (control), the Biomedical Image Analysis ChallengeS (BIAS) initiative developed a set of recommendations for the reporting of challenges. The BIAS statement aims to improve the transparency of the reporting of a biomedical image analysis challenge regardless of field of application, image modality or task category assessed. This article describes how the BIAS statement was developed and presents a checklist which authors of biomedical image analysis challenges are encouraged to include in their submission when giving a paper on a challenge into review. The purpose of the checklist is to standardize and facilitate the review process and raise interpretability and reproducibility of challenge results by making relevant information explicit.


Tracking poles with an autoregressive model: a confidence index for the analysis of the intrapartum cardiotocogram.
Clinicians often rely upon the cardiotocogram, a display of the fetal heart rate and maternal uterine activity (UA) over time, as a means of monitoring fetal health during labour. Fetal health can be monitored adequately only when the signal quality of the cardiotocogram is good. We propose an automated assessment of UA signal quality in order to create a confidence index for subsequent analysis of the intrapartum cardiotocogram. We use an autoregressive (AR) model of the UA to estimate the power at the contraction frequency, with high power indicative of "good" UA signal quality. 5th, 10th, and 15th-order AR models are used to assess the signal quality of 12 intrapartum UA traces as "good/medium" or "poor". We compare our results to two experts' visual assessments of signal quality. The 10th-order model exhibits the highest percent agreement rate of 62%. It also exhibits the most balanced false positive and false negative rates, where "good" or "medium" signal quality is considered a positive and "poor" signal quality a negative. The 10th-order model can therefore be used as a confidence index to reduce the errors made in the identification of uterine contractions in the UA trace and in the subsequent analysis of the cardiotocogram as a whole.


Remarkably low mtDNA control region diversity in an abundant demersal fish.
Cape hake, Merluccius paradoxus, is a valuable commercially exploited demersal species. Using the 5' mtDNA control region we show that 96% of 1013 fishes sampled over a three-year period share one of two dominant haplotypes; 19 haplotypes were recovered in total, suggesting a genetically homogenous population of fish. Accordingly, haplotype and nucleotide diversities are low (h = 0.53, pi = 0.0014); an asymptotic haplotype accumulation curve suggests that few additional haplotypes exist. Comparing h and pi with other fish species shows that M. paradoxus and other southern African fish species have remarkably low genetic diversity values compared with other global marine fishes. Despite low genetic variability, frequency differences among M. paradoxus haplotypes suggest weakly structured populations between Namibia and South Africa. However, given the remarkably homogeneous mtDNA population genetic structure between fishes sampled along 1800 km, it is clear that faster evolving markers such a microsatellites are also needed before inferences can be made regarding stock identification and management of this species.


Incidence, clinical predictors, and prognostic impact of worsening renal function in elderly patients with chronic heart failure on intensive medical therapy.
Incidence, predictors, and prognostic impact of worsening renal function (WRF) in elderly patients with chronic heart failure (HF) undergoing intensive contemporary medical therapy are unknown. In 566 patients (age 77 ± 8 years) included in the TIME-CHF, serum creatinine (sCr) was repeatedly measured up to 6 months. Worsening renal function was classified as increase in sCr by 0.2 to 0.3 (WRFI), 0.3 to 0.5 (WRFII), or ≥0.5 mg/dL (WRFIII) within the first 6 months. Outcome events were assessed for 18 months. The incidence of WRF I, II, and III was 12%, 19%, and 22%, respectively. Worsening renal function III was associated with increased mortality (hazard ratio 1.98 [95% CI 1.27-3.07, P = .002] vs no WRF), whereas WRF I/II was not. History of renal failure, spironolactone treatment, higher baseline dose, and higher maximal increase in loop diuretic dose were independently associated with the occurrence of WRF III, whereas angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and β-blocker use and allocation to N-terminal pro-B-type natriuretic peptide-guided management were not. Worsening renal function III was an independent predictor of death, death or hospitalization, and death or HF hospitalization also after adjusting for baseline characteristics. One fifth of elderly patients with chronic HF experienced WRF III on 6-month intensive HF treatment. These patients had higher mortality, whereas patients with smaller sCr rises did not. Occurrence of WRF III was associated with high doses of loop diuretics and spironolactone use but not with other treatments.


Cost-effectiveness of alternative minimum recall intervals between whole blood donations.
The INTERVAL trial showed shorter inter-donation intervals could safely increase the frequency of whole-blood donation. We extended the INTERVAL trial to consider the relative cost-effectiveness of reduced inter-donation intervals. Our within-trial cost-effectiveness analysis (CEA) used data from 44,863 whole-blood donors randomly assigned to 12, 10 or 8 week (males), and 16, 14 or 12 week inter-donation intervals (females). The CEA analysed the number of whole-blood donations, deferrals including low- haemoglobin deferrals, and donors' health-related quality of life (QoL) to report costs and cost-effectiveness over two years. The mean number of blood donation visits over two years was higher for the reduced interval strategies, for males (7.76, 6.60 and 5.68 average donations in the 8-, 10- and 12- week arms) and for females (5.10, 4.60 and 4.01 donations in the 12-, 14- and 16- week arms). For males, the average rate of deferral for low haemoglobin per session attended, was 5.71% (8- week arm), 3.73% (10- week), and 2.55% (12- week), and for females the rates were: 7.92% (12-week), 6.63% (14- week), and 5.05% (16- week). Donors' QoL was similar across strategies, although self-reported symptoms were increased with shorter donation intervals. The shorter interval strategies increased average cost, with incremental cost-effectiveness ratios of £9.51 (95% CI 9.33 to 9.69) per additional whole-blood donation for the 8- versus 12- week interval for males, and £10.17 (95% CI 9.80 to 10.54) for the 12- versus 16- week interval arm for females. Over two years, reducing the minimum donation interval could provide additional units of whole-blood at a small additional cost, including for those donor subgroups whose blood type is in relatively high demand. However, the significance of self-reported symptoms needs to be investigated further before these policies are expanded.


