Protective efficacy of a 62-kilodalton antigen, HIS-62, from the cell wall and cell membrane of Histoplasma capsulatum yeast cells.
We reported previously that a detergent extract of the cell wall and cell membrane of Histoplasma capsulatum yeast cells contains antigens recognized by T cells. In T-cell immunoblot analysis, a region encompassing 62 kDa was stimulatory for an H. capsulatum-reactive T-cell line and T-cell clones derived from C57BL/6 mice. In this study, we isolated a 62-kDa band, termed HIS-62, from electrophoresed cell wall and cell membrane of H. capsulatum yeast cells and examined its antigenicity and immunogenicity. C57BL/6, BALB/c, and CBA/J mice that were immunized with viable H. capsulatum yeast cells mounted a delayed-type hypersensitivity response to HIS-62 that was stronger than that of normal controls. Spleen cells from each strain of mouse immunized with viable yeast cells proliferated vigorously in response to HIS-62; conversely, splenocytes from control animals did not recognize this antigen. A T-cell line and 5 of 5 T-cell clones from C57BL/6 mice, 10 of 15 BALB/c T-cell hybridomas, and 8 of 12 CBA/J T-cell hybridomas recognized HIS-62. A cutaneous delayed-type hypersensitivity response to the antigen was apparent in each strain of mouse that was injected with 80 micrograms of HIS-62 mixed with Freund adjuvant. In addition, spleen cells from HIS-62-immunized mice proliferated in vitro in response to this antigen. Vaccination of each strain of mouse with 80 micrograms of HIS-62 conferred protection against a lethal intravenous challenge with H. capsulatum yeast cells. Thus, HIS-62 appears to be an important target of the cellular immune response to H. capsulatum and induces a protective immune response in mice.


Binding of crocetin to plasma albumin.
The binding of the carotenoid crocetin to human and bovine plasma albumin was studied using absorption and fluorescence techniques. Shifts in the absorption spectrum of crocetin, quenching of the albumin fluorescence, and competitive binding studies all provided information about the binding of crocetin to albumin. These studies suggest that crocetin binds to plasma albumin by occupying the free fatty acid binding sites. The binding constants for the first two binding sites are in the 10(5)-10(7) M-1 range and are an order of magnitude less than the values reported for other conjugated polyene fatty acids. The importance of this strong plasma albumin binding to the pharmacology of crocetin is discussed.


Multicenter Evaluation of the Prostate Health Index to Detect Aggressive Prostate Cancer in Biopsy Naïve Men.
We evaluated the ability of PHI to discriminate aggressive prostate cancer from indolent or no cancer in a biopsy naïve population. Two independent prospective cohorts of 561 and 395 subjects, respectively, with no prior prostate biopsy who were enrolled at different clinical sites were used to validate the results. We compared the diagnostic specificity of PHI to prebiopsy total and percent free prostate specific antigen using prostate biopsy results. We also determined the optimal PHI threshold to discriminate aggressive prostate cancer (Gleason score 7 or greater) from indolent or no prostate cancer (Gleason score 6 or less). In the primary cohort higher PHI values were significantly associated with Gleason score 7 or greater. The AUC to detect aggressive prostate cancer was 0.815. At 95% sensitivity PHI specificity was 36.0% vs 17.2% and 19.4% for total and percent free prostate specific antigen, respectively. At 95% sensitivity for detecting aggressive prostate cancer the optimal PHI cutoff was 24, which would help avoid 41% of unnecessary biopsies. A cutoff of 24 led to 36% biopsies avoided with few aggressive cancers missed. These results were confirmed in the validation cohort. The PHI detected aggressive prostate cancer with better specificity than total and percent free prostate specific antigen in a biopsy naïve population. It could be a useful tool to decrease unnecessary prostate biopsies.


Glomerulonephritis and managing the risks of chronic renal disease.
The rising global burden of chronic renal disease, the high cost of providing renal replacement therapies, and renal disease also being a risk factor for cardiovascular disease is increasing focus on renal disease prevention. This article focuses on the aspects of renal disease (specifically poststreptococcal glomerulonephritis [PSGN] and chronic kidney disease [CKD]) in Indigenous populations in Australia, New Zealand, Canada, and the United States that diverge from those typically seen in the general population of those countries. The spectrum of renal and many other diseases seen in Indigenous people in developed countries is similar to that seen in developing countries. Diseases like PSGN that have largely disappeared in developed countries still occur frequently in Indigenous people. CKD during the childhood years is due to congenital anomalies of the kidney and urinary tract in up to 70% of cases and occurs later in polycystic kidney disease and childhood-onset diabetes. Several risk factors for CKD in adulthood are already present in childhood.


Molecular mechanisms of the inhibitory effects of jiangu granule‑containing serum on RANKL‑induced osteoclastogenesis.
Postmenopausal osteoporosis (PMOP) is characterized by increased bone loss due to enhanced osteoclastogenesis and bone resorption. A Chinese herbal formula, jiangugranule (JG), exhibited great efficacy in the clinical treatment of PMOP. However, the molecular mechanisms underlying the therapeutic effects remain unclear. The present study aimed to examine the effects of JG‑containing serum on receptor activator of nuclear factor‑κB (NF‑κB) ligand (RANKL)‑induced osteoclastogenesis. Osteoclast precursor RAW264.7 cells were cultured and treated with JG‑containing serum in the presence of RANKL. Following 6 days of culture, the cells were stained with tartrate‑resistant acid phosphatase and the rate of differentiation was calculated. In addition, cells were treated with JG‑containing serum for 24, 48 and 96 h and total RNA and proteins were extracted for reverse transcription‑quantitative polymerase chain reaction and western blot analysis to detect mRNA and protein expression, respectively, of key molecules in the RANK/RANKL signaling pathway, including RANK, tumor necrosis factor receptor‑associated factor 6, NF‑κB (p50 and p52 subunits), c‑Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). The results revealed that JG‑containing serum inhibited RANKL‑induced osteoclastogenesis and reduced mRNA and protein expression of RANK, c‑Fos and NFATc1. The results suggested that JG may regulate osteoclast differentiation through the RANK/RANKL signaling pathway, which may be a possible mechanism for the therapeutic effects of JG on PMOP.


Evaluation of radiologically implanted central venous port systems explanted due to complications.
The aim of this study was to evaluate explantations of central venous port systems that were implanted by interventional radiologists in cases where complications demanded the removal of the port device. In this retrospective single-center study, explantation rates of central venous port catheter systems (CVPS) associated with complications were investigated over a 10-year period. All CVPS were implanted and explanted in our radiology department's interventional suite. Port catheter dysfunctions were divided into early and late complications, as well as into nonthrombotic and thrombotic events. Indications for implantation and explantation as well as clinical demographics were considered. One hundred and ninety-three CVPS were removed from 182 patients, due to complications. The total indwelling time of all CVPS was 55,132 catheter-days (mean 285.7; range 1-2,704). The most common diagnoses were gastrointestinal cancers 77 (39.9%) and hematological malignancies 32 (16.6%). Bloodstream infections 134 (69.4%) were the most common indication for the explantation procedure. These were followed by catheter-related thrombosis 28 (14.5%), nonthrombotic CVPS dysfunction 18 (9.3%), port pocket infections 9 (4.7%), and others 4 (2.1%). The highest percentages of explantations related to bloodstream infections were observed in patients with malabsorption (81.8%) and hematological malignancies (81.3%). Bloodstream infections were the most common cause for port explantation, followed by catheter-related thrombosis. Complication-related explantations were mainly for late-onset complications. Prevention and management strategies should be applied regarding care and usage of port systems to reduce the rate of complication-related explantations.


