Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial.
Use of nonpharmacological behavioral therapy has been suggested for treatment of chronic primary insomnia, but well-blinded, placebo-controlled trials demonstrating effective behavioral therapy for sleep-maintenance insomnia are lacking. To test the efficacy of a hybrid cognitive behavioral therapy (CBT) compared with both a first-generation behavioral treatment and a placebo therapy for treating primary sleep-maintenance insomnia. Randomized, double-blind, placebo-controlled clinical trial conducted at a single academic medical center, with recruitment from January 1995 to July 1997. Seventy-five adults (n = 35 women; mean age, 55.3 years) with chronic primary sleep-maintenance insomnia (mean duration of symptoms, 13.6 years). Patients were randomly assigned to receive CBT (sleep education, stimulus control, and time-in-bed restrictions; n = 25), progressive muscle relaxation training (RT; n = 25), or a quasi-desensitization (placebo) treatment (n = 25). Outpatient treatment lasted 6 weeks, with follow-up conducted at 6 months. Objective (polysomnography) and subjective (sleep log) measures of total sleep time, middle and terminal wake time after sleep onset (WASO), and sleep efficiency; questionnaire measures of global insomnia symptoms, sleep-related self-efficacy, and mood. Cognitive behavioral therapy produced larger improvements across the majority of outcome measures than did RT or placebo treatment. For example, sleep logs showed that CBT-treated patients achieved an average 54% reduction in their WASO whereas RT-treated and placebo-treated patients, respectively, achieved only 16% and 12% reductions in this measure. Recipients of CBT also showed a greater normalization of sleep and subjective symptoms than did the other groups with an average sleep time of more than 6 hours, middle WASO of 26.6 minutes, and sleep efficiency of 85.1%. In contrast, RT-treated patients continued to report a middle WASO of 43.3 minutes and sleep efficiency of 78.8%. Our results suggest that CBT represents a viable intervention for primary sleep-maintenance insomnia. This treatment leads to clinically significant sleep improvements within 6 weeks and these improvements appear to endure through 6 months of follow-up.


Quantitative 31P-NMR for the purity determination of the organophosphorus compound brigatinib and its method validation.
The spectrum of 31P-NMR is fundamentally simpler than that of 1H-NMR; consequently identifying the target signal(s) for quantitation is simpler using quantitative 31P-NMR (31P-qNMR) than using quantitative 1H-NMR (1H-qNMR), which has been already established as an absolute determination method. We have previously reported a 31P-qNMR method for the absolute determination of cyclophosphamide hydrate and sofosbuvir as water-soluble and water-insoluble organophosphorus compounds, respectively. This study introduces the purity determination of brigatinib (BR), an organophosphorus compound with limited water solubility, using 31P-qNMR at multiple laboratories.Phosphonoacetic acid (PAA) and 1,4-BTMSB-d4 were selected as the reference standards (RSs) for 31P-qNMR and 1H-qNMR, respectively. The qNMR solvents were chosen based on the solubilities of BR and the RSs for qNMR. CD3OH was selected as the solvent for 31P-qNMR measurements to prevent the influence of deuterium exchange caused by the presence of exchangeable intramolecular protons of BR and PAA on the quantitative values, while CD3OD was the solvent of choice for the 1H-qNMR measurements to prevent the influence of water signals and the exchangeable intramolecular protons of BR and PAA. The mean purity of BR determined by 31P-qNMR was 97.94 ± 0.69%, which was in agreement with that determined by 1H-qNMR (97.26 ± 0.71%), thus indicating the feasibility of purity determination of BR by 31P-qNMR. Therefore, the findings of this study may provide an effective method that is simpler than conventional 1H-qNMR for the determination of organophosphorus compounds.


Automated acquisition of vast numbers of electron holograms with atomic-scale phase information.
An automated acquisition system for collecting a large number of electron holograms, to improve the statistical precision of phase analysis, was developed. A technique for shifting the electron beam in combination with stage movement allows data to be acquired over a wide area of a TEM-specimen grid. Undesired drift in the hologram position, which may occur during the hologram acquisition, can be corrected in real time by automated detection of the interference-fringe region in an image. To demonstrate the usefulness of the developed automated hologram acquisition system, gold nanoparticles dispersed on a carbon foil were observed with a 1.2-MV atomic resolution holography electron microscope. The system could obtain 1024 holograms, which provided phase maps for more than 500 nanoparticles with a lateral resolution of 0.14 nm, in just 1 h. The observation results revealed an anomalous increase in mean inner potential for a particle size smaller than 4 nm. The developed automated hologram acquisition system can be applied to improve the precision of phase measurement by averaging many phase images, as demonstrated by single particle analysis for biological entities. Moreover, the system makes it possible to study electrostatic potential of catalysts and other functional nanoparticles at atomic resolution.


The thrombolytic and hemorrhagic effects of tissue type plasminogen activator: influence of dosage regimens in rabbits.
Tissue type plasminogen activator (t-PA) is an effective thrombolytic agent in experimental animals and in humans. We have previously observed that the thrombolytic effect of t-PA persists beyond its time of clearance from the circulation and that wound bleeding induced by a high dose infusion of t-PA is delayed for at least one and a half hours after commencing the infusion. These observations suggest that improved thrombolysis may be obtained with t-PA by infusing a high dose over a short period of time. To test this hypothesis we compared the thrombolytic and hemorrhagic effects of t-PA infused over 240, 60, 30 and 15 minutes in the rabbit. A 4 hour infusion of 30,000 U/kg of t-PA produced 36% thrombolysis. The same dose of t-PA infused over 60, 30 and 15 minutes produced 87%, 88% and 96% thrombolysis, respectively (p less than 0.01). The 1 hour infusion of 30,000 U/kg of t-PA produced a significant increase in blood loss relative to saline infusion (p less than 0.01). The same dose infused over 30 and 15 minutes did not produce significantly more bleeding than saline. A higher dose of t-PA, 60,000 U/kg, infused over 4 hours, produced 95% thrombolysis, but was associated with a significant increase of blood loss (p less than 0.001). Our findings suggest that improved thrombolysis with t-PA with minimal bleeding side-effects is achieved in rabbits when t-PA is administered in a relatively high dose given over a short period of time.


Cardiovascular diseases in the cohort of workers first employed at Mayak PA in 1948-1958.
Incidence of and mortality from cardiovascular diseases have been studied in a cohort of 12,210 workers first employed at one of the main plants of the Mayak nuclear facility during 1948-1958 and followed up to 31 December 2000. Information on external gamma-ray doses is available for virtually all of these workers (99.9%); the mean total gamma-ray dose (+/-SD) was 0.91 +/- 0.95 Gy (99% percentile 3.9 Gy) for men and 0.65 +/- 0.75 Gy (99% percentile 2.99 Gy) for women. In contrast, plutonium body burden was measured for only 30.0% of workers; among those monitored, the mean cumulative liver dose from plutonium alpha exposure (+/- SD) was 0.40 +/- 1.15 Gy (99% percentile 5.88 Gy) for men and 0.81 +/- 4.60 Gy (99% percentile 15.95 Gy) for women. A total of 3751 cases of ischemic heart disease (IHD), including 683 cases of acute myocardial infarction (AMI), and 1495 IHD deaths, including 338 AMI deaths, were identified in the study cohort during the follow-up period. Having adjusted for non-radiation factors, there were statistically significant increasing trends with both total external gamma-ray dose and internal liver dose in IHD incidence. The trend with internal dose was weaker and was not statistically significant after adjusting for external dose, whereas the external dose trend was little changed after adjusting for internal dose. The trend with external dose in IHD mortality was not statistically significantly greater than zero but was consistent with the corresponding trend in IHD incidence. The estimated trend in IHD mortality with internal dose was lower and was not statistically significant once adjustment was made for external dose. There was a statistically significantly increasing trend in AMI incidence but not AMI incidence with external dose. The risk estimates for IHD in relation to external radiation are generally compatible with those from other large occupational studies and the Japanese A-bomb survivors.


Cas4-Cas1 Is a Protospacer Adjacent Motif-Processing Factor Mediating Half-Site Spacer Integration During CRISPR Adaptation.
The immunization of bacteria and archaea against invading viruses via CRISPR adaptation is critically reliant on the efficient capture, accurate processing, and integration of CRISPR spacers into the host genome. The adaptation proteins Cas1 and Cas2 are sufficient for successful spacer acquisition in some CRISPR-Cas systems. However, many CRISPR-Cas systems additionally require the Cas4 protein for efficient adaptation. Cas4 has been implied in the selection and processing of spacer precursors, but the detailed mechanistic understanding of how Cas4 contributes to CRISPR adaptation is lacking. Here, we biochemically reconstitute the CRISPR-Cas type I-D adaptation system and show two functionally distinct adaptation complexes: Cas4-Cas1 and Cas1-Cas2. The Cas4-Cas1 complex recognizes and cleaves protospacer adjacent motif (PAM) sequences in 3' overhangs in a sequence-specific manner, while the Cas1-Cas2 complex defines the cleavage of non-PAM sites via host-factor nucleases. Both sub-complexes are capable of mediating half-site integration, facilitating the integration of processed spacers in the correct interference-proficient orientation. We provide a model in which an asymmetric adaptation complex differentially acts on PAM- and non-PAM-containing overhangs, providing cues for the correct orientation of spacer integration.


Limited and unlimited growth of SV40-transformed cells from human diploid MRC-5 fibroblasts.
Human foetal lung strain, MRC-5, was treated with simian virus 40 and cultures were obtained that had many of the properties of transformed populations. In 10 experiments, only two produced permanent lines, designated MRC-5V1 and MRC-5V2, which have grown to passage 750 and 650, respectively. In all cases, the SV40-treated cultures acquired many of the features of transformation, including production of T-antigen, loss of contact-inhibition, and ability to grow in low concentrations of serum. The presence or absence of other transformed characteristics, such as altered morphology, abnormal karyotype or ability to grow in soft agar, can be used to distinguish between individual newly infected cultures. However, the cells invariably entered a period of slow growth, or crisis, and in eight experiments the cultures subsequently died without the emergence of a permanent line. The report that late-passage diploid cultures ae more easily transformed to permanent lines than young cultures has not been confirmed. MRC-5V1 initially had a sub-diploid chromosome number, but during serial passaging this gradually increased. MRC-5V2, which has a more extreme transformed phenotype than MRC-5V1, had a hyper-diploid chromosome number, which also increased during long-term growth. MRC-5V1 became polymorphic for glucose-6-phosphate dehydrogenase, as judged by the heat-lability and electrophoretic mobility of the enzyme. Fusions between MRC-5V1 and Lesch-Nyhan fibroblasts yielded hybrids with a limited lifespan, and certain sub-lines of MRC-5V1 also slowed down, exhibited characteristic signs of senescence and ceased to grow.