Interactive medical image segmentation via a point-based interaction.
Due to low tissue contrast, irregular shape, and large location variance, segmenting the objects from different medical imaging modalities (e.g., CT, MR) is considered as an important yet challenging task. In this paper, a novel method is presented for interactive medical image segmentation with the following merits. (1) Its design is fundamentally different from previous pure patch-based and image-based segmentation methods. It is observed that during delineation, the physician repeatedly check the intensity from area inside-object to outside-object to determine the boundary, which indicates that comparison in an inside-out manner is extremely important. Thus, the method innovatively models the segmentation task as learning the representation of bi-directional sequential patches, starting from (or ending in) the given central point of the object. This can be realized by the proposed ConvRNN network embedded with a gated memory propagation unit. (2) Unlike previous interactive methods (requiring bounding box or seed points), the proposed method only asks the physician to merely click on the rough central point of the object before segmentation, which could simultaneously enhance the performance and reduce the segmentation time. (3) The method is utilized in a multi-level framework for better performance. It has been systematically evaluated in three different segmentation tasks, including CT kidney tumor, MR prostate, and PROMISE12 challenge, showing promising results compared with state-of-the-art methods.


Effective contrast of colored stimuli in the mesopic range: a metric for perceived contrast based on achromatic luminance contrast.
Little is known about how color signals and cone- and rod-based luminance signals contribute to perceived contrast in the mesopic range. In this study the perceived contrast of colored, mesopic stimuli was matched with that of spatially equivalent achromatic stimuli. The objective was to develop a metric for perceived contrast in the mesopic range in terms of an equivalent achromatic luminance contrast, referred to here as effective contrast. Stimulus photopic luminance contrast, scotopic luminance contrast, and chromatic difference from the background all contributed to effective contrast over the mid-mesopic range, but their contributions were not independent and varied markedly with background luminance. Surprisingly, color made a significant contribution to effective contrast from 10 to approximately 0.003 cd m(-2). A model describing this relationship is introduced (R2 = 0.89) and compared with predictions of mesopic luminance contrast obtained from a number of models proposed as systems of mesopic photometry.


Angiographic evaluation of right upper-limb arterial anomalies: implications for transradial coronary interventions.
Upper-limb arterial anomalies are sometimes encountered during transradial coronary procedures. These anomalies may contribute to procedural failure or to vascular complications, and are a major reason why many operators tend to avoid transradial procedures. We investigated the frequency of right upperlimb arterial anomalies using antegrade arteriography in patients undergoing transbrachial coronary angiography or intervention, and discuss the potential impact of these anomalies on the transradial procedure. We prospectively studied 163 consecutive patients who underwent right transbrachial coronary angiography or intervention for the first time during the period from May 2007 to December 2007. Following the transbrachial procedure, we performed antegrade transbrachial arteriography of right upper-limb arteries in these patients and investigated the frequency and anatomy of arterial anomalies. A total of 40 upper-limb arterial anomalies were observed in 38 patients (23.3%). These included 8 abnormal origins (4.9%), 2 radio-ulnar loops (1.2%), 25 tortuosities (15.3%), 4 stenoses (2.5%) and 1 loop (0.6%). In patients with congenital lesions (8 patients; 4.9%), abnormal origin of the radial artery was the most common anomaly encountered, and in the acquired group (25 patients; 15.3%), tortuosity was the most common abnormality. Even with a 23.3% incidence of right upper-limb arterial abnormalities, 98.8% of patients were acceptable for transradial coronary intervention except for 1.2% of radio-ulnar loops.


Practical management of well differentiated thyroid carcinoma in Korea.
The optimal extent of surgery and postoperative management of patients with well differentiated thyroid carcinoma (WDTC) vary among countries and institutions. We assessed the practical management of WDTC in Korea by questionnaire and compared these results with those obtained in similar surveys of members of the Japanese Society of Thyroid Surgery (JSTS) and the International Association of Endocrine Surgeons (IAES). Questionnaires were sent by mail or e-mail to 266 members of the Korean Association of Endocrine Surgeons (KAES). Ninety members (33.8%) completed the questionnaire; their responses were compared with those of the JSTS and IAES surveys. Total thyroidectomy was more prevalent in the KAES and IAES than in the JSTS, irrespective of tumor size in the low-risk group. Patients with papillary microcarcinoma were more likely to undergo aggressive central compartment node dissection in the KAES than in the IAES or JSTS. Thyroid stimulating hormone suppression therapy was administered to a higher proportion of patients and for longer times in the KAES and IAES than in the JSTS. Postoperative radioactive iodine treatment was more prevalent in the KAES than in the JSTS. There were no differences between the KAES and the JSTS in the treatment of patients with locally advanced thyroid carcinoma. External irradiation and radioactive iodine treatment for recurrent papillary thyroid carcinoma were favored more by the KAES than the IAES and JSTS. The actual practices of members of the KAES were almost similar to those of the IAES, but differed from those in Japan in some aspects. In general, however, members of the KAES favored more aggressive treatment of WDTC than did physicians in other countries.


The RecQ DNA helicases in DNA repair.
The RecQ helicases are conserved from bacteria to humans and play a critical role in genome stability. In humans, loss of RecQ gene function is associated with cancer predisposition and/or premature aging. Recent experiments have shown that the RecQ helicases function during distinct steps during DNA repair; DNA end resection, displacement-loop (D-loop) processing, branch migration, and resolution of double Holliday junctions (dHJs). RecQ function in these different processing steps has important implications for its role in repair of double-strand breaks (DSBs) that occur during DNA replication and meiosis, as well as at specific genomic loci such as telomeres.