How will melting of ice affect volcanic hazards in the twenty-first century?
Glaciers and ice sheets on many active volcanoes are rapidly receding. There is compelling evidence that melting of ice during the last deglaciation triggered a dramatic acceleration in volcanic activity. Will melting of ice this century, which is associated with climate change, similarly affect volcanic activity and associated hazards? This paper provides a critical overview of the evidence that current melting of ice will increase the frequency or size of hazardous volcanic eruptions. Many aspects of the link between ice recession and accelerated volcanic activity remain poorly understood. Key questions include how rapidly volcanic systems react to melting of ice, whether volcanoes are sensitive to small changes in ice thickness and how recession of ice affects the generation, storage and eruption of magma at stratovolcanoes. A greater frequency of collapse events at glaciated stratovolcanoes can be expected in the near future, and there is strong potential for positive feedbacks between melting of ice and enhanced volcanism. Nonetheless, much further research is required to remove current uncertainties about the implications of climate change for volcanic hazards in the twenty-first century.


Molecular determinants of agonist and antagonist signaling through the IL-36 receptor.
The IL-1 family consists of 11 cytokines that control a complex network of proinflammatory signals critical for regulating immune responses to infections. They also play a central role in numerous chronic inflammatory disorders. Accordingly, inhibiting the activities of these cytokines is an important therapeutic strategy for treating autoimmune diseases and lymphomas. Agonist cytokines in the IL-1 family activate signaling by binding their cognate receptor and then recruiting a receptor accessory protein. Conversely, antagonist cytokines bind their cognate receptor but prohibit recruitment of receptor accessory protein, which precludes functional signaling complexes. The IL-36 subfamily of cytokines is the most diverse, including three agonists and at least one antagonist, and is the least well-characterized group within this family. Signaling through the IL-36 receptor directly stimulates dendritic cells and primes naive CD4 T cells for Th1 responses. Appropriately balanced IL-36 signaling is a critical determinant of skin and lung health. IL-36 signaling has been presumed to function analogously to IL-1 signaling. In this study, we have defined molecular determinants of agonist and antagonist signaling through the IL-36 receptor. We present the crystal structure of IL-36γ, which, to our knowledge, is the first reported structure of an IL-36 agonist. Using this structure as a guide, we designed a comprehensive series of IL-36 agonist/antagonist chimeric proteins for which we measured binding to the IL-36 receptor/IL-1 receptor accessory protein complex and functional activation and inhibition of signaling. Our data reveal how the fine specificity of IL-36 signaling is distinct from that of IL-1.


Effects of bovine lipid extract surfactant administration in preterm infants treated for respiratory distress syndrome.
To review the initial effectiveness of bovine lipid extract surfactant (BLES) for the treatment of respiratory distress syndrome in preterm infants. A retrospective review of data collected from infants born <37-week gestation with respiratory distress syndrome treated with BLES between February 1, 2015 and March 1, 2016. Data were analyzed to determine the timing of initial dose, the length of time to wean the fraction of inspired oxygen (FiO2) concentration to 0.21 following initial dose, and the number of repeated doses given during hospital admission. Infants were subgrouped by gestational age stratum, 230 to 276 weeks (group 1), 280 to 316 weeks (group 2), and 320 to 366 weeks (group 3). Ninety-eight infants received the surfactant during the study period. After applying exclusion criteria, 77 infants were analyzed. Mean (SD) gestational age was 28 (4) weeks, and mean (SD) birth weight was 1250 (602) g. Initial dose of BLES was given at a median (interquartile range) time of 29 (19-43) minutes in group 1, 150 (20-615) minutes in group 2, and 990 (53-2025) minutes in group 3. Median (interquartile range) length of time to wean the FiO2 concentration to 0.21 was 14 (5-56) minutes, 10 (5-53) minutes, and 10 (5-38) minutes in groups 1, 2, and 3, respectively. Ten infants required repeated doses. Given the rapid response of BLES in all the groups, careful monitoring of ventilator parameters is paramount to allow for rapid weaning and early extubation to avoid lung injury associated with mechanical ventilation.


Brain abscess caused by Cladophialophora bantiana in China.
A case of a 38-year-old male farmer with a brain abscess caused by Cladophialophora bantiana is described. He had a 2 year history of non-insulin-dependent diabetes and myelodysplastic syndrome. A cranial computed tomography scan demonstrated a hypodense ring lesion with peripheral oedema and a midline shift in the left frontal lobe. A darkly pigmented mould was isolated from the brain abscess. The isolate was identified as C. bantiana based on its morphological features and DNA sequence analysis. The patient was unresponsive to burr hole aspiration and irrigation, as well as liposomal amphotericin B infusion, and died after discharge from the hospital. This is believed to be the first case of a cerebral abscess due to C. bantiana in China.


Probing specific molecular processes and intermediates by time-resolved Fourier transform infrared spectroscopy: application to the bacteriorhodopsin photocycle.
We present a general approach for probing the kinetics of specific molecular processes in proteins by time-resolved Fourier transform infrared (IR) spectroscopy. Using bacteriorhodopsin (bR) as a model we demonstrate that by appropriately monitoring some selected IR bands it is possible obtaining the kinetics of the most important events occurring in the photocycle, namely changes in the chromophore and the protein backbone conformation, and changes in the protonation state of the key residues implicated in the proton transfers. Besides confirming widely accepted views of the bR photocycle, our analysis also sheds light into some disputed issues: the degree of retinal torsion in the L intermediate to respect the ground state; the possibility of a proton transfer from Asp85 to Asp212; the relationship between the protonation/deprotonation of Asp85 and the proton release complex; and the timing of the protein backbone dynamics. By providing a direct way to estimate the kinetics of photocycle intermediates the present approach opens new prospects for a robust quantitative kinetic analysis of the bR photocycle, which could also benefit the study of other proteins involved in photosynthesis, in phototaxis, or in respiratory chains.