Clinical implications of long-term ECG monitoring: from loop recorder to devices remote control.
Long-term ECG monitoring has become nowadays an indispensable technology for prevention, management and treatment of many cardiac issues. Today long-term ECG monitoring is achievable through loop recorders and cardiac devices like pacemaker, implantable cardioverter-defibrillators and cardiac resynchronization therapy device-defibrillators, all of which associated with remote monitoring. Targeted long-term ECG monitoring patients who have recurrent non-documented episodes of palpitations, unexplained episodes of syncope, cryptogenic stroke or patients with a cardiomyopathy needing a risk stratification, may benefit from long-term ECG monitoring.


The insulin-like growth factor system in the prostate.
The insulin-like growth factor (IGF) system is involved in the regulation of cell growth. The system involves a network of molecules that includes the IGFs themselves (IGF-I and -II), IGF receptors (types I and II), IGF-binding proteins (IGFBP-1 through -6), and IGFBP proteases. Characterization of this complex system in the prostate has recently been initiated. Prostatic cell lines as well as primary cultures of prostatic epithelial and stromal cells have been analyzed for expression of IGFs, receptors, and IGFBPs. Prostatic epithelial cells and, quite likely, stromal cells as well respond to the mitogenic activity of IGFs via the type I IGF receptor. Prostatic stromal cells synthesize and secrete IGF-II; there is evidence that prostatic cell lines also synthesize IGFs, but this has not been confirmed in primary cultures of prostatic epithelial cells. Prostatic stromal and epithelial cells secrete a number of IGFBPs. The biological impact of some of these IGFBPs on the growth of prostatic cells has been examined, and proteolytic cleavage of IGFBP-3 by prostate-specific antigen (PSA) has been demonstrated. Aberrations in several elements of the IGF system have been observed in stromal cells derived from benign prostatic hyperplasia (BPH). The IGF system may therefore have a part in the etiology of BPH as well as in normal and malignant processes in the prostate.


Filariasis in a child from southern Turkey: a case report.
Filariasis is a parasitic condition in which the lymphatic system is invaded by filarial nematodes. The initial signs are those of lymphangitis and lymphadenitis. The manifestations include edema in the extremities and elephantiasis due to lymphatic obstruction. Filariasis is endemic to most parts of the world, but occurs only sporadically in Turkey. This report describes a case of filariasis in a child who presented with fever and extensive lower-extremity edema.


Charting the molecular landscape of the cell.
Biological function of macromolecules is closely tied to their cellular location, as well as to interactions with other molecules within the native environment of the cell. Therefore, to obtain detailed mechanistic insights into macromolecular functionality, one of the outstanding targets for structural biology is to produce an atomic-level understanding of the cell. One structural biology technique that has already been used to directly derive atomic models of macromolecules from cells, without any additional external information, is electron cryotomography (cryoET). In this perspective article, we discuss possible routes to chart the molecular landscape of the cell by advancing cryoET imaging as well as by embedding cryoET into correlative imaging workflows.


Conversion to sirolimus therapy in kidney transplant recipients with new onset diabetes mellitus after transplantation.
New-onset diabetes mellitus after transplantation (NODAT) may complicate 2-50% of kidney transplantation, and it is associated with reduced graft and patient survivals. In this retrospective study, we applied a conversion protocol to sirolimus in a cohort of kidney transplant recipients with NODAT. Among 344 kidney transplant recipients, 29 patients developed a NODAT (6.6%) and continued with a reduced dose of calcineurin inhibitors (CNI) (8 patients, Group A) or were converted to sirolimus (SIR) (21 patients, Group B). NODAT resolved in 37.5% and in 80% patients in Group A and Group B, respectively. In Group A, patient and graft survivals were 100% and 75%, respectively, not significantly different from Group B (83.4% and 68%, resp., P = 0.847). Graft function improved after conversion to sirolimus therapy: serum creatinine was 1.8 ± 0.7 mg/dL at the time of conversion and 1.6 ± 0.4 mg/dL five years after conversion to sirolimus therapy (P < 0.05), while in the group of patients remaining with a reduced dose of CNI, serum creatinine was 1.7 ± 0.6 mg/dL at the time of conversion and 1.65 ± 0.6 mg/dL at five-year followup (P = 0.732). This study demonstrated that the conversion from CNI to SIR in patients could improve significantly the metabolic parameters of patients with NODAT, without increasing the risk of acute graft rejection.


Evolution of sexual size dimorphisms in emydid turtles: ecological dimorphism, rensch's rule, and sympatric divergence.
The origin of sexual size dimorphisms (SSD) has long been a central topic in evolutionary biology. However, there is little agreement as to which factors are most important in driving the evolution of SSD, and several hypotheses concerning SSD evolution have never been tested empirically. Emydid turtles include species with both male and female-biased SSD, and some emydids exhibit among the most extreme SSD in tetrapods. Here, we use a comparative phylogenetic approach in emydids to analyze the origins of SSD and test several hypotheses for the evolution of SSD, some for the first time. We test the Fairbairn-Preziosi hypothesis for the origin of Rensch's rule, and support it in lineages with male-biased SSD but not those with female-biased SSD. We also find support for the secondary ecological dimorphism hypothesis, which proposes that selection for ecological divergence between sexes exaggerates preexisting SSD. Finally, we find only equivocal support for the Bolnick-Doebeli hypothesis, which relates intersexual ecological divergence to interspecific ecological divergence. Our results also illustrate how global analyses of SSD may mislead in groups in which the factors that drive the evolution of SSD vary among clades.


Risk factors for RhD immunisation despite antenatal and postnatal anti-D prophylaxis.
To identify risk factors for Rhesus D (RhD) immunisation in pregnancy, despite adequate antenatal and postnatal anti-D prophylaxis in the previous pregnancy. To generate evidence for improved primary prevention by extra administration of anti-D Ig in the presence of a risk factor. Case-control study. Nation-wide evaluation of the Dutch antenatal anti-D-prophylaxis programme. 42 RhD-immunised parae-1, recognised by first-trimester routine red cell antibody screening in their current pregnancy, who received antenatal and postnatal anti-D Ig prophylaxis (gifts of 1000 iu) in their first pregnancy. 339 parae-1 without red cell antibodies. Data were collected via obstetric care workers and/or personal interviews with women. Significant risk factors for RhD immunisation in multivariate analysis. Independent risk factors were non-spontaneous delivery (assisted vaginal delivery or caesarean section) (OR 2.23; 95% CI:1.04-4.74), postmaturity (>or=42 weeks of completed gestation: OR 3.07; 95% CI:1.02-9.02), pregnancy-related red blood cell transfusion (OR 3.51; 95% CI:0.97-12.7 and age (OR 0.89/year; 95% CI:0.80-0.98). In 43% of cases, none of the categorical risk factors was present. In at least half of the failures of anti-D Ig prophylaxis, a condition related to increased fetomaternal haemorrhage (FMH) and/or insufficient anti-D Ig levels was observed. Hence, RhD immunisation may be further reduced by strict compliance to guidelines concerning determination of FMH and accordingly adjusted anti-D Ig prophylaxis, or by routine administration of extra anti-D Ig after a non-spontaneous delivery and/or a complicated or prolonged third stage of labour.


Virtual implant planning and fully guided implant surgery using magnetic resonance imaging-Proof of principle.
To present a workflow of virtual implant planning and guided implant surgery with magnetic resonance imaging (MRI) and virtual dental models without the use of ionizing radiation. Five patients scheduled for implant placement underwent an MR examination at three Tesla using individualized 2D and 3D turbo spin-echo (TSE) sequences and dedicated head coils. The MRI data and virtual dental models derived from either optical model scans or intraoral scans were imported to a virtual implant planning software (coDiagnostiX, Dental Wings, Montreal, Canada). Virtual prosthetic planning and implant planning were performed regarding the hard and soft tissue anatomy. A drill guide was designed on the virtual dental model using computer-aided design (CAD) and manufactured in-house, using a 3D printer (Eden 260V, Stratasys, Eden Prairie, MN, USA). The MRI displayed all relevant anatomical structures for dental implant planning such as cortical and cancellous bone, floor of the nasal and maxillary sinus, inferior alveolar nerve and neighboring teeth. The manual alignment of virtual dental models with the MRI was possible using anatomical landmarks. Dental implant planning, CAD/CAM of a drill guide and fully guided implant placement were successfully performed. Guided implant surgery is feasible with MRI without ionizing radiation. Further studies will have to be conducted to study the accuracy of the presented protocol and compare it to the current workflow of guided surgery using CBCT.


Microbe-dependent and nonspecific effects of procedures to eliminate the resident microbiota from Drosophila melanogaster.
Comparisons of animals bearing and lacking microorganisms can offer valuable insight into the interactions between animal hosts and their resident microbiota. Most hosts are naturally infected, and therefore, these comparisons require specific procedures (e.g., antibiotic treatment or physical exclusion of microorganisms) to disrupt the microbiota, but the potential for confounding nonspecific effects of the procedure on the traits of the host exists. Microbe-dependent and nonspecific effects can be discriminated by using multiple procedures: microbe-dependent effects are evident in hosts made microbe free by different procedures, but nonspecific effects are unique to individual procedures. As a demonstration, two procedures, oral administration of chlortetracycline (50 μg ml(-1) diet) and microbiota removal by egg dechorionation, were applied to Drosophila melanogaster in a 2-by-2 factorial design. Microorganisms were undetectable in flies from dechorionated eggs and reduced by >99% in chlortetracycline-treated flies. Drosophila flies subjected to both protocols displayed an extended preadult development time, suggesting that the microbiota promotes the development rate. Female chlortetracycline-treated flies, whether from untreated or dechorionated eggs, displayed reduced protein content and egg fecundity, which could be attributed to the nonspecific effect of the antibiotic. We recommend that procedures used to disrupt the microbiota of animals should be selected, following systematic analysis of alternative mechanistically distinct procedures, on the basis of two criteria: those that achieve the greatest reduction (ideally, elimination) of the microbiota and those that achieve minimal nonspecific effects.