Long-term body weight fluctuation is associated with metabolic syndrome independent of current body mass index among Japanese men.
The relation between weight fluctuation and the risk of cardiovascular disease (CVD) is fairly consistent, although the physiologic basis for the relationship is uncertain. In the present study the association between long-term weight fluctuation and the development of metabolic syndrome (MS), a potent CVD risk factor, was investigated. A cross-sectional study of 664 Japanese men aged 40-49 years was conducted. The root mean square error around the slope of weight on age (weight - RMSE) was calculated by a simple linear regression model, in which the subject's actual weights at ages 20, 25, 30 years and 5 years prior to the study, as well as current weight, were dependent variables against the subject's age as the independent variable. Weight-RMSE was significantly and positively associated with the prevalence of each MS components (high blood pressure, hypertriglyceridemia, low-high density lipoprotein-cholesterol, high fasting glucose, and obesity). Such associations, as well as clustering of the MS component together with RMSE increase, were apparent among subjects with body mass index (BMI) <25 kg/m2, although the prevalence of MS or its components was much higher among overweight subjects (BMI >or=25 kg/m2). Development of MS possibly explains the risk of CVD not only in overweight or obese persons, but also in normal-weight persons with large weight fluctuation.


Deviation of optical constants extracted in terahertz transmission spectroscopy.
We present a simulation with a Lorentz oscillator model to evaluate the accuracy of the extracted optical constants in terahertz transmission spectroscopy. The contributions of various error sources including the deflection of the incident angle, the delay-line timing error, and two other kinds of noises are analyzed. It is revealed that the influence of the deflection angle is an approximate parabolic dependence. The delay-line timing uncertainty introduces an exponential frequency dependence in the deviation of the extinction coefficient and a distinct change in the refractive index data in the resonant region. When background and 1/f noises are introduced, the deviation mainly concentrates in the resonant region.


LumbSten: the lumbar spinal stenosis outcome study.
Lumbar spinal stenosis is the most frequent reason for spinal surgery in elderly people. For patients with moderate or severe symptoms different conservative and surgical treatment modalities are recommended, but knowledge about the effectiveness, in particular of the conservative treatments, is scarce. There is some evidence that surgery improves outcome in about two thirds of the patients. The aims of this study are to derive and validate a prognostic prediction aid to estimate the probability of clinically relevant improvement after surgery and to gain more knowledge about the future course of patients treated by conservative treatment modalities. This is a prospective, multi-centre cohort study within four hospitals of Zurich, Switzerland. We will enroll patients with neurogenic claudication and lumbar spinal stenosis verified by Computer Tomography or Magnetic Resonance Imaging. Participating in the study will have no influence on treatment modality. Clinical data, including relevant prognostic data, will be collected at baseline and the Swiss Spinal Stenosis Questionnaire will be used to quantify severity of symptoms, physical function characteristics, and patient's satisfaction after treatment (primary outcome). Data on outcome will be collected 6 weeks, and 6, 12, 24 and 36 months after inclusion in the study. Applying multivariable statistical methods, a prediction rule to estimate the course after surgery will be derived. The ultimate goal of the study is to facilitate optimal, knowledge based and individualized treatment recommendations for patients with symptomatic lumbar spinal stenosis.


A common neural scale for the subjective pleasantness of different primary rewards.
When an economic decision is taken, it is between goals with different values, and the values must be on the same scale. Here, we used functional MRI to search for a brain region that represents the subjective pleasantness of two different rewards on the same neural scale. We found activity in the ventral prefrontal cortex that correlated with the subjective pleasantness of two fundamentally different rewards, taste in the mouth and warmth on the hand. The evidence came from two different investigations, a between-group comparison of two independent fMRI studies, and from a within-subject study. In the latter, we showed that neural activity in the same voxels in the ventral prefrontal cortex correlated with the subjective pleasantness of the different rewards. Moreover, the slope and intercept for the regression lines describing the relationship between activations and subjective pleasantness were highly similar for the different rewards. We also provide evidence that the activations did not simply represent multisensory integration or the salience of the rewards. The findings demonstrate the existence of a specific region in the human brain where neural activity scales with the subjective pleasantness of qualitatively different primary rewards. This suggests a principle of brain processing of importance in reward valuation and decision-making.


Redesign of a plugged beta-barrel membrane protein.
The redesign of biological nanopores is focused on bacterial outer membrane proteins and pore-forming toxins, because their robust β-barrel structure makes them the best choice for developing stochastic biosensing elements. Using membrane protein engineering and single-channel electrical recordings, we explored the ferric hydroxamate uptake component A (FhuA), a monomeric 22-stranded β-barrel protein from the outer membrane of Escherichia coli. FhuA has a luminal cross-section of 3.1 × 4.4 nm and is filled by a globular N-terminal cork domain. Various redesigned FhuA proteins were investigated, including single, double, and multiple deletions of the large extracellular loops and the cork domain. We identified four large extracellular loops that partially occlude the lumen when the cork domain is removed. The newly engineered protein, FhuAΔC/Δ4L, was the result of a removal of almost one-third of the total number of amino acids of the wild-type FhuA (WT-FhuA) protein. This extensive protein engineering encompassed the entire cork domain and four extracellular loops. Remarkably, FhuAΔC/Δ4L forms a functional open pore in planar lipid bilayers, with a measured unitary conductance of ∼4.8 nanosiemens, which is much greater than the values recorded previously with other engineered FhuA protein channels. There are numerous advantages and prospects of using such an engineered outer membrane protein not only in fundamental studies of membrane protein folding and design, and the mechanisms of ion conductance and gating, but also in more applicative areas of stochastic single-molecule sensing of proteins and nucleic acids.