The Paris Climate Agreement and future sea-level rise from Antarctica.
The Paris Agreement aims to limit global mean warming in the twenty-first century to less than 2 degrees Celsius above preindustrial levels, and to promote further efforts to limit warming to 1.5 degrees Celsius1. The amount of greenhouse gas emissions in coming decades will be consequential for global mean sea level (GMSL) on century and longer timescales through a combination of ocean thermal expansion and loss of land ice2. The Antarctic Ice Sheet (AIS) is Earth's largest land ice reservoir (equivalent to 57.9 metres of GMSL)3, and its ice loss is accelerating4. Extensive regions of the AIS are grounded below sea level and susceptible to dynamical instabilities5-8 that are capable of producing very rapid retreat8. Yet the potential for the implementation of the Paris Agreement temperature targets to slow or stop the onset of these instabilities has not been directly tested with physics-based models. Here we use an observationally calibrated ice sheet-shelf model to show that with global warming limited to 2 degrees Celsius or less, Antarctic ice loss will continue at a pace similar to today's throughout the twenty-first century. However, scenarios more consistent with current policies (allowing 3 degrees Celsius of warming) give an abrupt jump in the pace of Antarctic ice loss after around 2060, contributing about 0.5 centimetres GMSL rise per year by 2100-an order of magnitude faster than today4. More fossil-fuel-intensive scenarios9 result in even greater acceleration. Ice-sheet retreat initiated by the thinning and loss of buttressing ice shelves continues for centuries, regardless of bedrock and sea-level feedback mechanisms10-12 or geoengineered carbon dioxide reduction. These results demonstrate the possibility that rapid and unstoppable sea-level rise from Antarctica will be triggered if Paris Agreement targets are exceeded.


Enhancement of external quantum efficiency and quality of heterojunction white LEDs by varying the size of ZnO nanorods.
The size of ZnO nanorods (NRs) plays an important role in tuning the external quantum efficiency (EQE) and quality of light generated by white light emitting diodes (LEDs). In this work, we report on the enhancement of EQE and the quality of ZnO NR-based hetrojunction white LEDs fabricated on a p-GaN substrate using a low temperature solution method. Cathodoluminescence spectra demonstrate that ultraviolet (UV) emission decreases and visible deep band emission increases with an increase in the length of the ZnO NRs. The UV emission could be internally reabsorbed by the ZnO NR excitation, thus enhancing the emission intensity of the visible deep band. Photocurrent measurements validated the fact that the EQE depends on the size of ZnO NRs, increasing by 87% with an increase in the length of the ZnO NRs. Furthermore, the quality of white light was measured and clearly indicated an increase in the color rendering indices of the LEDs with an increase in the length of the ZnO NRs, confirming that the quality of light generated by LEDs can be tuned by varying the length of the ZnO NRs. These results suggest that the EQE and visible deep band emission from n-ZnONRs/p-GaN heterojunction LEDs can be effectively controlled by adjusting the length of the ZnO NRs, which can be useful for realizing tunable white LEDs.


Improved outcomes with endovascular stent grafts for thoracic aorta transections.
To retrospectively assess the outcome of endovascular stent-graft implantation for thoracic aortic transections (ETAT). Retrospective review. 16 patients median age 30 years, treated between May 2000 and April 2007. Median injury severity score was 33 (range 29 to 66) in 14 acute patients; 2 patients had thoracic pseudoaneurysms. The Cook-Zenith endograft was used in eight patients, Medtronic-Talent (6) and Gore-Excluder (2). Average procedure time was 90 minutes, blood loss 100 (range 40 to 3000) mls, screening time 10.8 (range 5.9 to 22.6) minutes, and contrast dose was 195 (range 60 to 400) mls. Graft deployment was successful in all cases. There was one death within 30 days. The left subclavian artery was completely covered in one case, and partially in three. Two patients had Type I endoleak, and one delayed Type II endoleak. One patient had iatrogenic right coronary artery dissection. Two patients developed difficult to treat hypertension, and one acute renal failure. Endovascular intervention is a safe and effective treatment for aortic transection in multiple trauma patients. ETAT reduces the major morbidity and mortality associated with open repair in multiple trauma patients. The majority of these patients are young and long-term follow up is necessary to assess graft durability.


Public health investments and mortality risk in Brazilian peritoneal dialysis patients.
End-stage kidney disease (ESKD) treatment is very costly and accounts for a significant percentage of public healthcare expenditures. Beyond direct costs, dialysis patients use other healthcare levels, but the impact of public investment on each of these levels is unclear. This study aimed to investigate the association between direct financing at different healthcare levels and overall mortality in peritoneal dialysis (PD) patients. We included all adult incident PD patients from a Brazilian prospective, nationwide PD cohort. Overall mortality was the primary outcome of interest. We used a three-level multilevel survival analysis to investigate whether mortality was associated with the investments destined to different levels of healthcare complexity: (i) primary, (ii) medium and high and (iii) professional healthcare training and community awareness. We evaluated 5707 incident PD patients from 78 Brazilian cities, which were divided into four quartiles for each healthcare level (Groups I-IV). After taking the highest quartile (Group IV) as a reference, investment in the primary health level was not associated with patient survival. Otherwise, medium and high complexity levels were associated with higher mortality risk. Also, investment in healthcare manager training and community awareness had an impact on patient survival. Investments in different levels of the healthcare system have distinct impacts on PD patient survival. Investment in healthcare manager training and community awareness seems to be a promising strategy on which to focus, given the relatively low cost and positive impact on outcome.


A hybrid approach of neural network and memory-based learning to data mining.
We propose a hybrid prediction system of neural network and memory-based learning. Neural network (NN) and memory-based reasoning (MBR) are frequently applied to data mining with various objectives. They have common advantages over other learning strategies. NN and MBR can be directly applied to classification and regression without additional transformation mechanisms. They also have strength in learning the dynamic behavior of the system over a period of time. Unfortunately, they have shortcomings when applied to data mining tasks. Though the neural network is considered as one of the most powerful and universal predictors, the knowledge representation of NN is unreadable to humans, and this "black box" property restricts the application of NN to data mining problems, which require proper explanations for the prediction. On the other hand, MBR suffers from the feature-weighting problem. When MBR measures the distance between cases, some input features should be treated as more important than other features. Feature weighting should be executed prior to prediction in order to provide the information on the feature importance. In our hybrid system of NN and MBR, the feature weight set, which is calculated from the trained neural network, plays the core role in connecting both learning strategies, and the explanation for prediction can be given by obtaining and presenting the most similar examples from the case base. Moreover, the proposed system has advantages in the typical data mining problems such as scalability to large datasets, high dimensions, and adaptability to dynamic situations. Experimental results show that the hybrid system has a high potential in solving data mining problems.


Nickel-catalyzed hydroalkylation and hydroalkenylation of 1,3-dienes with hydrazones.
Transition-metal-catalyzed hydrofunctionalization of 1,3-dienes is a useful and atom-economical method for constructing allylic compounds. Although substantial progress on hydroalkylation of dienes with stabilized carbon nucleophiles has been made, hydroalkylation of dienes with unstabilized carbon nucleophiles has remained a challenge. In this article, we report a protocol for nickel-catalyzed hydroalkylation of dienes with hydrazones, which serve as equivalents of alkyl carbon nucleophiles. In addition, we developed a protocol for hydroalkenylation of dienes with α,β-unsaturated hydrazones, providing a new method for the synthesis of 1,4-dienes. These hydroalkylation and hydroalkenylation reactions feature mild conditions and a wide substrate scope, and the utility of the reaction products is demonstrated by the preparation of an activator of soluble guanylate cyclase.


Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women.
Growing antibiotic resistance warrants studying nonantibiotic prophylaxis for recurrent urinary tract infections (UTIs). Use of lactobacilli appears to be promising. Between January 2005 and August 2007, we randomized 252 postmenopausal women with recurrent UTIs taking part in a double-blind noninferiority trial to receive 12 months of prophylaxis with trimethoprim-sulfamethoxazole, 480 mg, once daily or oral capsules containing 109 colony-forming units of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 twice daily. Primary end points were the mean number of symptomatic UTIs, proportion of participants with at least 1 UTI during 12 months, time to first UTI, and development of antibiotic resistance by Escherichia coli. The mean number of symptomatic UTIs in the year preceding randomization was 7.0 in the trimethoprim-sulfamethoxazole group and 6.8 in the lactobacilli group. In the intention-to-treat analysis, after 12 months of prophylaxis, these numbers were 2.9 and 3.3, respectively. The between-treatment difference of 0.4 UTIs per year (95% CI, -0.4 to 1.5) was outside our noninferiority margin. At least 1 symptomatic UTI occurred in 69.3% and 79.1% of the trimethoprim-sulfamethoxazole and lactobacilli participants, respectively; median times to the first UTI were 6 and 3 months, respectively. After 1 month of trimethoprim-sulfamethoxazole prophylaxis, resistance to trimethoprim-sulfamethoxazole, trimethoprim, and amoxicillin had increased from approximately 20% to 40% to approximately 80% to 95% in E coli from the feces and urine of asymptomatic women and among E coli causing a UTI. During the 3 months after trimethoprim-sulfamethoxazole discontinuation, resistance levels gradually decreased. Resistance did not increase during lactobacilli prophylaxis. In postmenopausal women with recurrent UTIs, L rhamnosus GR-1 and L reuteri RC-14 do not meet the noninferiority criteria in the prevention of UTIs when compared with trimethoprim-sulfamethoxazole. However, unlike trimethoprim-sulfamethoxazole, lactobacilli do not increase antibiotic resistance. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN50717094.


Noise sampling method: an ANOVA approach allowing robust selection of differentially regulated genes measured by DNA microarrays.
A crucial step in microarray data analysis is the selection of subsets of interesting genes from the initial set of genes. In many cases, especially when comparing a specific condition to a reference, the genes of interest are those which are differentially expressed. Two common methods for gene selection are: (a) selection by fold difference (at least n fold variation) and (b) selection by altered ratio (at least n standard deviations away from the mean ratio). The novel method proposed here is based on ANOVA and uses replicate spots to estimate an empirical distribution of the noise. The measured intensity range is divided in a number of intervals. A noise distribution is constructed for each such interval. Bootstrapping is used to map the desired confidence levels from the noise distribution corresponding to a given interval to the measured log ratios in that interval. If the method is applied on individual arrays having replicate spots, the method can calculate an overall width of the noise distribution which can be used as an indicator of the array quality. We compared this method with the fold change and unusual ratio method. We also discuss the relationship with an ANOVA model proposed by Churchill et al. In silico experiments were performed while controlling the degree of regulation as well as the amount of noise. Such experiments show the performance of the classical methods can be very unsatisfactory. We also compared the results of the 2-fold method with the results of the noise sampling method using pre and post immortalization cell lines derived from the MDAH041 fibroblasts hybridized on Affymetrix GeneChip arrays. The 2-fold method reported 198 genes as upregulated and 493 genes as downregulated. The noise sampling method reported 98 gene upregulated and 240 genes downregulated at the 99.99% confidence level. The methods agreed on 221 genes downregulated and 66 genes upregulated. Fourteen genes from the subset of genes reported by both methods were all confirmed by Q-RT-PCR. Alternative assays on various subsets of genes on which the two methods disagreed suggested that the noise sampling method is likely to provide fewer false positives.


CT venography for deep venous thrombosis: continuous images versus reformatted discontinuous images using PIOPED II data.
This study was designed to determine whether discontinuous CT of the lower extremities for the detection of deep venous thrombosis (DVT) yields results similar to those of complete helical imaging using cases from the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II). In PIOPED II, CT venography followed CT angiography (CTA) to detect pulmonary embolus, using 7.5-mm continuous helical imaging from the iliac crest to the tibial plateau. DVT was detected in 105 of 737 patients (14.2%). We randomly chose 54 positive cases and 96 negative cases for our study. The continuous helical images were reformatted as 7.5-mm images and two of every three images were deleted. These images (7.5 mm; skip = 15 mm) were then sent--without identifying information--to the original reviewers. From 1 to 3.5 years had elapsed since the original interpretations. The results of the new interpretations were compared with the original CT venography consensus interpretations of PIOPED II. There was agreement for the presence of DVT in at least one leg (same leg) or for the absence of DVT in both legs in 133 of the 150 study patients (89%). The kappa statistic showed substantial agreement between the consensus interpretations and the test interpretations (kappa = 0.75; 95% CI = 0.64-0.86) per patient. There was good--but not perfect--agreement between continuous helical and discontinuous axial imaging for the detection of DVT. Given the vagaries of interobserver and intraobserver variation, there appears to be little difference between the two approaches. Adopting discontinuous imaging and other dose-reduction strategies can reduce pelvic radiation by more than 75%.


Effects of a space modulation on the behavior of a 1D alternating Heisenberg spin-1/2 model.
The effects of a magnetic field (h) and a space modulation (δ) on the magnetic properties of a one-dimensional antiferromagnetic-ferromagnetic Heisenberg spin-1/2 model have been studied by means of numerical exact diagonalization of finite size systems, the nonlinear σ model, and a bosonization approach. The space modulation is considered on the antiferromagnetic couplings. At δ = 0, the model is mapped to a gapless Lüttinger liquid phase by increasing the magnetic field. However, the space modulation induces a new gap in the spectrum of the system and the system experiences different quantum phases which are separated by four critical fields. By opening the new gap, a magnetization plateau appears at ½M(sat). The effects of the space modulation are reflected in the emergence of a plateau in other physical functions such as the F-dimer and the bond-dimer order parameters, and the pair-wise entanglement.


[Ski shoe versus knee joint--3: Risk for falling backward].
In contrast to the drop in the incidence of fractures of the lower leg that has been observed in recent years, the incidence of knee injuries has not decreased in skiing. There has even been a relative increase of severe knee lesions and isolated ACL ruptures, prompting us to conduct a comprehensive study of the causes of this phenomena. The goal of the study was to develop a new measuring device for alpine skiing research by combining motion analysis, pressure and force measurement, comprehensive examine the forward/backward movement in skiboots in the lab and by means of telemetry on the slope (Skiboot versus knee joint part 1/Sportverlerletzung. Sportschaden 3, 1989, pp. 149-161) and to come up with a proposal for a new safety concept to reduce the high number of knee injuries in alpine skiing in the future. The first study was devoted to the forward movement in skiboots (Skiboot versus knee joint part 2/Sportverletzung. Sportschaden 4, 1990, pp. 1-13). The results showed that a skiing style in backward lean position was adopted by skiers wearing boots with a stiff forward flexion and was supported by the fixed backward spoiler. In order to quantify the influence of the backward spoiler a special skiboot was constructed allowing the rear spoiler to give way at a variable, defined stiffness and register the angular displacement and horizontal force Fh. The results showed most clearly that even a medium rear spoiler resistance will sign, reduce the peak force values by a factor of 5.5. The acceleration at the knee joint level is significantly higher (factor 1.6, p less than 0.05) in case of a rigid spoiler. The lab tests could be confirmed on the slope (sign. reduction of max. force by factor 8). It also proved that normal skiing can be performed in such a boot without limitations. In consideration of our facts it is concluded that the principle of safety bindings must definitely apply in future in equal measure also to the ski boot. As a proposal for future safety ski boot, that allowed for the first time the rear part to give way after a certain amount of force (adjustable preload). The backward release bindings, which can often produce dangerous malfunctions if a strong force acts on them for a short period of time, could thus be complemented by a safety system in the boots. In all probability this would be a contributing factor to reducing the high incidence of knee injuries in skiing.