Utility of the 16-cm Axial Volume Scan Technique for Coronary Artery Calcium Scoring on Non-Enhanced Chest CT: A Prospective Pilot Study.
This study aimed to evaluate the utility of the 16-cm axial volume scan technique for calculating the coronary artery calcium score (CACS) using non-enhanced chest CT. This study prospectively enrolled 20 participants who underwent both, non-enhanced chest CT (16-cm-coverage axial volume scan technique) and calcium-score CT, with the same parameters, differing only in slice thickness (in non-enhanced chest CT = 0.625, 1.25, 2.5 mm; in calcium score CT = 2.5 mm). The CACS was calculated using the conventional Agatston method. The difference between the CACS obtained from the two CT scans was compared, and the degree of agreement for the clinical significance of the CACS was confirmed through sectional analysis. Each calcified lesion was classified by location and size, and a one-to-one comparison of non-contrast-enhanced chest CT and calcium score CT was performed. The correlation coefficients of the CACS obtained from the two CT scans for slice thickness of 2.5, 1.25, and 0.625 mm were 0.9850, 0.9688, and 0.9834, respectively. The mean differences between the CACS were -21.4% at 0.625 mm, -39.4% at 1.25 mm, and -76.2% at 2.5 mm slice thicknesses. Sectional analysis revealed that 16 (80%), 16 (80%), and 13 (65%) patients showed agreement for the degree of coronary artery disease at each slice interval, respectively. Inter-reader agreement was high for each slice interval. The 0.625 mm CT showed the highest sensitivity for detecting calcified lesions. The values in the non-contrast-enhanced chest CT, using the 16-cm axial volume scan technique, were similar to those obtained using the CACS in the calcium score CT, at 0.625 mm slice thickness without electrocardiogram gating. This can ultimately help predict cardiovascular risk without additional radiation exposure.


Enhancing performance in numerical magnitude processing and mental arithmetic using transcranial Direct Current Stimulation (tDCS).
The ability to accurately process numerical magnitudes and solve mental arithmetic is of highest importance for schooling and professional career. Although impairments in these domains in disorders such as developmental dyscalculia (DD) are highly detrimental, remediation is still sparse. In recent years, transcranial brain stimulation methods such as transcranial Direct Current Stimulation (tDCS) have been suggested as a treatment for various neurologic and neuropsychiatric disorders. The posterior parietal cortex (PPC) is known to be crucially involved in numerical magnitude processing and mental arithmetic. In this study, we evaluated whether tDCS has a beneficial effect on numerical magnitude processing and mental arithmetic. Due to the unclear lateralization, we stimulated the left, right as well as both hemispheres simultaneously in two experiments. We found that left anodal tDCS significantly enhanced performance in a number comparison and a subtraction task, while bilateral and right anodal tDCS did not induce any improvements compared to sham. Our findings demonstrate that the left PPC is causally involved in numerical magnitude processing and mental arithmetic. Furthermore, we show that these cognitive functions can be enhanced by means of tDCS. These findings encourage to further investigate the beneficial effect of tDCS in the domain of mathematics in healthy and impaired humans.


In vitro and in vivo photothermally enhanced chemotherapy by single-walled carbon nanohorns as a drug delivery system.
Single-walled carbon nanohorns (SWNHs) have exhibited many special advantages in biomedical applications. Herein, doxorubicin-loaded SWNHs (DOX-SWNHs) are prepared and further modified by amphiphilic deoxycholic acid modified-hydropropyl chitosan (DCA-HPCHS) to improve their biocompatibility. The obtained DOX-SWNH/DCA-HPCHS drug delivery system (DDS) possesses high stability in physiological media and excellent photothermal properties when exposed to laser irradiation in the near-infrared (NIR) region, which dramatically enhances the chemotherapy of DOX. Cell viability assays show that the growth of 4T1 cells are remarkably inhibitory under the conditions of incubation with DOX-SWNH/DCA-HPCHS and subsequent exposure to 808 nm laser irradiation to produce mild photothermal heating to 43 °C. Further investigation reveals that the photothermally enhanced chemotherapy derived from a promotion of DOX-SWNH/DCA-HPCHS uptake by the cancer cells rather than a light-triggered release of DOX. DOX-SWNH/DCA-HPCHS in combination with the use of laser irradiation exhibits a much better anticancer effect than the controls. Hence, the DOX-SWNH/DCA-HPCHS as a multifunctional DDS has been proposed and is hopeful for medicinal use in the future.


Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol.
To investigate the efficacy and tolerability of allopurinol as the first-choice antihyperuricaemic treatment for gout, and compare the efficacy and tolerability of benzbromarone and probenecid as second-choice treatment. Prospective, multicentre, open-label, two-stage randomised controlled trial in gout patients with normal renal function. Enrolled patients were given 300 mg allopurinol for 2 months (stage 1). Those patients who could not tolerate allopurinol or who did not attain the target serum urate concentration (sUr) < or=0.30 mmol/l (5.0 mg/dl), which was defined as successful, were randomised to benzbromarone 200 mg/day or probenecid 2 g/day for another 2 months (stage 2). 96 patients were enrolled in stage 1. 82 patients (85%) were eligible for the analysis at the end of stage 1: there was a mean (SD) decrease in sUr concentration of 35 (11)% from baseline; 20 patients (24%) attained target sUr < or=0.30 mmol/l; and 9 patients (11%) stopped allopurinol because of adverse drug reactions. 62 patients were enrolled in stage 2. 27 patients received benzbromarone (3 patients not eligible for analysis) and 35 received probenecid (4 patients not eligible for analysis). Treatment with benzbromarone was successful in 22/24 patients (92%) and with probenecid in 20/31 patients (65%) (p = 0.03 compared with benzbromarone). Compared with baseline values, there was a mean (SD) decrease of sUr concentration of 64 (9)% with benzbromarone and 50 (7)% with probenecid (p<0.001). This study showed that allopurinol 300 mg/day has a poor efficacy and tolerability profile when used to attain a biochemical predefined target level of sUr < or =0.30 mmol/l, following 2 months of treatment. In stage 2, benzbromarone 200 mg/day was more effective and better tolerated than probenecid 2 g/day.


Health implications of transition from a planned to a free-market economy--an overview.
China and the Former Soviet Union have both undergone substantial political and economic change in recent years as they began the transition from planned to more liberal market economies. The approaches to market liberalization in Russia (privatization in the minimum time) and China (gradual liberalization of prices and slow withdrawal of agricultural subsidies) were quite different. This paper examines some of the health implications associated with these changes, particularly in relation to the increasing burden of diet-related chronic diseases. The changing patterns of tobacco and alcohol use, increase in sedentary lifestyles and increased consumption of non-traditional, energy-dense processed foods, high in salt, fat and sugar are examined, as are the strategies used by foreign direct investors in these emerging markets to ensure market penetration, to gain a fuller understanding of how children and adults' choices of food are being influenced as a result of these socioeconomic changes. Some of the threats and opportunities facing Chinese and foreign food producers in these new conditions are assessed. It is suggested that to ensure successful prevention of future diet-related chronic diseases in such rapidly changing conditions, there needs to be a move beyond reliance solely on health education programmes and individual or local community-based interventions. A series of strategies involving multiple stakeholders should be considered as options for intervention.


Crystal structure of the MJ0490 gene product of the hyperthermophilic archaebacterium Methanococcus jannaschii, a novel member of the lactate/malate family of dehydrogenases.
The MJ0490 gene, one of the only two genes of Methanococcus jannaschii showing sequence similarity to the lactate/malate family of dehydrogenases, was classified initially as coding for a putative l-lactate dehydrogenase (LDH). It has been re-classified as a malate dehydrogenase (MDH) gene, because it shows significant sequence similarity to MT0188, MDH II from Methanobacterium thermoautotrophicum strain DeltaH. The three-dimensional structure of its gene product has been determined in two crystal forms: a "dimeric" structure in the orthorhombic crystal at 1.9 A resolution and a "tetrameric" structure in the tetragonal crystal at 2.8 A. These structures share a similar subunit fold with other LDHs and MDHs. The tetrameric structure resembles typical tetrameric LDHs. The dimeric structure is equivalent to the P-dimer of tetrameric LDHs, unlike dimeric MDHs, which correspond to the Q-dimer. The structure reveals that the cofactor NADP(H) is bound at the active site, despite the fact that it was not intentionally added during protein purification and crystallization. The preference of NADP(H) over NAD(H) has been supported by activity assays. The cofactor preference is explained by the presence of a glycine residue in the cofactor binding pocket (Gly33), which replaces a conserved aspartate (or glutamate) residue in other NAD-dependent LDHs or MDHs. Preference for NADP(H) is contributed by hydrogen bonds between the oxygen atoms of the monophosphate group and the ribose sugar of adenosine in NADP(H) and the side-chains of Ser9, Arg34, His36, and Ser37. The MDH activity of MJ0490 is made possible by Arg86, which is conserved in MDHs but not in LDHs. The enzymatic assay showed that the MJ0490 protein possesses the fructose-1,6-bisphosphate-activated LDH activity (reduction). Thus the MJ0490 gene product appears to be a novel member of the lactate/malate dehydrogenase family, displaying an LDH scaffold and exhibiting a relaxed substrate and cofactor specificities in NADP(H) and NAD(H)-dependent malate and lactate dehydrogenase reactions.


The effect of active core exercise on fitness and foot pressure in Taekwondo club students.
[Purpose] The effects of core training using slings and Togus on the improvement of posture control in Taekwondo club students, that is, balance ability, were investigated. To that end, changes in the Taekwondo players' balance ability resulting from active core training for eight weeks were examined through fitness and foot pressure. [Subjects] The present study was conducted with 13 male Taekwondo players of K University in Deagu, South Korea. Once the experiment process was explained, consent was obtained from those who participated voluntarily. [Methods] Air cushions (Germany), Jumpers (Germany), and Aero-Steps (Germany) were used as lumbar stabilization exercise tools. As a method of training proprioceptive senses by stimulating somatesthesia in standing postures, the subjects performed balance squats, supine pelvic lifts, and push-up plus exercise using slings while standing on an Aero-Step and performed hip extension parallel squats (Wall Gym Ball), and standing press-ups on a Togu using their own weight. The subjects performed four sets of these isometric exercises while maintaining an exercise time per set at 30 seconds in each session and repeated this session three times per week. [Result] Left grip strength significantly increased and number of sit-ups, which indicates muscle endurance, also significantly increased after the eight weeks exercise compared with before the exercise. The values measured during the sit and reach test, which indicate flexibility, also significantly increase after the eight weeks of exercise compared with before the exercise but only in the left foot. [Conclusion] The result of present study suggest that active core exercise using Slings and Togus can be applied as a very effective exercise program for enhancing balance, which is an important physical factor for Taekwondo club students.