Sphingosine kinase 1 is a reliable prognostic factor and a novel therapeutic target for uterine cervical cancer.
Sphingosine kinase 1 (SPHK1), an oncogenic kinase, has previously been found to be upregulated in various types of human malignancy and to play a crucial role in tumor development and progression. Although SPHK1 has gained increasing prominence as an important enzyme in cancer biology, its potential as a predictive biomarker and a therapeutic target in cervical cancer remains unknown. SPHK1 expression was examined in 287 formalin-fixed, paraffin-embedded cervical cancer tissues using immunohistochemistry, and its clinical implications and prognostic significance were analyzed. Cervical cancer cell lines including HeLa and SiHa were treated with the SPHK inhibitors SKI-II or FTY720, and effects on cell survival, apoptosis, angiogenesis, and invasion were examined. Moreover, the effects of FTY720 on tumor growth were evaluated using a patient-derived xenograft (PDX) model of cervical cancer. Immunohistochemical analysis revealed that expression of SPHK1 was significantly increased in cervical cancer compared with normal tissues. SPHK1 expression was significantly associated with tumor size, invasion depth, FIGO stage, lymph node metastasis, and lymphovascular invasion. Patients with high SPHK1 expression had lower overall survival and recurrence-free survival rates than those with low expression. Treatment with SPHK inhibitors significantly reduced viability and increased apoptosis in cervical cancer cells. Furthermore, FTY720 significantly decreased in vivo tumor weight in the PDX model of cervical cancer. We provide the first convincing evidence that SPHK1 is involved in tumor development and progression of cervical cancer. Our data suggest that SPHK1 might be a potential prognostic marker and therapeutic target for the treatment of cervical cancer.


Application of a standard test to the in vitro performance of mouthguards.
To use a simulated upper jaw made from a rubber arch containing replaceable ceramic teeth and a renewable composite ceramic jawbone to compare the effectiveness of seven custom made mouthguard designs and a "boil and bite" mouthguard. Following an earlier development of a standard impact test using a selection of projectile shapes and energies, the most sensitive conditions were selected. These were then applied to a series of six guards constructed in ethylene vinyl acetate and styrene butadiene. The guards were constructed to reflect possible variations in both design and materials. Significant differences between the mouthguard performances were observed in response to the impact conditions selected. All the custom made designs gave better performance than the "boil and bite" mouthguard. The differences observed indicated that the standard test should be sensitive enough to be used as an assessment procedure for the approval of the manufacture of these safety devices. A sequence of tests on eight identical mouthguards selected from a batch of 12, based on the best design, gave remarkably consistent results, indicating that both the manufacturing technique and the test method are reliable. The features of the best design should be incorporated into the current "best practice" for the construction of these devices.


Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation.
Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities, and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver, and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to the impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g., ill/critically ill, post-trauma, sepsis, exhausted athletes), it is currently difficult to determine whether glutamine supplementation (oral/enteral or parenteral) should be recommended based on the amino acid plasma/bloodstream concentration (also known as glutaminemia). Although the beneficial immune-based effects of glutamine supplementation are already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review of how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism and action, and important issues related to the effects of glutamine supplementation in catabolic situations.


Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat.
Seventeen adult cats were chronically implanted with electrodes for polygraphic recordings in order to assess the role of catecholamines in the arousal effects of oral administrations of modafinil, a presumed noradrenergic agonist, and amphetamine, a well-known catecholamine-releasing agent. Whereas both modafinil (1, 2.5 and 5 mg/kg) and amphetamine (0.25, 0.5 and 1 mg/kg) caused a significant and dose-dependent increase in wakefulness and brain temperature, amphetamine, but not modafinil, elicited marked signs of behavioral excitation. Pretreatments with alpha-methyl-DL-p-tyrosine methyl ester (50 mg/kg, i.p.), an inhibitor of catecholamine synthesis, almost completely prevented the effects of amphetamine (0.25 and 1 mg/kg), but only slightly reduced the duration of the waking effect of modafinil (2.5 and 5 mg/kg). Pretreatments with phentolamine (10 mg/kg, i.p.), prazosin (1.5 mg/kg, per os) and propranolol (5 mg/kg, i.p.), an alpha-, alpha 1- and beta-receptor antagonist, respectively, attenuated significantly the arousal effect of modafinil (1 mg/kg, the same as below) but not of amphetamine (0.25 mg/kg, the same as below). Intraperitoneal injections of haloperidol (0.5 mg/kg), a dopamine-receptor antagonist, blocked significantly the arousal of amphetamine but not of modafinil. The effects of both modafinil and amphetamine were enhanced by a pretreatment with yohimbine (1 mg/kg, i.p.), an alpha 2-receptor antagonist. These results suggest that the arousal effect of modafinil does not depend on the availability of the endogenous catecholamines but results from an enhancement of alpha 1- and beta-receptor activity and that the waking and behavioral effects of amphetamine may be mainly due to an increase in dopamine release.


The sodium-activated sodium channel is expressed in the rat kidney thick ascending limb and collecting duct cells and is upregulated during high salt intake.
Increased dietary salt triggers oxidative stress and kidney injury in salt-sensitive hypertension; however, the mechanism for sensing increased extracellular Na(+) concentration ([Na(+)]) remains unclear. A Na(+)-activated Na(+) channel (Na sensor) described in the brain operates as a sensor of extracellular fluid [Na(+)]; nonetheless, its presence in the kidney has not been established. In the present study, we demonstrated the gene expression of the Na sensor by RT-PCR and Western blotting in the Sprague-Dawley rat kidney. Using immunofluorescence, the Na sensor was localized to the luminal side in tubular epithelial cells of collecting ducts colocalizing with aquaporin-2, a marker of principal cells, and in thick ascending limb, colocalizing with the glycoprotein Tamm-Horsfall. To determine the effect of a high-salt diet (HSD) on Na sensor gene expression, we quantified its transcript and protein levels primarily in renal medullas from control rats and rats subjected to 8% NaCl for 7 days (n = 5). HSD increased Na sensor expression levels (mRNA: from 1.2 ± 0.2 to 5.1 ± 1.3 au; protein: from 0.98 ± 0.15 to 1.74 ± 0.28 au P < 0.05) in the kidney medulla, but not in the cortex. These data indicate that rat kidney epithelial cells of the thick ascending limb and principal cells of the collecting duct possess a Na sensor that is upregulated by HSD, suggesting an important role in monitoring changes in tubular fluid [Na(+)].