Continuous body fluid monitoring for zomepirac by fully automated high-performance liquid chromatography.
A sensitive, specific and rapid determination of 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid sodium salt dihydrate (zomepirac sodium, Zomax) in human plasma and urine by a continuous body fluid monitoring system based on high-performance liquid chromatography is described. Samples are directly injected into the apparatus which consists of commonly available HPLC-modules. Manual sample clean-up procedures as well as the addition of an internal standard are not needed. Using 50-microliter aliquots, the detection limit is lower than 0.05 microgram/ml and the calibration ranges from 0.5 to 100 micrograms/ml are linear for both, spiked samples and references. The recovery is 97% for plasma and 95% for urine samples at a sampling rate of about 15 samples/h.


Laing Myopathy: Report of 4 New Families With Novel MYH7 Mutations, Double Mutations, and Severe Phenotype.
Laing distal myopathy (LDM) is an autosomal dominant disorder caused by mutations in the slow skeletal muscle fiber myosin heavy chain (MYH7) gene on chromosome 14q11.2. The classic LDM phenotype-including early-onset, initial involvement of foot dorsiflexors and great toe extensors, followed by weakness of neck flexors and finger extensors-is well documented. Since the original report by Laing et al in 1995, the spectrum of MYH7-related myopathies has expanded to include congenital myopathies, late-onset myopathies, myosin storage myopathy, and scapuloperoneal myopathies. Most patients with LDM harbor mutations in the midrod domain of the MYH7 gene, but rare cases document disease-associated mutations in the globular head region. In this report, we add to the medical literature by describing the clinicopathological findings in 8 affected family members from 4 new LDM families-including 2 with novel MYH7 mutations (Y162D and A1438P), one with dual mutations (V39M and K1617del), and one family (E1508del) with severe early-onset weakness associated with contractures, respiratory insufficiency, and dilated cardiomyopathy. Our families highlight the ever-expanding clinical spectrum and genetic variation of the skeletal myopathies related to MYH7 gene mutations.


Development of oral lyophilisates containing meloxicam nanocrystals using QbD approach.
The aim of this study was to develop oral lyophilisates with improved meloxicam (MEL) dissolution, optimizing each step of the preparation by design of experiments. First, meloxicam nanosuspensions were prepared by high-pressure homogenization (HPH), using PVP, Poloxamer or PEG as stabilizers and were subjected to freeze-drying using mannitol as cryoprotectant. The effects of the stabilizers and cryoprotectant were assessed and an optimal formulation was generated within the Design Space where the particle sizes and the PDIs are at their lowest values. The optimal formulation was used at the preparation of oral lyophilisates. Sodium alginate (SA) and croscarmellose sodium (CCS) were tested as matrix forming agents and three different freezing regimes were applied. The formulation was optimized, choosing the polymer that yielded both high mechanical strength and fast MEL dissolution. Poloxamer led to particle size reduction down to 10.27% of the initial size, meaning 477.6±7.5nm, with a slight increase during freeze-drying process. PEG showed lower nanonizing capacity during HPH, but freeze-drying produced further diminution of the particle size. Since Poloxamer provided advanced size reduction while preserving MEL crystallinity, it was used for the optimized formulation containing 1% Poloxamer and 5% mannitol added before freeze-drying. SA showed good structural properties when compared to CCS and allowed fast MEL dissolution at low ratios. The optimal formulation contained 1.157% of SA was subjected to thermal treatment during freeze-drying. It disintegrated in 3.33s and released 77.14% of the MEL after 2min. The quality by design (QbD) approach for the development of pharmaceutical products ensured high quality of the dosage form and good understanding of the preparation process.


[Cystic fibrosis in a woman aged seventy].
A seventy-year-old woman was admitted to hospital with a Staphylococcus aureus respiratory tract infection. She had a history of extensive bronchiectasis and allergic bronchopulmonary aspergillosis (ABPA). Cystic fibrosis (CF) was suspected and cystic fibrosis transmembrane conductance regulator (CFTR) gene analysis showed F508del and R117H-7T mutations. In these mutations there is residual activity in the chloride channel in the cell membrane coded by the CFTR gene. This results in a much milder disease pattern varying from no disease at all to isolated organ disease. This type of disease is known as non-classical cystic fibrosis. In our patient the diagnosis of cystic fibrosis was made exceptionally late in life.


Proliferation and apoptosis in early molar morphogenesis-- voles as models in odontogenesis.
Proliferation and apoptosis play crucial roles in the development of multicellular organisms. Their precise balance is necessary for tissue homeostasis throughout life. The developing dentition is a suitable model to study proliferation and apoptosis during embryogenesis, but the corresponding studies have been carried out principally in the mouse. The present study aimed to examine proliferation and apoptosis in the vole (Microtus sp., Rodentia) during the early morphogenesis of the first upper molar and compare it to what is known from the mouse. To this end, apoptosis and proliferation were investigated using histology and computer-aided 3D reconstruction. Mitoses accumulated predominantly in the developing cervical loop. Apoptosis during early odontogenesis showed highly specific spatio-temporal patterns in the dental epithelium. Apoptotic bodies were localised in non-dividing cell populations. They accumulated in the same places as described in the mouse: antemolar vestiges (ED 12.5 15.5), enamel knot (ED 14.5 15.5), stalk and palatally along the whole first molar tooth germ longitudinal axis (ED 15 - 15.5). Early tooth development in the field vole, including the distribution of apoptosis and mitosis, is very similar to that reported in the mouse, with the exception of the antemolar region. The microtine antemolar vestige is preserved longer than the murine one. It is conceivable that additional distinct differences in morphogenetic processes appear later in tooth development.


Adaptation and coordinated evolution of plant hydraulic traits.
Hydraulic properties control plant responses to climate and are likely to be under strong selective pressure, but their macro-evolutionary history remains poorly characterised. To fill this gap, we compiled a global dataset of hydraulic traits describing xylem conductivity (Ks ), xylem resistance to embolism (P50), sapwood allocation relative to leaf area (Hv) and drought exposure (ψmin ), and matched it with global seed plant phylogenies. Individually, these traits present medium to high levels of phylogenetic signal, partly related to environmental selective pressures shaping lineage evolution. Most of these traits evolved independently of each other, being co-selected by the same environmental pressures. However, the evolutionary correlations between P50 and ψmin and between Ks and Hv show signs of deeper evolutionary integration because of functional, developmental or genetic constraints, conforming to evolutionary modules. We do not detect evolutionary integration between conductivity and resistance to embolism, rejecting a hardwired trade-off for this pair of traits.