Characterization of intronic uridine-rich sequence elements acting as possible targets for nuclear proteins during pre-mRNA splicing in Nicotiana plumbaginifolia.
Introns of nuclear pre-mRNAs in dicotyledonous plants, unlike introns in vertebrates or yeast, are distinctly rich in A+U nucleotides and this feature is essential for their processing. In order to define more precisely sequence elements important for intron recognition in plants, we investigated the effects of short insertions, either U-rich or A-rich, on splicing of synthetic introns in transfected protoplast of Nicotiana plumbaginifolia. It was found that insertions of U-rich (sequence UUUUUAU) but not A-rich (AUAAAAA) segments can activate splicing of a GC-rich synthetic infron, and that U-rich segments, or multimers thereof, can function irrespective of the site of insertion within the intron. Insertions of multiple U-rich segments, either at the same or different locations, generally had an additive, stimulatory effect on splicing. Mutational analysis showed that replacement of one or two U residues in the UUUUUAU sequence with A or C residues had only a small effect on splicing, but replacement with G residues was strongly inhibitory. Proteins that interact with fragments of natural and synthetic pre-mRNAs in vitro were identified in nuclear extracts of N.plumbaginifolia by UV cross- linking. The profile of cross-linked plant proteins was considerably less complex than that obtained with a HeLa cell nuclear extract. Two major cross-linkable plant proteins had apparent molecular mass of 50 and 54 kDa and showed affinity for oligouridilates present in synGC introns or for poly(U).


Effect of Huang-Lian Jie-Du Decoction on Glucose and Lipid Metabolism in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.
Background: Type 2 diabetes mellitus (T2DM) is a heterogeneous disease characterized by persistent hyperglycemia. Huang-Lian Jie-Du decoction (HLJDD) is a traditional Chinese medicine formula which is widely used in treating T2DM in China. A thorough understanding of current body of evidence is needed. Objective: this study aims to summarize the clinical evidence of HLJDD for T2DM to provide an up-to-date and accurate understanding of this issue for research and clinical practice. Methods: Six databases were searched from inception to June 27, 2020 without language and publication status restrictions and randomized controlled trials about HLJDD on T2DM were included. Two evaluators searched and screened citations independently. Risk of bias was assessed by 2019 version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB2). Risk ratio (RR) with 95% confidence interval (CI) was used as an effect measure for dichotomous outcomes and mean difference (MD) with 95% CI was used for continuous outcomes. Subgroup analyses and sensitivity analyses were carried out. Results: Nine studies including 811 participants were included in this study. The overall risk of bias was high risk. Compared with metformin alone, combination treatment of HLJDD and metformin may result in a reduction in HbA1c, FBG, 2hPG, HOMA-IR and an improved lipid metabolism. Evidence comparing HLJDD and metformin or no intervention or placebo was insufficient. The quality of evidence was low. Conclusions: Current evidence about HLJDD on T2DM is still uncertain and more high-quality studies are needed to firmly establish the clinical efficacy and safety of HLJJD.


Overexpression of the receptor tyrosine kinase Tie-1 intracellular domain in breast cancer.
Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie-1) is a receptor tyrosine kinase that regulates angiogenesis and antiapoptotic survival signaling. Tie-1 expression is generally associated with endothelial cells and neovascularization. We previously identified Tie-1 in human breast tumor samples using a PCR-based screen for protein kinases expressed in breast tumors. The purpose of this study was to determine the cell types expressing Tie-1, whether Tie-1 is expressed in tumor cells, and to examine the regulation of Tie-1 in breast cancer. Tie-1 expression was analyzed by Western blot and immunohistochemistry using an antibody to the carboxy terminus of Tie-1. Tie-1 expression was determined in a variety of cancer cell lines, clinical breast and colon tumor samples, and in corresponding benign tissue from the same patient. Tie-1 expression and distribution in breast tumors was scored by immunohistochemistry. Tie-1 was overexpressed in 14/23 breast tumors compared with 0/9 corresponding normal tissues from the same patients. Immunohistochemistry revealed that Tie-1 was overexpressed in epithelial breast cancer cells and ductal carcinoma in situ. In all breast tumor samples, Tie-1 was expressed as a truncated 40- to 43-kD doublet consisting of the intracellular portion of the protein, which contains the tyrosine kinase catalytic domain. The 40- to 43-kD Tie-1 doublet was expressed in a broad variety of cell lines. We have shown that breast cancer cells overexpress a cleaved form of the Tie-1 protein. Our results implicate the intracellular domain of Tie-1, which includes the catalytic kinase domain, in breast cancer progression.


Murein components rescue developmental sporulation of Myxococcus xanthus.
Murein (peptidoglycan) components are able to rescue sporulation in certain sporulation-defective mutants of Myxococcus xanthus. N-Acetylglucosamine, N-acetylmuramic acid, diaminopimelic acid, and D-alanine each increase the number of spores produced by SpoC mutants. When all four components are included they have a synergistic effect, raising the number of spores produced by SpoC mutants to the wild-type level. Murein-rescued spores are resistant to heat and sonic oscillation and germinate when plated on a nutrient-rich medium. They appear to be identical to fruiting body spores in their ultrastructure, in their protein composition, and in their resistance to boiling sodium dodecyl sulfate. Murein rescue of sporulation, like fruiting body sporulation, requires high cell density, a low nutrient level, and a solid surface.


Carrageenin-induced arthritis. VI. Alterations in amino acid transport by articular cartilage in acute inflammatory arthritis.
The mechanism of transport of alanine and aminoisobutyric acid into chondrocytes in rabbit articular cartilage was shown to be mediated by transport systems similar to that described for other eukaryotic cells namely the A, ASC, and L systems. Three days after the initiation of an acute inflammatory arthritis by the intra-articular injection of carrageenin into one knee joint the rate of transport of both these amino acids was decreased. Although all three transport systems were depressed, it appeared that the A and ASC systems were partially susceptible to damage by the induced inflammation. The rate of amino acid transport by the affected cartilage had recovered by 28 days after carrageenin treatment. This depression in amino acid transport is discussed in relation to a decrease in general metabolic processes in chondrocytes as a consequence of inflammation.


Genetic and environmental effects on carotid flow velocities: an international twin study.
Altered carotid blood flow velocities (CFV) have a complex background but the underlying genetic contribution is still unclear. We sought to evaluate the influence of genetics, shared and unshared environmental components on individual differences of CFV. 193 healthy twin pairs, 126 monozygotic (MZ) and 67 dizygotic (DZ) (mean age 53 ± 14 years) recruited in Italy, in the United States and in Hungary underwent bilateral color-coded Doppler flow assessment of the common carotid artery (CCA) and of the internal carotid artery (ICA) in order to assess the peak systolic (PSV) and end diastolic (EDV) velocities. Means of bilateral CFV values were used in the analysis. Age- and country-adjusted intra-class correlations were higher in monozygotic than in dizygotic pairs for mean PSV of the ICA indicating a heritability of 63%. Unique environmental factors contributed to 37% of ICA PSV. With regards to the mean PSV and EDV of the CCA, and EDV of the ICA, heritability analysis indicated no discernible role for genetic components, while the contributions of shared and unshared environmental factors ranged between 56% and 63%, and between 37% and 44% adjusted for age and country, respectively. Mean ICA/CCA ratio was driven by unique environmental factors (82%) with modest heritability (18%). Our study showed that the heritability of ICA PSV and ICA/CCA ratio is moderate, while the findings do not support heritability of other investigated CFV values. Environmental effects account for a moderate to major portion of the variance. These findings support the value of early ultrasound screening as well as the prevention of modifiable environmental factors in case of altered carotid flow velocities.


Cytokine levels as predictors of mortality in critically ill patients with severe COVID-19 pneumonia: Case-control study nested within a cohort in Colombia.
High levels of different cytokines have been associated in COVID-19 as predictors of mortality; however, not all studies have found this association and its role to cause multi-organ failure and death has not been fully defined. This study aimed to investigate the association of the levels of 10 cytokines with mortality in patients with COVID-19 admitted to the intensive care unit (ICU). This is a case-control study nested within a cohort of patients with COVID-19 who were on mechanical ventilation and were not hospitalized for more than 48 h across nine ICUs in Medellín, Colombia. Serum samples were collected upon admission to the ICU and 7 days later and used to measure cytokine levels. Upon admission, no differences in mortality between the cytokine levels were observed when comparisons were made quantitatively. However, in the multivariate analysis, patients with median IL-1β levels <1.365 pg/ml showed an increase in mortality (OR = 3.1; 1.24<7.71; p = 0.015). On day 7 in the ICU, IL-1β median levels were lower (0.34 vs. 2.41 pg/ml, p = 0.042) and IL-10 higher (2.08 vs. 1.05 pg/ml, p = 0.009) in patients who died. However, in the multivariate analysis, only IL-12p70 was associated with mortality (OR = 0.23; 0.07<0.73; p = 0.012). The mean difference in the levels between day 1 and day 7 decreased in both IFN-γ (3.939 pg/ml, p < 0.039) and in IL-18 (16.312 pg/ml, p < 0.014) in the patients who died. A low IL-1β/IL-10 ratio was associated with mortality on both day 1 and day 7, while an IL-1β/IL-10 ratio below the cut-off on day 7 was associated with decreased survival. The lowest TNFα/IL-10 ratio was associated with mortality only on day 7. At the time of admission, patients with median IL-1β levels lower than 1.365 pg/ml had increased mortality. An IL-1β/IL-10 ratio <2 at day 7 and IL-12p70 levels >1.666 pg/ml was associated with decreased survival.