Chronic arsenic exposure and cardiac repolarization abnormalities with QT interval prolongation in a population-based study.
Chronic arsenic exposure is associated with cardiovascular abnormalities. Prolongation of the QT (time between initial deflection of QRS complex to the end of T wave) interval and profound repolarization changes on electrocardiogram (ECG) have been reported in patients with acute promyelocytic leukemia treated with arsenic trioxide. This acquired form of long QT syndrome can result in life-threatening arrhythmias. The objective of this study was to assess the cardiac effects of arsenic by investigating QT interval alterations in a human population chronically exposed to arsenic. Residents in Ba Men, Inner Mongolia, have been chronically exposed to arsenic via consumption of water from artesian wells. A total of 313 Ba Men residents with the mean arsenic exposure of 15 years were divided into three arsenic exposure groups: low (< or = 21 microg/L), medium (100-300 microg/L), and high (430-690 microg/L). ECGs were obtained on all study subjects. The normal range for QTc (corrected QT) interval is 0.33-0.44 sec, and QTc > or = 0.45 sec was considered to be prolonged. The prevalence rates of QT prolongation and water arsenic concentrations showed a dose-dependent relationship (p = 0.001). The prevalence rates of QTc prolongation were 3.9, 11.1, 20.6% for low, medium, and high arsenic exposure, respectively. QTc prolongation was also associated with sex (p < 0.0001) but not age (p = 0.486) or smoking (p = 0.1018). Females were more susceptible to QT prolongation than males. We found significant association between chronic arsenic exposure and QT interval prolongation in a human population. QT interval may potentially be useful in the detection of early cardiac arsenic toxicity.


Chronic conditions and health problems in rheumatic diseases: comparisons with rheumatoid arthritis, noninflammatory rheumatic disorders, systemic lupus erythematosus, and fibromyalgia.
To describe and compare the prevalence of lifetime and current self-reported comorbidity and associated quality of life in 4 rheumatic diseases, and to investigate comorbid conditions in light of the overlap between the index condition and comorbid conditions (CC), and in the context of symptom-type diagnoses. We studied comorbidity in 11,704 patients with fibromyalgia (FM), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and noninflammatory rheumatic disorders (NIRD). Patients completed semiannual self-reports relating to 22 present and past illnesses and completed the EuroQol (EQ-5D) utility index. CC were most common in FM, followed by SLE. FM comorbidity was dominated by depression, mental illness, and symptom-type comorbidity (e.g., gastrointestinal and genitourinary disorders). In SLE, there were substantial increases in hypertension, depression, cataract, fractures, and cardiovascular and cerebrovascular, neurologic, lung, gall bladder and endocrine disorders compared with RA. Any current CC reduced the EQ-5D utility by 0.08 to 0.16 units. The lowest EQ-5D score was noted for current psychiatric illness (0.55) and current depression (0.60). Four patterns of comorbidity emerged: that associated with aging; that associated with aging but enhanced by the index condition, as in SLE and cardiovascular disease; comorbidity that is part of the symptoms complex of the index condition; and CC that represent lifetime traits or manifestations of the underlying illness. Depression was the most strongly associated correlate of EQ-5D quality of life, and current depression was present in about 15% of patients with RA or NIRD and 34% to 39% of those with SLE and FM.


The Role of Financial Incentives Along the Antiretroviral Therapy Adherence Continuum: A Qualitative Sub-study of the HPTN 065 (TLC-Plus) Study.
The stages of change (SOC) theory suggests individuals adapt incrementally to behaviors like adherence, requiring different strategies over the behavior change continuum. Offering financial incentives (FIs) is one strategy to motivate adherence. This qualitative sub-study examined adherence barriers and the role of FIs to increase viral suppression (VS) among HIV Prevention Trials Network (HPTN) 065 study participants categorized into SOC-related adherence stages based on changes from baseline to follow-up viral load tests. Of 73 participants, most were in Maintenance stage (n = 31), defined as having achieved VS throughout HPTN 065, or in Action stage (n = 29), defined as moving from virally unsuppressed to suppressed in 50% or more of tests. Only 13 were Low Adherers, having achieved VS in fewer than 50% of tests. The latter group faced substantial social and structural adherence barriers. Participants in the Action stage made positive changes to adherence routines to achieve VS. Those in Maintenance were less incentivized by FIs, as they were already committed. Results from this sub-study suggest FI effectiveness may vary across the SOC continuum, with greatest impact for those initiating antiretroviral or without explicit adherence routines. FIs may be insufficient to overcome strong social or structural barriers, and unnecessary for those intrinsically committed to remaining adherent.


Assessment of DFT and DFT-D for Potential Energy Surfaces of Rare Gas Trimers-Implementation and Analysis of Functionals and Extrapolation Procedures.
Given the recent developments in methodology associated with the accurate computation of molecular systems with weak interactions, it is of particular interest to revisit systems that are notoriously challenging for determining reliable potential energy surface (PES) descriptions. Additionally, challenges associated with carrying out complete basis set extrapolation procedures and treatment of basis set superposition error (BSSE) are of importance in these descriptions. In this work, investigation into the ability to accurately predict the potential energy surfaces of the main Rg3 molecules (Rg = He, Ne, Ar) is made across a range of wave function types and large basis sets, including the use of several established extrapolation procedures and counterpoise corrections. Wave function types span most classes of density functional types, including the newest DFT-D schemes, and are benchmarked against high accuracy CCSD(T)/CBS methodology. Study of such systems is valuable, as they serve as simple models for many complex properties, most importantly n-body weak interaction energies.