The history of the Space Dermatology Foundation.
The five-year history of the Space Dermatology Foundation is reviewed. How the organization was conceived, its purpose, and what it intends to accomplish are presented.


Metabolic and nutritional sequelae in the non-steroid treated head injury patient.
Energy production, substrate oxidation, serum protein levels, and weight change were studied in 16 non-steroid treated patients with severe head injury. Patients were evaluated during an average of 31.3 days from hospital admission to discharge. The mean measured energy expenditure (MEE) was 1.40 +/- 0.5 times predicted energy expenditure. Caloric balance [calories received = calories expended] was achieved by the 2nd week. Despite caloric balance and the administration of at least 1.5 g of protein per kg of body weight per day, the mean nitrogen balance was negative. There was a positive nitrogen balance in only 2 patients. These patients received a mean of 1.43 times the MEE in total kilocalories and 2.3 g of protein per kg of body weight. Fat and protein oxidation exceeded protein and fat administration for 3 weeks postinjury. Albumin levels dropped from a mean of 3.09 +/- 0.2 on admission to 1.98 +/- 0.4 within 2 weeks. The initial retinol binding protein levels were within the normal range, and the levels increased over time. There was marked weight loss (mean, 15.6 +/- 5.9 lb). Head injury induces a profound traumatic response identified by increased energy expenditure, a negative nitrogen balance, weight loss, hypoalbuminemia, and altered substrate oxidation. This response seems to be caused by the head injury alone and is not due to the administration of corticosteroids.


Inheritance of gluten-sensitive enteropathy in Irish Setters.
To establish a model for inheritance of gluten-sensitive enteropathy (GSE) in Irish Setters. 44 dogs of a 6-generation family of Irish Setters with GSE and 7 healthy Irish Setters. Phenotype of each dog was determined after oral administration of gluten in the weaning diet, using morphometric evaluation of jejunal biopsies (all generations) and measurement of small intestinal permeability by use of a lactulose-rhamnose permeation test (generations 1, 2, and 3). Overall probability for each of 4 genetic models of inheritance (autosomal recessive, autosomal dominant, sex-linked recessive, and sex-linked dominant) accounting for segregation of partial villus atrophy within the entire family was calculated. The autosomal recessive model was most tenable and was 56,250 times more likely to account for segregation of partial villus atrophy than the autosomal dominant model, assuming disease prevalence of 0.8%. Both sex-linked models were untenable. These conclusions were robust to the error attached to estimation of disease prevalence. High intestinal permeability without morphometric jejunal abnormalities in 4 of 20 dogs in the 3 youngest generations suggested heterogeneity of lesions associated with GSE. Genetic transmission of GSE is under the control of a single major autosomal recessive locus.


Key factors affecting healthcare professionals to adopt knowledge management: The case of infection control departments of Taiwanese hospitals.
Facing new infectious diseases that are result of continuous mutation of virus and bacteria and ever advancing communication and medical technologies, infection control professionals (ICPs) in the healthcare industry must be able to obtain instantly the needed knowledge in order to increase efficiency and effectiveness in their practice. The purpose of this study is, after an exhaustive literature review and necessary interviews with specialists in this field, to propose a research framework that explores the factors that affect the ICPs' willingness to adopt knowledge management (KM) into their tasks and to validate the usefulness of this research framework through a survey study. The research framework includes four constructs that affect infection control professionals' decision and willingness to introduce and to adopt infection control KM, and they are namely: hospital characteristics, infection control department, external environment, and project planning. The study conducted a survey among ICPs from 425 hospitals in Taiwan. A total of 227 valid questionnaire responses were returned from the ICPs from 90 hospitals. Among these responses, 55.00% are from medical centers and 47.83% are from regional hospitals. After analyzing the responses through the discriminant analysis method, the study found that "Hospital Resource Support," "Colleagues' Attitude," and "Users' Participation" are the three factors that significantly impact the professionals' willingness for adopting KM in infection control departments. This study not only provides the healthcare industry an understanding about introduction and impact of KM, which can assist in their decision making, but also emphasizes the importance of use of actual data in the study of research framework for introduction of KM in healthcare industry. Therefore, this study presents important results in both practical and academic aspects.


Culture conditions defining glioblastoma cells behavior: what is the impact for novel discoveries?
In cancer research, the use of established cell lines has gradually been replaced by primary cell cultures due to their better representation of in vivo cancer cell behaviors. However, a major challenge with primary culture involves the finding of growth conditions that minimize alterations in the biological state of the cells. To ensure reproducibility and translational potentials for research findings, culture conditions need to be chosen so that the cell population in culture best mimics tumor cells in vivo. Glioblastoma (GBM) is one of the most aggressive and heterogeneous tumor types and the GBM research field would certainly benefit from culture conditions that could maintain the original plethora of phenotype of the cells. Here, we review culture media and supplementation options for GBM cultures, the rationale behind their use, and how much those choices affect drug-screening outcomes. We provide an overview of 120 papers that use primary GBM cultures and discuss the current predominant conditions. We also show important primary research data indicating that "mis-cultured" glioma cells can acquire unnatural drug sensitivity, which would have devastating effects for clinical translations. Finally, we propose the concurrent test of four culture conditions to minimize the loss of cell coverage in culture.


Ligand-induced internalization of neurotensin in transfected COS-7 cells: differential intracellular trafficking of ligand and receptor.
The neuropeptide neurotensin (NT) is known to be internalized in a receptor-mediated fashion into its target cells. To gain insight into the mechanisms underlying this process, we monitored in parallel the migration of the NT1 neurotensin receptor subtype and a fluorescent analog of NT (fluo-NT) in COS-7 cells transfected with a tagged NT1 construct. Fluo-NT internalization was prevented by hypertonic sucrose, potassium depletion and cytosol acidification, demonstrating that it proceeded via clathrin-coated pits. Within 0-30 minutes, fluo-NT accumulated together with its receptor in Acridine Orange-positive, acidic organelles. These organelles concentrated transferrin and immunostained positively for rab 5A, therefore they were early endosomes. After 30-45 minutes, the ligand and its receptor no longer colocalized. Fluo-NT was first found in rab 7-positive late endosomes and later in a nonacidic juxtanuclear compartment identified as the Trans-Golgi Network (TGN) by virtue of its staining for syntaxin 6. This juxtanuclear compartment also stained positively for rab 7 and for the TGN/pericentriolar recycling endosome marker rab 11, suggesting that the ligand could have been recruited to the TGN from either late or recycling endosomes. By that time, internalized receptors were detected in Lamp-1-immunoreactive lysosomes. These results demonstrate that neurotensin/NT1 receptor complexes follow a recycling cycle that is unique among the G protein-coupled receptors studied to date, and provide the first evidence for the targeting of a nonendogenous protein from endosomes to the TGN.