Limitation on image resolution imposed by a random medium.
In underwater photography, it was reported that clear photographs were obtained through water with large (10-15) optical distances even though the MTF rolls off at a few cycles per mrad. This paper presents an explanation of this apparent contradiction by showing that at a large optical distance where the total coherent intensity is negligibly small compared with the total incoherent intensity, it is still possible to form the Airy disk due to the coherent intensity. We present the condition under which this can take place and applied the results to an imaging system in still water and in water with particulate matter.


Key2Ann: a tool to process sequence sets by replacing database identifiers with a human-readable annotation.
Deducing common properties or degrees of phylogenetic relationship by analyzing a grouping or clustering of sequence sets is a frequently used technique in computational biology. If interpreted by means of visual inspection, the conclusions depend for many of these applications on meaningful names for the input data. In accordance with the aim of the analysis, the sequences should be provided with names indicating the function of the genes or gene-products, the phylogenetic position or other properties characterizing the contributing species. However, sequences extracted from databases are most often annotated with identifiers which only implicitly contain the desired information. To solve this problem, we have designed and implemented a tool named Key2Ann, which replaces in multiple fasta files the database keys with short terms indicating the taxonomic position or other features like the gene name or the EC-number. In addition, properties like habitat, growth temperature or the degree of pathogenicity can be coded for microbial species. To allow for highest flexibility, the user can control the composition of the names by means of command line parameters. Key2Ann is written in Java and can be downloaded via http://www-bioinf.uni-regensburg.de/downl/Key2Ann.zip. We demonstrate the usage of Key2Ann by discussing three typical examples of phylogenetic analysis.


Materials with on-demand refractive indices in the terahertz range.
We demonstrate the possibility to create materials with chosen refractive indices and a strong birefringence in the terahertz range by etching of patterns with appropriate filling factors in a dielectric substrate. We show that by using deep inductive plasma etching of silicon wafers, it is possible to achieve a birefringence as high as 1.2 in an 80 microm thick layer. The resulting stacks were used as building blocks for a photonic crystal displaying sharp defect mode peaks in transmittance.


Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza.
The immune responses to influenza, a virus that exhibits strain variation, show complex dynamics where prior immunity shapes the response to the subsequent infecting strains. Original antigenic sin (OAS) describes the observation that antibodies to the first encountered influenza strain, specifically antibodies to the epitopes on the head of influenza's main surface glycoprotein, haemagglutinin (HA), dominate following infection with new drifted strains. OAS suggests that responses to the original strain are preferentially boosted. Recent studies also show limited boosting of the antibodies to conserved epitopes on the stem of HA, which are attractive targets for a 'universal vaccine'. We develop multi-epitope models to explore how pre-existing immunity modulates the immune response to new strains following immunization. Our models suggest that the masking of antigenic epitopes by antibodies may play an important role in describing the complex dynamics of OAS and limited boosting of antibodies to the stem of HA. Analysis of recently published data confirms model predictions for how pre-existing antibodies to an epitope on HA decrease the magnitude of boosting of the antibody response to this epitope following immunization. We explore strategies for boosting of antibodies to conserved epitopes and generating broadly protective immunity to multiple strains.


Preeclampsia and Neurodevelopmental Outcomes: Potential Pathogenic Roles for Inflammation and Oxidative Stress?
Preeclampsia (PE) is a common and serious hypertensive disorder of pregnancy that occurs in approximately 3-5% of first-time pregnancies and is a well-known leading cause of maternal and neonatal mortality and morbidity. In recent years, there has been accumulating evidence that in utero exposure to PE acts as an environmental risk factor for various neurodevelopmental disorders, particularly autism spectrum disorder and ADHD. At present, the mechanism(s) mediating this relationship are uncertain. In this review, we outline the most recent evidence implicating a causal role for PE exposure in the aetiology of various neurodevelopmental disorders and provide a novel interpretation of neuroanatomical alterations in PE-exposed offspring and how these relate to their sub-optimal neurodevelopmental trajectory. We then postulate that inflammation and oxidative stress, two prominent features of the pathophysiology of PE, are likely to play a major role in mediating this association. The increased inflammation in the maternal circulation, placenta and fetal circulation in PE expose the offspring to both prenatal maternal immune activation-a risk factor for neurodevelopmental disorders, which has been well-characterised in animal models-and directly higher concentrations of pro-inflammatory cytokines, which adversely affect neuronal development. Similarly, the exaggerated oxidative stress in the mother, placenta and foetus induces the placenta to secrete factors deleterious to neurons, and exposes the fetal brain to directly elevated oxidative stress and thus adversely affects neurodevelopmental processes. Finally, we describe the interplay between inflammation and oxidative stress in PE, and how both systems interact to potentially alter neurodevelopmental trajectory in exposed offspring.


Persistence and compliance to antidepressant treatment in patients with depression: a chart review.
Adherence has recently been suggested to be divided into these two components: persistence (i.e., whether patients continue treatment or not) and compliance (i.e., whether patients take doses as instructed). However, no study has yet assessed these two clinically relevant components at the same time in adherence to antidepressant treatment in the clinical outpatient setting. In this retrospective chart-review, 6-month adherence to antidepressants was examined in 367 outpatients with a major depressive disorder (ICD-10) (170 males; mean +/- SD age 37.6 +/- 13.9 years), who started antidepressant treatment from April 2006 through March 2007. Additionally, we evaluated Medication Possession Rate (MPR), defined as the total days a medication was dispensed to patients divided by the treatment period. Only 161 patients (44.3%) continued antidepressant treatment for 6 months. Among 252 patients who discontinued their initial antidepressant, 63.1% of these patients did so without consulting their physicians. Sertraline use was associated with a higher persistence rate at month 6 (odds ratio 2.59 in comparison with sulpiride), and the use of anxiolytic benzodiazepines had a positive effect on persistence to antidepressant treatment only at month 1 (odds ratio 2.14). An overall MPR was 0.77; 55.6% of patients were considered compliant (i.e., a MPR of > or = 0.8). Given a high rate of antidepressant discontinuation without consulting their physicians, closer communication between patients and their physicians should be encouraged. Although the use of anxiolytic benzodiazepines was associated with a higher persistence to antidepressant treatment at month 1, the use of these drugs should be avoided as a rule, given their well-known serious adverse effects.


The issues of chemical dependency in dentistry.
The problem of chemical dependency is a topical issue in society today. With the increase in the number and types of prescription drugs, the proliferation of illegal drugs, and easy access to alcohol, chemical dependency has no socioeconomic boundaries. Professionals, blue collar workers and students, both male and female, are susceptible to the problem. The purpose of this paper is to review the literature on chemical dependency as it relates to the profession of dentistry. It will also look at the definition, prevalence, etiology, recognition, treatment and prevention of chemical dependency. Most of the evidence from the literature indicates that chemical dependency is a disease; it is treatable and can be prevented. The treatment of the disease requires the input of support groups at the professional level as well as at student level. The prevention of chemical dependency must begin in the curricula of dental schools with emphasis on the pharmacology and interaction of drugs.


Alterations in Rapid Social Evaluations in Individuals with High Autism Traits.
Typically developing adults with low and high Autism Spectrum Quotient (AQ) scores made rapid social evaluations of neutral faces when these were primed by briefly presented emotional faces. High AQ participants rated neutral faces as more threatening than low AQ participants, regardless of the prime condition. Both groups rated target neutral faces as more threatening with fearful compared with neutral primes, while neither group demonstrated an effect of happy primes on the ratings of neutral target faces. These results demonstrate subtle anomalies in rapid visual processing of emotional faces across the broader autism spectrum. They suggest that higher autism traits may be associated with a generalized threat bias in rapid social evaluations.


A sensitive phosphorescent thiol chemosensor based on an iridium(III) complex with alpha,beta-unsaturated ketone functionalized 2,2'-bipyridyl ligand.
An iridium(III)-containing phosphorescent chemosensor Ir(ppy)(2)(L)(PF(6)) (1, ppy = 2-phenylpyridine) containing a 2,2'-bipyridyl ligand (L) functionalized with an alpha,beta-unsaturated ketone for selective detection of thiol was synthesized and characterized by spectroscopic and photophysical measurements. The structure of complex 1 was determined by X-ray crystallography. In order to get an insight into 1,4-addition reactions of thiol to complex 1, the adduct 2 from reaction of 1 with benzenethiol was successfully prepared and characterized. Complex 1 shows a lowest energy absorption at ca. 450 nm, primarily ascribable to an intraligand charge transfer (ILCT) transition from the HOMO (pi) resident on the fragment -C(O)C(6)H(4)N(C(2)H(5))(2) to the LUMO (pi*) localized on the 2,2'-bipyridyl moiety in the functionalized 2,2'-bipyridyl ligand as suggested from DFT computational studies. Complex 1 is weakly emissive at ca. 587 nm at ambient temperature, arising likely from the (3)ILCT excited state. Upon addition of thiol to a semi-aqueous solution of complex 1, the lowest energy absorption is obviously blue-shifted and the emission is remarkably enhanced due probably to a conversion from the primary ILCT state to the predominant [pi(ppy)-->pi*(L)] LLCT and the [5d(Ir)-->pi*(L)] MLCT state caused by the formation of the 1-thiol adduct. The sensing properties of 1 to thiol were also investigated by ESI-MS spectrometry and (1)H NMR spectroscopy.


Catatonia in childhood and adolescence.
Child and adolescent catatonia has been poorly investigated. A literature review was undertaken to clarify phenomenology, diagnosis, etiology, and treatment as well as ethical problems of catatonia in childhood and adolescence. Although there are no accepted standardized criteria for catatonia in childhood and adolescence, catatonic features described by child psychiatrists are similar to Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria for catatonia. With respect to etiology, the motor and behavioral symptoms that are part of catatonia bear some similarities with those seen in autism. Several case reports suggest an association between catatonia and general medical conditions. Certain drugs abused by youngsters as well as prescribed medicine can induce catatonia. Regarding catatonic cases originally diagnosed as schizophrenia, it is unclear whether all of these cases should be identified as schizophrenia or whether some of them are pervasive developmental disorders that develop psychic features in adolescence. Environmental changes preceding the onset of catatonia in patients with mood disorder play a possibly important role. Examples that suggest stress-induced catatonia, although rare, also exist. A few patients exhibit features of malignant catatonia, some without taking neuroleptics and others having taken them. Benzodiazepines and electroconvulsive therapy are considered to be effective treatments for catatonic youngsters.