Influence of Geometric Changes in the Thoracic Aorta due to Arterial Switch Operations on the Wall Shear Stress Distribution.
The transposition of the great arteries (TGA) is one of the most severe congenital heart diseases. The arterial switch operation (ASO) is the preferred procedure to treat TGA. Although numerous reports have shown good results after ASOs, some patients suffer from circulatory system problems following the procedure. One reason for problems post-ASO is the local changes in the curvature and torsion of the thoracic aorta. The influence of these geometric changes on the blood flow field needs to be investigated in detail to consider possible cardiovascular problems after an ASO. In this study, we conduct blood flow simulations in the thoracic aorta post-ASO, evaluate geometric changes in the aorta due to the ASO in terms of curvature and torsion, and consider the effect of geometric changes on blood flow in the aorta. It was found that a large curvature near the aortic root causes an increase in the maximal wall shear stress value in the middle systole. Moreover, a large torsion results in a circumferential change in the maximal wall shear stress region. It was also found that the maximal wall shear stress in the post-ASO models is significantly higher than that in the normal models. This indicates that the aortic aneurysm initiation risk for a post-ASO artery may be higher than that of a normal artery. To reduce the risk of initiating an aneurism, it is suggested that the curvature near the aortic root should be decreased during the ASO.


Allergic sensitization and the environment: latest update.
The prevalence of asthma and other allergic diseases is still increasing both in developed and developing countries. Allergic sensitization against common inhalant allergens is common and, although not sufficient, a necessary step in the development of allergic diseases. Despite a small number of proteins from certain plants and animals being common allergens in humans, we still do not fully understand who will develop sensitization and to which allergens. Environmental exposure to these allergens is essential for the development of sensitization, but what has emerged clearly in the literature in the recent years is that the adjuvants to which an individual is exposed at the same time as the allergen are probably an equally important determinant of the immune response to the allergen. These adjuvants act on all steps in the development of sensitization from modifying epithelial barriers, to facilitating antigen presentation, to driving T-cell responses, to altering mast cell and basophil hyperreactivity. The adjuvants come from biogenic sources, including microbes and the plants and animals that produce the allergens, and from man-made sources (anthropogenic), including unintended by-products of combustion and chemicals now ubiquitous in modern life. As we better understand how individuals are exposed to these adjuvants and how the exposure influences the likelihood of an allergic response, we may be able to design individual and community-level interventions that will reverse the increase in allergic disease prevalence, but we are not there yet.


The Biomechanical Characteristics of the Strongman Yoke Walk.
The yoke walk is a popular strongman exercise where athletes carry a heavily loaded frame balanced across the back of their shoulders over a set distance as quickly as possible. The aim of this study was to use ecologically realistic training loads and carry distances to (1) establish the preliminary biomechanical characteristics of the yoke walk; (2) identify any biomechanical differences between male and female athletes performing the yoke walk; and (3) determine spatiotemporal and kinematic differences between stages (intervals) of the yoke walk. Kinematic and spatiotemporal measures of hip and knee joint angle, and mean velocity, stride length, stride rate and stance duration of each 5 m interval were taken whilst 19 strongman athletes performed three sets of a 20 m yoke walk at 85% of their pre-determined 20 m yoke walk one repetition maximum. The yoke walk was characterised by flexion of the hip and slight to neutral flexion of the knee at heel strike, slight to neutral extension of the hip and flexion of the knee at toe-off and moderate hip and knee range of motion (ROM), with high stride rate and stance duration, and short stride length. Between-interval comparisons revealed increased stride length, stride rate and lower limb ROM, and decreased stance duration at greater velocity. Although no main between-sex differences were observed, two-way interactions revealed female athletes exhibited greater knee extension at toe-off and reduced hip ROM during the initial (0-5 m) when compared with the final three intervals (5-20 m), and covered a greater distance before reaching maximal normalised stride length than males. The findings from this study may better inform strongman coaches, athletes and strength and conditioning coaches with the biomechanical knowledge to: provide athletes with recommendation on how to perform the yoke walk based on the technique used by experienced strongman athletes; better prescribe exercises to target training adaptations required for improved yoke walk performance; and better coach the yoke walk as a training tool for non-strongman athletes.


Brachypodium distachyon and Setaria viridis: Model Genetic Systems for the Grasses.
The family of grasses encompasses the world's most important food, feed, and bioenergy crops, yet we are only now beginning to develop the genetic resources to explore the diversity of form and function that underlies economically important traits. Two emerging model systems, Brachypodium distachyon and Setaria viridis, promise to greatly accelerate the process of gene discovery in the grasses and to serve as bridges in the exploration of panicoid and pooid grasses, arguably two of the most important clades of plants from a food security perspective. We provide both a historical view of the development of plant model systems and highlight several recent reports that are providing these developing communities with the tools for gene discovery and pathway engineering.