Modulation of the fate of zein nanoparticles by their coating with a Gantrez® AN-thiamine polymer conjugate.
The aim of this work was to evaluate the mucus-permeating properties of nanocarriers using zein nanoparticles (NPZ) coated with a Gantrez® AN-thiamine conjugate (GT). NPZ were coated by incubation at different GT-to-zein ratios: 2.5% coating with GT (GT-NPZ1), 5% (GT-NPZ2) and 10% (GT-NPZ3). During the process, the GT conjugate formed a polymer layer around the surface of zein nanoparticles. For GT-NPZ2, the thickness of this corona was estimated between 15 and 20 nm. These nanocarriers displayed a more negative zeta potential than uncoated NPZ. The diffusivity of nanoparticles was evaluated in pig intestinal mucus by multiple particle tracking analysis. GT-NPZ2 displayed a 28-fold higher diffusion coefficient within the mucus layer than NPZ particles. These results align with in vivo biodistribution studies in which NPZ displayed a localisation restricted to the mucus layer, whereas GT-NPZ2 were capable of reaching the intestinal epithelium. The gastro-intestinal transit of mucoadhesive (NPZ) and mucus-permeating nanoparticles (GT-NPZ2) was also found to be different. Thus, mucoadhesive nanoparticles displayed a significant accumulation in the stomach of animals, whereas mucus-penetrating nanoparticles appeared to exit the stomach more rapidly to access the small intestine of animals.


A review of the management of 323 consecutive patients seen in a specific learning difficulties clinic.
Visual correlates of specific learning difficulties (SpLD) include: binocular instability, low amplitude of accommodation, and Meares-Irlen Syndrome. Meares-Irlen Syndrome describes asthenopia and perceptual distortions which are alleviated by using individually prescribed coloured filters. Data from 323 consecutive patients seen over a 15 month period in an optometric clinic specialising in SpLD are reviewed. Visual symptoms and headaches were common. 48% of patients were given a conventional optometric intervention (spectacles, orthoptic exercises) and 50% were issued with coloured filters, usually for a trial period. 40% of those who were given orthoptic exercises were later issued with coloured overlays. 32% of those who were issued with coloured overlays were ultimately prescribed Precision Tinted lenses. Approximately half the sample were telephoned more than a year after the last clinical appointment. More than 70% of those who were prescribed Precision Tints were still wearing them daily, and results for this intervention compared favourably with data for non-tinted spectacles. The data suggest that many people with SpLD need optometric care and that the optometrist needs to be skilled in orthoptic techniques and cognisant of recent research on coloured filters.


Land resource sustainability for urban development: spatial decision support system prototype.
Land resource sustainability for urban development characterizes the problem of decision-making with multiplicity and uncertainty. A decision support system prototype aids in the assessment of incremental land development plan proposals put forth within the long-term community priority of a sustainable growth. Facilitating this assessment is the analytic hierarchy process (AHP), a multi-criteria evaluation and decision support system. The decision support system incorporates multiple sustainability criteria, weighted strategically responsive to local public policy priorities and community-specific situations and values, while gauging and directing desirable future courses of development. Furthermore, the decision support system uses a GIS, which facilitates an assessment of urban form with multiple indicators of sustainability as spatial criteria thematically. The resultant land-use sustainability scores indicate, on the ratio-scale of AHP, whether or not a desirable urban form is likely in the long run, and if so, to what degree. The two alternative modes of synthesis in AHP-ideal and distributive-provide assessments of a land development plan incrementally (short-term) and city-wide pattern comprehensively (long-term), respectively. Thus, the spatial decision support system facilitates proactive and collective public policy determination of land resource for future sustainable urban development.


Adaptive mechanisms of resistance to anti-neoplastic agents.
Intrinsic and acquired resistance to conventional and targeted therapeutics is a fundamental reason for treatment failure in many cancer patients. Targeted approaches to overcome chemoresistance as well as resistance to targeted approaches require in depth understanding of the underlying molecular mechanisms. The anti-cancer activity of a drug can be limited by a broad variety of molecular events at different levels of drug action in a cell-autonomous and non-cell-autonomous manner. This review summarizes recent insights into the adaptive mechanisms used by tumours to resist therapy including cellular phenotypic plasticity, dynamic alterations of the tumour microenvironment, activation of redundant signal transduction pathways, modulation of drug target expression levels, and exploitation of pro-survival responses.


Incidental detection of raised serum levels of vitamin B12 and its association with neoplasms.
Elevated serum levels of vitamin B12 have been associated with oncohematological diseases. However, the relevance of its incidental detection in subjects without a previous diagnosis of cancer is unknown. The aim of this study was to evaluate the relationship between incidental hypercobalaminemia (vitamin B12 > 1000 pg/ml) and the diagnosis of a tumor process in patients without a diagnosis and to establish the risk factors. Retrospective observational study of a cohort of patients with hypercobalaminemia. The incidence of neoplasms was compared with a cohort of patients with vitamin B12 levels <1000 pg/ml. Vitamin B12 determinations of 4800 subjects were selected. Of them, 345 (7.1%) had levels >1000 pg/ml. 68 (28.4%) were excluded due to exogenous administration, 12 (5%) due to insufficient data and 15 (3%) due to having an active neoplasia, selecting 250 patients, with a median follow-up of 22 (IQR 12-39) months. Structural liver disease was detected in 59 (23.6%). 18.2% (44 patients) had solid organ cancer and 17 (7.1%) had malignant hemopathy. The average time from the detection of hypercobalaminemia to the diagnosis of cancer was about 10 months. The median until the diagnosis of neoplasia was higher in the high vitamin B12 group (13 vs 51 months p < 0.001). Hypercobalaminemia (HR 11.8; 95% CI 2.8-49.6; p = 0.001) and smoking (HR 4.0; 95% CI, 2.15-7.59; p < 0.001) were independent predictors of neoplasia in the multivariate analysis. Incidental detection of serum vitamin B12 levels >1000 pg/ml is high in the population. The diagnosis of solid organ and hematological neoplasia is frequent during the following year of follow-up, with hypercobalaminemia and smoking being predictors of a higher risk of cancer.


Incidence of Sinus Mucosa Perforations During Healing After Sinus Elevation Using Deproteinized Bovine Bone Mineral as Grafting Material: A Histologic Evaluation in a Rabbit Model.
To examine the reaction of mucosa over time to a close contact with biomaterial after sinus elevation performed with deproteinized bovine bone mineral (DBBM) granules of two different sizes. Bilateral sinus mucosa elevation was performed in 18 New Zealand rabbits through access on the nasal dorsum. DBBM with granule dimensions of either 1 to 2 mm (large group) or 0.250 to 1.0 mm (small group) were used to randomly fill the subantral hollow spaces. Biopsy specimens of the experimental sites from six animals in each group were obtained 2, 4, and 8 weeks after the surgery. The integrity of the sinus mucosa was clinically evaluated during surgery using a ×2.5 magnifying visual device. The sinus mucosa in contact with the biomaterial granules was found to be thinned compared with the pristine mucosa in all periods examined. Three hundred fifty-two thinned zones were found considering all 36 sinuses treated. Perforations of the sinus mucosa with extrusion of granules toward the sinus were observed, increasing in number over time. In the 8-week healing period, five perforations in three sinuses and eight perforations in four sinuses were found in the large and small groups, respectively. No differences were seen between the large and small groups. The differences between 2 and 8 weeks were statistically significant for the thinned mucosa width in both the large and the small groups and for the number of sinuses and perforations for the small group. Thinning zones and perforations of the sinus mucosa were seen increasing in number over time in regions in contact with graft granules in both the large and small groups.