Impacting Delirium in the Trauma ICU Utilizing the ICU Liberation Collaborative Benchmark Report.
Delirium is a frequent complication of intensive care unit (ICU) admissions, manifesting as acute confusion with inattention and disordered thinking. Patients in the ICU who develop acute delirium are more likely to experience long-term disability and mortality. The Society of Critical Care Medicine published guidelines for the management of pain, agitation, and delirium (PAD) in the ICU in 2013. Based on these PAD guidelines, the ABCDEF bundle was created. Research is lacking on how adherence to the ABCDEF bundle elements impacts specific populations such as trauma patients. This represents a significant gap for patients whose multisystem injuries and comorbidities add a higher level of complexity to their care and outcomes. The medical ICU at a large community hospital participated in a 2-year quality improvement project as part of the Society of Critical Care Medicine's ICU Liberation Collaborative. However the organization's trauma ICU (TICU) was excluded from the study. The purpose of this study was to conduct a baseline assessment of trauma patient records to determine which bundle elements were already being applied in the TICU, and if the resources required for implementing the full ABCDEF bundle would be beneficial to the TICU patient outcomes. Benchmark data from the organization's participation in the ICU Liberation Collaborative quality improvement project served as the primary source of evidence. Analysis revealed strengths and opportunities for improvement. Incidence of delirium remained unchanged and far below national averages, indicating the need for further investigation into practices to verify this finding. An opportunity was identified to expand implementation of certain elements of the ABCDEF bundle in the trauma ICU. There is an opportunity for nurses to take the lead in improving patient outcomes. With improved education, evidence-based assessment tools, and best practice guidelines, nurses can help decrease the incidence of delirium by as much as 30%.


Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy: Subgroup analysis of a randomized, double-blind, multicenter, phase 3 study (SIRROUND-T).
To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy. This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed. Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs. Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.


[Trends and perspectives of nursing administration: a study in the Santa Casa hospital of Belo Horizonte-MG].
The "Santa Casa" Hospital of Belo Horizonte has implemented a new management system that has characterized it as a flexible organization. Based on this context, the authors of this research defined the following objectives: to analyze nursing administration by considering the implementation of the Management System (SIGESC), to describe how the nursing team perceives communication, the decision-making process and interpersonal relationships, to identify possible trends and perspectives present in the administrative practice developed. A time of transition in nursing administration that presents characteristics of classical management and contemporaneous management was shown as well as trends and perspectives that will contribute to the reorganization of nursing work in hospitals.


Use of mandibular implant overdentures: treatment policy in prosthodontic specialist clinics in Sweden.
The aim was to examine the use of mandibular implant overdentures in Swedish prosthodontic specialist clinics. Questionnaires related to treatment with mandibular implant overdentures during 2001 were sent to the heads of the 30 prosthodontic specialist clinics of the Public Dental Health Service in Sweden. Completed questionnaires were received from 28 (93%). The number of treatments with mandibular implant overdentures varied much among the clinics (0 to 22). Seven clinics had not performed any such treatment, and the median number was 2. The number of fixed implant-supported prostheses was much higher (median value 17, range 4 to 100). The correlation between the number of implant overdentures and fixed implant-supported prostheses in edentulous mandibles was weak (r = 0.33; P = 0.10). The most common anchorage system was ball attachments on two unsplinted implants. The most common reason for the choice of the overdenture treatment was the reduced cost, whereas the patient's main wish to improve denture retention came next. The question whether the demand for implant overdentures had increased during the last few years, was answered with "no" by 19, with "yes" by 5 and with "don't know" by 4 clinics. All but one responded that their attitude to implant overdentures had not changed after the introduction of free pricing in Swedish dentistry. It can be concluded that compared to the rapidly increasing international use of mandibular implant overdentures, this treatment of edentulous patients is rare in Sweden, where fixed implant-supported prostheses still are predominant.


Isolation and characterization of dynein ATPase from bull spermatozoa.
Dialysis of demembranated bull spermatozoa against a low-salt buffer resulted in the solubilization of the outer dynein arms and 15-25% of the total ATPase activity. Low-salt extracts contained three high-Mr peptides with Mr values above 300,000. The ATPase activity was associated with two particles sedimenting at 19 S and 12 S. The heavier particle contained two major high-Mr peptides with Mr values above 300,000, one major and one minor intermediate peptides with Mr values of 91,000 and 140,000 respectively and lower-Mr peptides. The 12 S particle contained one high-Mr peptide positioned between the two heavy peptides of the 19 S particle. Even though the peptide compositions of these two particles were different, the enzymic properties of their ATPases were similar. Both particles hydrolysed in the following preference order: ATP greater than CTP greater than UTP greater than ITP greater than GTP. ATPase activities were not affected by ouabain and oligomycin but were inhibited by vanadate, erythro-9-[3-(2-hydroxynonyl)]adenine and EDTA. Enzyme activities were dependent on the presence of a bivalent cation with the following preference order: Mn2+ greater than Mg2+ greater than Ca2+ greater than Ni2+. Optimal activity was observed between pH 6.5 and 9.5. The Km for ATP ranged from 40 to 50 microM for both 19 S and 12 S ATPases. These results suggest that the 12 S and 19 S particles are dyneins from outer dynein arms.


The validity of a simple outcome measure to assess stuttering therapy.
The validity of a simple and not time-consuming self-assessment (SA) Scale was tested to establish progress after or during stuttering therapy. The scores on the SA scale were related to (1) objective measures (percentage of stuttered syllables, and syllables per minute) and (2) (self-)evaluation tests (self-evaluation questionnaires and perceptual evaluations or judgments of disfluency, naturalness and comfort by naïve listeners). Data were collected from two groups of stutterers at four measurement times: pretherapy, posttherapy, 12 months after therapy and 24 months after therapy. The first group attended the Comprehensive Stuttering Program: an integrated program based on fluency shaping techniques, and the second group participated in a Dutch group therapy: the Doetinchem Method that focuses on emotions and cognitions related to stuttering. Results showed similar score patterns on the SA scale, the self-evaluation questionnaires, the objective measures over time, and significant correlations between the SA scale and syllables per minute, percentage of stuttered syllables, Struggle subscale of the Perceptions of Stuttering Inventory and judged fluency on the T1-T2 difference scores. We concluded that the validity of the SA measure was proved and therefore encourage the use of such an instrument when (stuttering) treatment efficacy is studied.


NLRC4 Gene Single Nucleotide Polymorphisms Are Associated with the Prognosis of Hemophagocytic Lymphohistiocytosis.
To analyze and study the correlation between NLR family CARD domain-containing 4 (NLRC4) gene single nucleotide polymorphisms and the prognosis of patients with hemophagocytic lymphohistiocytosis (HLH). In this study, we retrospectively studied the clinical data of 62 HLH patients, including 40 males and 22 females. The genomic DNA was extracted, and the genotypes at rs385076 locus and rs479333 locus of the NLRC4 gene were analyzed. The level of blood interleukin-18 (IL-18) was analyzed by enzyme-linked immunosorbent assay (ELISA). Compared with the TT genotype at the NLRC4 gene rs385076 locus, the mortality of HLH patients with TC genotype and CC genotype was higher (RR = 3.205, 95% CI: 1.277-4.788, p = 0.012; RR = 3.052, 95% CI: 1.098-4.753, p = 0.031). Taking the CC genotype at rs479333 of the NLRC4 gene as a reference, HLH patients with CG genotype and GG genotype had a higher risk of death (RR = 3.475, 95% CI: 1.488-5.775, p = 0.003; RR = 2.986, 95% CI: 1.014-5.570, p = 0.047). NLRC4 gene rs385076 T>C and rs479333 C>G were significantly related to the poor prognosis of HLH patients. The area under the curve (AUC) of the receiver operating curve (ROC) for the prognostic outcome of HLH with serum IL-18 level was 0.6813 (95% CI: 0.5365-0.8260, p = 0.0189). NLRC4 gene rs385076 T>C and rs479333 C>G were related to higher serum IL-18 levels. NLRC4 gene rs385076 T>C and rs479333 C>G are related to the poor prognosis of HLH patients.


Damage localization in piezo-ceramic using ultrasonic waves excited by dual point contact excitation and detection scheme.
A novel experimental technique based on point contact and Coulomb coupling is devised and optimized for ultrasonic imaging of bulk and guided waves propagation in piezo-ceramics. The Coulomb coupling technique exploits the coupling and transfer of electric field to mechanical vibrations by excitation of phonons. The point contact excitation and detection technique facilitates the spatial-temporal imaging of ultrasonic waves. The motivation of this research is the diagnosis and localization of surface cracks in the piezoelectric sensors and actuators. The underlying principle of the detection scheme is that any discontinuity on the surface causes high localization of electric gradient. The localized electric field at the defect boundaries enables then to behave as secondary passive ultrasonic sources resulting in strong back reflections. However, due to the interference between transmitted and reflected wave components from rigid boundaries and defect, the resolution on the localization of the damage is challenging. Therefore, an algorithm based on the two-dimensional spectral decomposition is utilized for selective suppression of the transmitted wave. The algorithm includes data transformation and vectorization in polar coordinates for efficient spectral decomposition. In the spectral domain, the complex wave component (phase and amplitude) are suppressed for the transmitted wave field. The reflected wave component in the spectral domain is retained and retrieved back using inverse spectral transformation. The algorithm is successful in retaining and exemplifying only the reflected wave sources arising from the strong scattering of ultrasonic waves from the surface and sub-surface defects. In summary, a novel experimental technique based on Coulomb coupling and spectral decomposition technique has been implemented for localization of surface defect in piezo-ceramic structures.


Naringenin attenuates experimental autoimmune encephalomyelitis by protecting the intact of blood-brain barrier and controlling inflammatory cell migration.
Targeting pathogenic immune cell trafficking poses an attractive opportunity to attenuate autoimmune disorders such as multiple sclerosis (MS). MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are characterized by the immune cells-mediated demyelination and neurodegeneration of the central nervous system (CNS). Our previous study has proven that dietary naringenin ameliorates EAE clinical symptoms via reducing the CNS cell infiltration. The present study examined the beneficial effects of naringenin on maintaining the blood-brain barrier in EAE mice via dietary naringenin intervention. The results showed that naringenin-treated EAE mice had an intact blood-CNS barrier by increasing tight junction-associated factors and decreasing Evans Blue dye in the CNS. Naringenin decreased the accumulation and maturation of conventional dendritic cells (cDCs), CCL19, and CCR7 in the CNS. Also, naringenin blocked the chemotaxis and antigen-presenting function of cDCs that resulted in reducing T-cell secreting cytokines (IFN-γ, IL-17, and IL-6) in the spleen. Importantly, naringenin blocked pathogenic T cells infiltrated into the CNS and attenuates passive EAE. Therefore, by blocking chemokine-mediated migration of DCs and pathogenic T cells into the CNS, naringenin attenuates EAE pathogenesis and might be a potential candidate for the treatment of autoimmune diseases, such as MS and other chronic T-cell mediated autoimmune diseases.