Quantitative trait loci mapping for leaf length and leaf width in rice cv. IR64 derived lines.
The present study was conducted to identify quantitative trait loci (QTLs) for leaf size traits in IR64 introgression lines (INLs). For this purpose, selected F(2) populations derived from crosses between recurrent parent IR64 and its derived INLs, unique for leaf length and leaf width, were used to confirm QTLs. A total of eight QTLs, mapped on three chromosomes, were identified for the four leaf size traits in six F(2) populations. A QTL for leaf length, qLLnpt-1, in HKL69 was identified around simple sequence repeat (SSR) marker RM3709 on chromosome 1. Two QTLs for flag leaf length, qFLLnpt-2 and qFLLnpt-4, in HFG39 were indentified on chromosomes 2 and 4, respectively. For flag leaf width, a QTL, qFLWnpt-4, in HFG39 was identified around RM17483 on chromosome 4. While another QTL for flag leaf width, qFLWnpt-1, in HFG27 was identified around RM3252 on chromosome 1. A QTL for leaf width, qLWnpt-2, in HKL75 was identified around RM7451 on chromosome 2. For leaf width, two QTLs, qLWnpt-4a, qLWnpt-4b, in HKL48 and HKL99 were identified around RM7208 and RM6909, respectively on chromosome 4. Results from this study suggest the possibilities to use marker-assisted selection and pyramiding these QTLs to improve rice water productivity.


Consumer understanding and use of nutrition labelling: a systematic review.
To explore published and unpublished research into consumer understanding and use of nutrition labelling which is culturally applicable in Europe. A systematic review undertaken between July 2002 and February 2003. One hundred and three papers were identified that reported on consumer understanding or use of nutrition labelling, most originating from North America or northern Europe. Only a few studies (9%) were judged to be of high or medium-high quality. We found that reported use of nutrition labels is high but more objective measures suggest that actual use of nutrition labelling during food purchase may be much lower. Whether or not consumers can understand and use nutrition labelling depends on the purpose of the task. Available evidence suggests that consumers who do look at nutrition labels can understand some of the terms used but are confused by other types of information. Most appear able to retrieve simple information and make simple calculations and comparisons between products using numerical information, but their ability to interpret the nutrition label accurately reduces as the complexity of the task increases. The addition of interpretational aids like verbal descriptors and recommended reference values helps in product comparison and in putting products into a total diet context. Improvements in nutrition labelling could make a small but important contribution towards making the existing point-of-purchase environment more conducive to the selection of healthy choices. In particular, interpretational aids can help consumers assess the nutrient contribution of specific foods to the overall diet.


A series of anionic host coordination polymers based on azoxybenzene carboxylate: structures, luminescence and magnetic properties.
A series of coordination polymers {[Ln(aobtc)(H2O)4]·Hbipy·H2O}n (H4aobtc = azoxybenzene-2,2',3,3'-tetracarboxylic acid, bipy = 4,4'-bipyridine, and Ln = Sm(1), Eu(2), Gd(3), Tb(4), Dy(5), Er(6)) have been synthesized and characterized systematically. The cationic Hbipy+ guest incorporated polymers are isostructural sets, featuring a one-dimensional (1D) zigzag double chain edifice composed of binuclear clusters [Ln2(H4aobtc)2], with the Hbipy+ guest being located on two sides. These 1D chains are further interlinked into a 2D layer structure, and further extended into a 3D framework through hydrogen bonding interactions. The luminescence emission spectra of polymers 2 and 3 are based on the H4aobtc acid ligands, while 1 and 4 display the characteristic f-f transitions of Ln(iii) ions. Magnetic measurements revealed the presence of ferromagnetic behavior in polymer 3. The magnetic behaviors of 4 and 6 are ascribed to the depopulation of the Stark levels and/or weak antiferromagnetic interactions within MOFs at lower temperature. Slow relaxation is observed through the alternating-current susceptibility measurements for 5 at lower temperature, and the coexistence of weak ferromagnetism corresponding to the spin-canting-like behavior.


A randomised controlled trial of anti-smoking advice: 10-year results.
Ten-year results are reported from a randomised controlled trial of anti-smoking advice in 1445 male smokers, aged 40-59, at high risk of cardiorespiratory disease. After one year reported cigarette consumption in the intervention group (714 men) was one-quarter that of the "normal care" group (731 men); over 10 years the net reported reduction averaged 53%. The intervention group experienced less nasal obstruction, cough, dyspnoea, and loss of ventilatory function. Over 10 years their mortality from coronary heart disease was 18% lower than controls (49 and 62 deaths), and that for lung cancer was 23% lower (18 and 24 deaths). Deaths from non-lung cancers were higher in the intervention group (28 v 12 deaths). This unexpected difference was due about equally to an excess in intervention and a deficiency in normal care men, it showed no site specificity, and it was unrelated to change in smoking habit. These findings suggest that it is more likely to have been due to change than to intervention. The total number of deaths were 123 in the intervention group and 128 in normal care (95% confidence limits of difference -22% to +23%). The policy of encouraging smokers to give up the habit should not be changed.


A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria.
ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses.


Requirement for the Rac GTPase in Chlamydia trachomatis invasion of non-phagocytic cells.
Chlamydiae are gram-negative obligate intracellular pathogens to which access to an intracellular environment is paramount to their survival and replication. To this end, chlamydiae have evolved extremely efficient means of invading nonphagocytic cells. To elucidate the host cell machinery utilized by Chlamydia trachomatis in invasion, we examined the roles of the Rho GTPase family members in the internalization of chlamydial elementary bodies. Upon binding of elementary bodies on the cell surface, actin is rapidly recruited to the sites of internalization. Members of the Rho GTPase family are frequently involved in localized recruitment of actin. Clostridial Toxin B, which is a known enzymatic inhibitor of Rac, Cdc42 and Rho GTPases, significantly reduced chlamydial invasion of HeLa cells. Expression of dominant negative constructs in HeLa cells revealed that chlamydial uptake was dependent on Rac, but not on Cdc42 or RhoA. Rac but not Cdc42 was found to be activated by chlamydial attachment. The effect of dominant negative Rac expression on chlamydial uptake is manifested through the inhibition of actin recruitment to the sites of chlamydial entry. Studies utilizing Green Fluorescent Protein fusion constructs of Rac, Cdc42 and RhoA, showed Rac to be the sole member of the Rho GTPase family recruited to the site of chlamydial entry.


The medical software quality deployment method.
The objective of this study was to develop a Quality Function Deployment (QFD) model for design of information systems in health-care environments. Consecutive blocked-subject case studies were conducted, based on action research methods. Starting with a QFD model for software development, a model for information system design, the Medical Software Quality Deployment (MSQD) model, was developed. The MSQD model was divided into the pre-study phase, in which the customer categories and their power to influence the design are determined; the data collection phase, in which the voice of customers (VoC) is identified by observations and interviews and quantified by Critical. Incident questionnaires; the need specification phase, where the VoC is specified into ranked customer needs; and the design phase where the customer needs are transformed stepwise to technical requirements and design attributes. QFD showed to be useful for integrating the values of different customer categories in software development for health-care settings. In the later design phases, other quality methods should be used for software implementation and testing.


Latent tuberculosis infection in children: a call for revised treatment guidelines.
Guidelines for latent tuberculosis infection do not consider drug-resistance patterns when recommending treatment for immigrant children. The purpose of this research was to decide at what rate of isoniazid resistance a different regimen other than isoniazid for 9 months should be considered. We constructed a decision tree by using published data. We studied 3 regimens considered to be effective for susceptible organisms: (1) isoniazid for 9 months, (2) rifampin for 6 months, and (3) isoniazid for 9 months plus rifampin for 6 months. In addition, we evaluated a regimen of isoniazid and rifampin for 3 months. Our base case was a 2-year-old child from Russia with a tuberculin skin test reaction of 12 mm. We assumed a societal perspective and expressed results as cost and cost per case of tuberculosis prevented. We conducted sensitivity analyses to test the stability of our model. In our baseline analysis, rifampin was the least costly treatment regimen for any child arriving from an area with an isoniazid-resistance rate of >/=11%. Treatment with isoniazid plus rifampin was the most effective but would cost more than $1 million per reactivation case prevented. Isoniazid would become the least costly regimen if any of the following thresholds were met: rifampin resistance given isoniazid resistance of more than 82%; rifampin resistance given no isoniazid resistance of >9%; cost of rifampin more than $47/month; effectiveness of rifampin lower than 63%; effectiveness of isoniazid higher than 74%; and cost of pulmonary tuberculosis less than $7661. Isoniazid and rifampin for 3 months was the least costly for all cases from areas with isoniazid resistance of <80% as long as the regimen's effectiveness was >50% for susceptible bacteria. However, this assumption remains to be proven. Because of the high prevalence of isoniazid resistance, rifampin should be considered for children with latent tuberculosis infection originating from countries with >11% isoniazid resistance.


A single dose of mirtazapine modulates neural responses to emotional faces in healthy people.
Single-dose administration of selective serotonin and noradrenaline reuptake blockers has been shown to alter emotional processing in both behavioral and fMRI studies in healthy volunteers. Mirtazapine is a clinically established antidepressant with different pharmacological actions from monoamine reuptake inhibitors, involving blockade of noradrenaline α(2)-adrenoceptors and multiple 5-HT receptor subtypes. The aim of this study was to investigate the effect of a single dose of mirtazapine on the neural processing of emotional faces in healthy volunteers. Twenty-eight participants were randomized to receive either a single dose of mirtazapine (15 mg) or placebo. Two hours later, participants underwent an fMRI scan, in which they classified fearful and happy faces on the basis of gender. Mood and subjective experience were also measured. Whole-brain analysis showed significant group × emotion interactions in a right amygdala-hippocampal region and left fronto-striatal cortex. Post hoc analyses revealed significantly reduced activation to fear and greater activation to happy faces in both regions under mirtazapine. Our findings indicate that a single dose of mirtazapine modulates neural activity to affective stimuli. Mirtazapine was found to decrease neural responses to fear and increase responses to happy facial expressions in regions implicated in the processing of emotional faces. These effects may be important for our understanding of the neural mechanisms of antidepressant action in anxiety and depression.


Identifying genetic and environmental risk factors for chronic orofacial pain syndromes: human models.
Chronic orofacial pain syndromes are produced by nerve injury, diseases, and toxins. They constitute an unsolved medical problem because they affect a considerable number of adults and are difficult to treat. There is a remarkable variability among adults in terms of susceptibility to chronic orofacial pain and its characteristics, which suggests that these syndromes are complex heritable traits controlled by alleles of certain polymorphic genes that interact with the environment. Each syndrome is assumed to be determined by a unique set of genes. In the present report, a practical study design is proposed to identify the genes responsible for interindividual variability in orofacial pain levels. This design is based on research strategies that have been used for studying other human diseases as well as pain syndromes outside the orofacial region. Specifically, this design has been used successfully by the authors and others over the past 8 years to study chronic pain syndromes such as migraines, radiculopathy, amputation pain, and postmastectomy pain. The strategies used to study these topics have been adapted to address the unique problems of orofacial pain. The authors believe that the study of genetics provides a novel research approach from which to identify targets for the development of individually tailored approaches in orofacial pain medicine, such as diagnostic and prognostic kits and novel drugs that would prevent pain chronicity in susceptible individuals or alleviate it once it had developed. This report focuses on human models. A follow-up report is intended to extend this design into animal models of orofacial pain syndromes.


Double-lock for image encryption with virtual optical wavelength.
A new method based on the concept of virtual optics for both encryption and decryption is proposed. The technique shows the possibility to encode/decode any digital information. A virtual wavelength and a pseudo-random covering mask (PRCM) are used to design "double locks" and "double keys" for image encryption. Numerical experiments are presented to test the sensitivity of the virtual wavelength. The possible dimensions of keys are roughly estimated and show a high security level.