Diet complexity and l-threonine supplementation: effects on growth performance, immune response, intestinal barrier function, and microbial metabolites in nursery pigs.
The aim of this study was to investigate the effects of diet complexity and l-Thr supplementation level on the growth performance, immune response, intestinal barrier function, and microbial metabolites in nursery pigs. Thirty-two weaned pigs (body weight 7.23 ± 0.48 kg) were randomly assigned to dietary treatments in a 2 × 2 factorial arrangement based on diet complexity (complex or simple) and dietary Thr content. The complex diet contained fish meal, plasma protein, and dried whey to mimic a conventional nursery diet. The simple diet was formulated with corn, wheat, and soybean meal and did not contain any animal products. l-Thr was supplemented to each diet to supply either 100% (STD Thr) or 115% (SUP Thr) of the NRC (2012) requirement for standardized ileal digestible Thr. Pigs were individually housed and fed experimental diets ad libitum for 14 d. Diet complexity, dietary Thr content, and their interactions were considered the main effects. Pigs fed the simple diet had greater (P < 0.05) plasma interleukin (IL)-10 and IL-6 concentrations compared with those fed the complex diet on days 7 and 14, respectively. Simple diet-fed pigs tended to show greater (P < 0.10) expression of genes encoding for tumor necrosis factor-α, claudin-1, and zonula occludens-1 in the jejunum compared with complex diet-fed pigs. The simple diet-fed pigs had greater (P < 0.05) concentrations of NH3-N in the jejunum digesta than did complex diet-fed pigs. The SUP Thr increased (P < 0.05) villus height and goblet cell (GC) density in villi and crypts in the jejunum and deepened (P < 0.05) crypts in the proximal colon. The SUP Thr resulted in the upregulation (P < 0.05) of occludin gene expression and a tendency toward the downregulation (P = 0.10) of IL-6 gene expression in the jejunum. Interactions (P < 0.05) between diet complexity and l-Thr supplementation level were observed in GC density in the crypt, NH3-N concentration in the jejunum, and the contents of acetate, propionate, and total volatile fatty acids in the colon. In conclusion, feeding a simple diet to nursery pigs resulted in systemic and intestinal inflammation. The SUP Thr diet did not normalize the simple diet-induced inflammation but improved gut integrity. SUP Thr seems to have greater benefits with a simple diet than with a complex diet. Therefore, SUP Thr in a simple diet could be a beneficial nutritional strategy for enhancing gut health.


Efficacy and safety of oral continuous low-dose versus short-term high-dose vitamin D: a prospective randomised trial conducted in a clinical setting.
To compare the efficacy and safety of a 10-day, high-dose v a 3-month, continuous low-dose oral cholecalciferol course in a vitamin D deficient population. The primary end points were the change in serum 25-hydroxyvitamin D (25(OH)D) concentrations at 3 months and the development of hypercalcaemia and hypercalciuria. Fifty-nine vitamin D deficient inpatients (serum 25(OH)D < or = 50 nmol/L) were enrolled in a prospective, randomised, open-label trial. Participants were randomly assigned to a high-dose regimen of cholecalciferol 50 000 IU daily for 10 days or a 3-month, continuous low-dose cholecalciferol regimen of 3000 IU daily for 30 days, followed by 1000 IU daily for 60 days. Both groups received calcium citrate 500 mg daily. Twenty-six patients completed the study within 3 - or + 1 months. The mean increases in serum 25(OH)D were similar in both the high- and low-dose groups (to 55 v 51 nmol/L, respectively; P = 0.9). There was no significant difference in the proportion of subjects who attained serum 25(OH)D concentrations > 50 nmol/L between the high- and low-dose groups (9/10 v 13/14, respectively; P = 1.0). Hypercalciuria (urine calcium > 7.5 mmol/day) occurred in three patients (two low-dose, one high-dose), while renal impairment worsened in one patient. No patient developed hypercalcaemia (corrected calcium > 2.6 mmol/L), vitamin D toxicity (25(OH)D > 200 nmol/L) or nephrolithiasis during the study. Both the 10-day, high-dose and the 3-month, low-dose cholecalciferol regimens effectively increased serum 25(OH)D to within the normal range. The high-dose regimen may be an effective and cheap alternative for patients with vitamin D deficiency. Australian Clinical Trials Registry ACTRN 12607000338460.


Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics.
Diphtheria toxin-like ADP-ribosyltransferases catalyse a posttranslational modification, ADP-ribosylation and form a protein family of 17 members in humans. Two of the family members, tankyrases 1 and 2, are involved in several cellular processes including mitosis and Wnt/β-catenin signalling pathway. They are often over-expressed in cancer cells and have been linked with the survival of cancer cells making them potential therapeutic targets. In this study, we identified nine tankyrase inhibitors through virtual and in vitro screening. Crystal structures of tankyrase 2 with the compounds showed that they bind to the nicotinamide binding site of the catalytic domain. Based on the co-crystal structures we designed and synthesized a series of tetrahydroquinazolin-4-one and pyridopyrimidin-4-one analogs and were subsequently able to improve the potency of a hit compound almost 100-fold (from 11 μM to 150 nM). The most potent compounds were selective towards tankyrases over a panel of other human ARTD enzymes. They also inhibited Wnt/β-catenin pathway in a cell-based reporter assay demonstrating the potential usefulness of the identified new scaffolds for further development.


The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells.
The majority of cancer cells rely on elevated telomerase expression and activity for rapid growth and proliferation. Telomerase-negative cancer cells, by contrast, often employ the alternative lengthening of telomeres (ALT) pathway to maintain telomeres. ALT cells are characterized by long and dynamic telomeres and the presence of ALT-associated promyelocytic leukemia (PML) bodies (APBs). Previous work has shown the importance of APBs to the ALT pathway, but their formation and precise role remain unclear. Here, we demonstrate that a homeobox-containing protein known as HMBOX1 can directly bind telomeric double-stranded DNA and associate with PML nuclear bodies. Hence, we renamed this protein TAH1 for telomere-associated homeobox-containing protein 1. TAH1 knockdown significantly reduced the number of APBs and led to an increase in DNA damage response signals at telomeres. Importantly, TAH1 inhibition also notably reduced the presence of telomere C-circles, indicating altered ALT activity. Our findings point to TAH1 as a novel link between pathways that regulate DNA damage responses, PML nuclear bodies, and telomere homeostasis in ALT cells, and provide insight into how ALT cells may achieve sustained growth and proliferation independent of the telomerase.


Schizophrenia diagnosis and anterior hippocampal volume make separate contributions to sensory gating.
Impaired P50 gating is thought to reflect a core deficit in schizophrenia, but the relevant neural network is not well understood. The present study used EEG and MEG to assess sensory gating and volumetric MRI to measure hippocampal volume to investigate relationships between them in 22 normal controls and 22 patients with schizophrenia. In the schizophrenia group, anterior but not posterior hippocampal volume was smaller, and both the P50 and M50 gating ratios were larger (worse) than in controls. Independent of group, left-hemisphere M50 gating ratio correlated negatively with left anterior hippocampal volume, and right-hemisphere M50 gating ratio correlated negatively with right anterior hippocampal volume. Schizophrenia diagnosis predicted M50 gating independent of hippocampal volume. These results are consistent with the finding that hippocampus is a critical part of a fronto-temporal circuit involved in auditory gating.


Catheter-Associated Urinary Tract Infections in Adults: Diagnosis, Treatment, and Prevention.
Urinary tract infections (UTIs) are among the most common healthcare-associated infections, and 70%-80% are catheter-associated urinary tract infections (CAUTIs). About 25% of hospitalized patients have an indwelling urinary catheter placed during their hospital stay, and therefore, are at risk for CAUTIs, which have been associated with worse patient outcomes. Additionally, hospitals face a significant financial impact since the Centers for Medicare & Medicaid Services incentive program penalizes hospitals with higher than expected CAUTIs. Hospitalists care for many patients with indwelling urinary catheters and should be aware of and engage in processes that reduce the rate of CAUTIs. This article will discuss the diagnosis, treatment, and prevention of CAUTIs in adults.


Thiamine transporter gene expression and exogenous thiamine modulate the expression of genes involved in drug and prostaglandin metabolism in breast cancer cells.
In previous studies, we have shown that RNA levels of the thiamine transporter THTR2 were down-regulated in breast cancer tumors in comparison with normal tissues and that THTR2-mediated increases in thiamine uptake activity contributed to increased apoptosis after exposure to ionizing radiation. To further understand the biological effects of the alteration of THTR2 expression, we conducted a DNA microarray study of gene expression in THTR2-transfected breast cancer cells and found that, in addition to increased expression of THTR2 attributable to the transgene, three other genes were up-regulated >2.5-fold in the transfected cells: cytochrome P450 isoform CYP4B1, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and transcription factor CRIP1. In addition, two genes were confirmed to be down-regulated in THTR2-transfected cells: trefoil factor 1 (TFF1) and Rho-GDP dissociation inhibitor (RGDI). Up-regulation of 15-PGDH and CYP4B1 expression was observed in other breast cancer cell lines transfected with THTR2, and down-regulation was observed after suppression of THTR2 with siRNA vectors. To determine the role of exogenous thiamine in the expression of these genes, we analyzed THTR2-transfected breast cancer cells grown in thiamine-depleted medium by quantitative reverse transcription-PCR and showed that three of these five genes showed evidence of regulation by exogenous thiamine in a manner concordant with the effects of THTR2 overexpression. One of the genes up-regulated by THTR2 transfection was down-regulated by thiamine depletion (CYP4B1), and two genes with decreased expression in THTR2-transfected breast cancer cells were up-regulated by thiamine depletion (TFF1 and RGDI). In summary, these studies show unexpected relationships between thiamine metabolism and genes that may be involved in the oncogenesis of breast and lung cancer.


Reasoned opinion on the toxicological properties and maximum residue levels for propoxur.
In accordance with Article 43 of Regulation (EC) No 396/2005, the European Commission requested EFSA to prepare a reasoned opinion on the toxicological properties and the existing maximum residue levels (MRLs) set for propoxur. EFSA was requested to assess the toxicological properties of propoxur and derive toxicological reference values, based on the toxicological assessment performed by Health Canada. EFSA was also requested to review the information provided by Member States and the UK on the metabolism of propoxur in plants and animals and on the current MRLs, as well as the limit of quantification (LOQ) that can be achieved with analytical methods used in MRL enforcement. Based on the information available to EFSA, toxicological reference values could not be derived for propoxur. No evidence was provided by Member States and UK that the existing EU MRLs need to be maintained as import tolerances. Information to support the current MRLs or alternative MRLs have not been provided by Member States and the UK. Codex MRLs are not in place. EFSA therefore recommended lowering of all existing EU MRLs for propoxur to the LOQ. According to the EU Reference Laboratories, sufficiently validated analytical methods are available to analyse for propoxur residues in all plant and animal commodities. Lacking toxicological reference values derived at EU level, a conclusion cannot be derived whether the setting of MRLs at the LOQs is sufficiently protective for the European consumers.


Tuning the bacterial detection sensitivity of nanostructured microelectrodes.
Fast, sensitive nucleic acid sensors that enable direct detection of bacteria and diagnosis of infectious disease would offer significant advantages over existing approaches that employ enzymatic amplification of nucleic acids. We have developed chip-based microelectrodes that are highly effective for bacterial detection and have shown that they can capture and permit the analysis of large slow moving mRNA targets. Here, we explore new approaches to tune their analytical sensitivity and investigate the effect of sensor size, material composition, and probe density on the electrochemical signals obtained in the presence of bacteria. Sensor size can be varied from 10 to 100 μm, and this parameter can change detection limits obtained by a factor of 100. Changing the surface coating can also be used to tune sensitivity, with more nanostructured coatings yielding the most sensitive detectors. Moreover, we assessed performance of the sensors by tuning probe density. Varying the density of the immobilized probe had a dramatic effect on sensitivity, with sparse probe monolayers providing superior levels of performance. Overall, this study points to several factors that can be used to tune detection limits.


Predictive factors and the effect of phenoxybenzamine on outcome in dogs undergoing adrenalectomy for pheochromocytoma.
Some studies in dogs undergoing adrenalectomy for pheochromocytoma suggest that anesthetic complications and perioperative mortality are common. In humans, surgical outcome has improved with the use of phenoxybenzamine (PBZ) before adrenalectomy. Dogs treated with PBZ before adrenalectomy have increased survival compared with untreated dogs. Forty-eight dogs that underwent adrenalectomy for pheochromocytoma. A retrospective medical record review for dogs that underwent adrenalectomy for pheochromocytoma at a veterinary medical teaching hospital over the period from January 1986 through December 2005. Twenty-three of 48 dogs were pretreated with PBZ (median dosage: 0.6 mg/kg PO q12h) for a median duration of 20 days before adrenalectomy. Duration of anesthesia and surgery, percentage of dogs with pheochromocytoma involving the right versus left adrenal gland, size of tumor, and presence of vascular invasion were similar for PBZ-treated and untreated dogs. Thirty-three (69%) of 48 dogs survived adrenalectomy in the perioperative period. PBZ-treated dogs had a significantly (P = .014) decreased mortality rate compared with untreated dogs (13 versus 48%, respectively). Additional significant prognostic factors for improved survival included younger age (P = .028), lack of intraoperative arrhythmias (P = .0075), and decreased surgical time (P = .0089). Results from this retrospective study support treatment with PBZ before surgical removal of pheochromocytoma in dogs.


Psoriasis and vascular disease-risk factors and outcomes: a systematic review of the literature.
Psoriasis afflicts 2-3% of the world's population. Affected patients commonly have risk factors for cardiovascular disease (CVD). In addition, psoriasis is independently associated with CVD and mortality. To determine which CVD risk factors are associated with psoriasis independent of confounders, whether psoriasis is associated with CVD independent of CVD risk factors, and whether there is increased mortality among patients with psoriasis. MEDLINE, Embase, and Cochrane Collaborations from inception through October 2009. We reviewed bibliographies of retrieved articles for additional references. Cross-sectional, cohort-based, case-control, and randomized controlled trials which involved patients with psoriasis. Two investigators independently reviewed studies and resolved any discrepancies by consensus. Of the 2,303 articles identified by literature search, 90 studies met inclusion criteria for this review; 15 were cohort-based studies, 45 were case-control, and 30 were cross-sectional. The quality of evidence was limited by study heterogeneity and lack of large scale prospective studies with long-term follow-up. Patients with psoriasis demonstrate a higher prevalence of cardiovascular risk factors and appear to be at increased risk for ischemic heart disease, cerebrovascular disease, and peripheral arterial disease. This increase in vascular disease may be independent of shared risk factors and may contribute to the increase in all-cause mortality. Future research should aim to more confidently distinguish between a true causal relationship or merely an association resulting from multiple shared risk factors. Physicians should screen for and aggressively treat modifiable risk factors for CVD in patients with psoriasis.


Implementation of programmes for the transition of adolescents to adult care.
Up to 15-20% of adolescents have a chronic health problem. Adolescence is a period of particular risk for the development or progression of chronic diseases for both individuals with more prevalent conditions and those affected by rare diseases. The transition from paediatric to adult care begins with preparing and training the paediatric patient, accustomed to supervised care, to assume responsibility for their self-care in an adult care setting. The transition takes place when the young person is transferred to adult care and discharged from paediatric care services. It is only complete when the youth is integrated and functioning competently within the adult care system. Adult care providers play a crucial role in welcoming and integrating young adults. A care transition programme can involve transitions of varying complexity, ranging from those required for common and known diseases such as asthma, whose management is more straightforward, to rare complex disorders requiring highly specialized personnel. The transition requires teamwork with the participation of numerous professionals: paediatricians and adult care physicians, nurses, clinical psychologists, health social workers, the pharmacy team and administrative staff. It is essential to involve adolescents in decision-making and for parents to let them take over gradually. A well-structured transition programme can improve health outcomes, patient experience, the use of health care resources and health care costs.


Selection, hitchhiking and disequilibrium analysis at three linked loci with application to HLA data.
The HLA system has been extensively studied from an evolutionary perspective. Although it is clear that selection has acted on the genes in the HLA complex, the nature of this selection has yet to be fully clarified. A study of constrained disequilibrium values is presented that is applicable to HLA and other less polymorphic systems with three or more linked loci, with the purpose of identifying selection events. The method uses the fact that three locus systems impose additional constraints on the range of possible disequilibrium values for any pair of loci. We have thus examined the behavior of the normalized pairwise disequilibrium measures using two locus (D'), and also three locus (D"), constraints on pairwise disequilibria in a three locus system when one of the three loci is under positive selection. The difference between these measures, delta = magnitude of D' - magnitude of D", has a distribution for the two unselected loci differing from that for the selected locus with either of the unselected loci (the hallmark is a high positive value of delta for the two unselected loci). An examination of genetic drift indicates that positive delta values are unlikely to be found in human populations in the absence of selection when recombination is greater than about 0.1%. This measure can thus provide insight into which allele of several linked loci might have been subject to selection. Application of this method to HLA haplotypes from a large French population study (Provinces Francaise) identifies selected alleles on particular haplotypes. Application of a complementary method, disequilibrium pattern analysis also confirms the action of selection on these haplotypes.


Carcinogens occurring naturally in foods.
Humans are susceptible to the carcinogenic action of a small group of organic and inorganic chemicals in certain industrial, medical, and social habit exposures. A larger number and wider variety of chemical carcinogens, primarily organic compounds, are known for experimental animals. Chemical carcinogens are also found among the metabolites of living cells. No common structure is evident among chemical carcinogens, and a majority of these agents are precarcinogens that require metabolic activation into reactive electrophilic ultimate carcinogens. These strong electrophiles combine covalently with nucleophilic sites in DNAs, RNAs, and proteins in target tissues. One or more of these adducts appear to initiate carcinogenesis. About 20 naturally occurring organic chemical carcinogens, primarily metabolites of green plants and fungi, are known; some occur in some human foods. Many other naturally chemical carcingens doubtless exist among the vast number of uncharacterized nonnutritive minor components of living systems, some of which are sources of human foods. The electrophilic forms of chemical carcinogens are mutagenic, and mammalian tissue-mediated mutagenicity assays appear promising in the detection of potential chemical carcinogens. These assays should serve at least as a prescreen for conventional lifetime tests in rodents for the carcinogenic activity of food components and contaminants. Epidemiological approaches appear necessary to evaluate the importance of the naturally occurring chemical carcinogens in the occurrence of human cancer.


CYP1B1 gene polymorphisms have higher risk for endometrial cancer, and positive correlations with estrogen receptor alpha and estrogen receptor beta expressions.
The estradiol metabolites by CYP1B1 received particular attention because of their causative role in malignant transformation of endometrium. We hypothesize that polymorphisms of CYP1B1 gene can predict higher incidence of endometrial cancer. To test this hypothesis, the genetic distributions of six different CYP1B1 gene polymorphisms were investigated, by sequence-specific PCR and direct DNA sequencing, in 113 Japanese endometrial cancer patients and 202 healthy controls. We also investigated whether the expression of estrogen receptors (ERalpha and ERbeta), progesterone receptor, and androgen receptor genes are influenced by the CYP1B1 genotypes in endometrial cancer. The results of our study demonstrated that the distributions of CYP1B1 genotypes at codons 119 and 432 were significantly different between endometrial cancer patients and healthy normal controls. The relative risks of 119T/T and 432G/G in endometrial cancer were calculated as 3.32 and 2.49 compared with wild-types. The 119T/T showed significant correlation for positivities of ERalpha and ERbeta. The 432G/G also showed weak correlations for ERalpha positivity. Other loci, intron 1, codon 48, and codon 449 were not different between endometrial cancer patients and healthy normal control. This is the first report that demonstrates that the rare polymorphisms at codons 119 and 432 of CYP1B1 gene have higher risk for endometrial cancer, and positive correlations with ERalpha and ERbeta expressions in endometrial cancer.