Central arterial stiffness and retinal vessel calibers: the Atherosclerosis Risk in Communities Study-Neurocognitive Study.
The retinal microvasculature provides a window to the cerebral vasculature and enables examination of changes in retinal caliber that may mimic those occurring in cerebrovascular disease. The association of central arterial stiffness and retinal vessel caliber in a population sample is not fully understood. In 1706 older adults (mean age 76.3, 58.1% women) from the population-based Atherosclerosis Risk in Communities Study, we examined the cross-sectional association of central arterial stiffness [carotid-femoral pulse wave velocity (cfPWV)] with retinal vessel calibers [central retinal arteriolar equivalent (CRAE) and central retinal vein equivalent (CRVE)]. We estimated the association of cfPWV with CRAE narrowing (<25th percentile) and CRVE widening (>75th percentile) after adjustment for age, sex, race-field center, BMI, smoking, and type 2 diabetes. We tested for effect modification by sex, hypertension, and type 2 diabetes. Carotid-femoral PWV (m/s) was not associated with the odds of CRAE narrowing [odds ratio (OR): 0.99; 95% CI: 0.95-1.03]. The association of cfPWV with CRVE widening was stronger in those without hypertension (OR: 1.10; 95% CI: 1.01-1.20) versus those with hypertension (OR: 1.01 95% CI: 0.96-1.05) and slightly stronger in those with type 2 diabetes (OR: 1.07; 95% CI: 1.00-1.14) versus without type 2 diabetes (OR: 1.01; 95% CI: 0.96-1.06). In older adults, cfPWV was associated with wider retinal venular caliber, particularly in individuals without hypertension. Central arterial stiffening may be associated with cerebral microvascular changes, as exhibited in its retinal vasculature component.


Molecular Imaging of the Cholinergic System in Alzheimer and Lewy Body Dementias: Expanding Views.
Brain cholinergic denervation is a major feature of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We reviewed the topography assessed by a cholinergic molecular imaging study in these two major types of dementia. A small meta-analysis directly comparing vesicular acetylcholine transporter (VAChT) PET scans of AD vs. DLB patients is presented. VAChT PET studies showed evidence of extensive cortical cholinergic denervation in both forms of dementia, while multiple subcortical structures were also in DLB. Novel analysis revealed evidence of metathalamic denervation in AD, and epithalamus, premotor/sensorimotor cortical, and striatal losses in DLB. Topographically distinct cortical and subcortical cholinergic lesions can distinguish AD and DLB, and new structures have been highlighted here. Differential vulnerability of specific cholinergic projections is likely associated with specific clinical features of these disorders. Improved understanding of the mechanisms and roles of cholinergic neurotransmission in regions with cholinergic deficits may lead to symptomatic therapies.


Thrombolysis for acute deep vein thrombosis.
Standard treatment for deep vein thrombosis aims to reduce immediate complications. Use of thrombolysis or clot dissolving drugs could reduce the long-term complications of post-thrombotic syndrome (PTS) (pain, swelling, skin discolouration, or venous ulceration) in the affected leg. This is the second update of a review first published in 2004. To assess the effects of thrombolytic therapy and anticoagulation versus anticoagulation in the management of people with acute deep vein thrombosis (DVT) of the lower limb as determined by the effects on pulmonary embolism, recurrent venous thromboembolism, major bleeding, post-thrombotic complications, venous patency and venous function. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2013) and CENTRAL (2013, Issue 4). Randomised controlled trials (RCTs) examining thrombolysis and anticoagulation versus anticoagulation for acute DVT were considered. In the previous review of 2010, one review author (LW) selected trials, extracted data and assessed study quality, with checking at all stages by the other review author (MPA). If necessary, we sought additional information from trialists. For this update (2013), LW and CB selected trials, extracted data independently, and sought advice from MPA where necessary. All studies, existing and new, required full risk of bias assessment in line with current Cochrane procedures. Two of LW, CB and MA independently assessed risk of bias with discussion with the third author where necessary. Seventeen studies with 1103 participants were included. Complete clot lysis occurred significantly more often in the treatment group in early follow up (risk ratio (RR) 4.91; 95% confidence interval (CI) 1.66 to 14.53, P = 0.004) and at intermediate follow up (RR 2.37; 95% CI 1.48 to 3.80, P = 0.0004). A similar effect was seen for any degree of improvement in venous patency. Significantly less PTS occurred in those receiving thrombolysis, (RR 0.64; 95% CI 0.52 to 0.79, P < 0.0001). Leg ulceration was reduced although the data were limited by small numbers (RR 0.48; 95% CI 0.12 to 1.88, P = 0.29). Those receiving thrombolysis had significantly more bleeding complications (RR 2.23; 95% CI 1.41 to 3.52, P = 0.0006). Three strokes occurred in the treatment group, all in trials conducted pre-1990, and none in the control group. There was no significant effect on mortality detected at either early or intermediate follow up. Data on the occurrence of pulmonary embolism (PE) and recurrent DVT were inconclusive. Systemic thrombolysis is now not commonly used and catheter-directed thrombolysis (CDT) is the more favoured means of administration. This has been studied in iliofemoral DVT, and results from two trials are consistent with those from trials of systemic thrombolysis in DVT at other levels of occlusion. Thrombolysis increases the patency of veins and reduces the incidence of PTS following proximal DVT by a third. Strict eligibility criteria are necessary to reduce the risk of bleeding complications and this limits the applicability of this treatment. In those who are treated there is a small increased risk of bleeding. In recent years CDT is the most studied route of administration, and results appear to be similar to systemic administration.


[Orbital and ocular adnexal lymphomas. Clinico-pathological correlation in 25 cases].
Clinical, histological features and outcome of a cohort of patients with orbital and adnexal lymphoproliferative tumors were evaluated. Twenty-five cases in an oncologic referral center from 1995 to 2008, were included in the study. Each case had detailed immunophenotypic analysis using a panel of monoclonal antibodies (CD45, CD20, CD3, CD5, CD23, BCL2, BCL6, BCL10, Ki67, CD30, CD15, BCL1, Kappa, Lambda, CD138). Lesions were classified by using WHO (2008) lymphomas classification. Twenty-three patients were found to have primary and two secondary lymphomas. Histological subtypes were: 16 patients with marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma, four diffuse large B cell lymphomas, two mantle cell lymphomas, two follicular lymphomas, and one Hodgkin lymphoma. Among the 25 patients studied, 22 had localized stage. Extranodal marginal zone lymphoma was the most frequent type of primary orbital and adnexal lymphoma. In this study localized disease was observed in most cases, and distant spread of the lymphomas was infrequent.


Repeated recurrence of osteosarcoma treated by resections and chemotherapy.
This paper presents 5 patients with repeated recurrence of osteosarcoma (RROS). The primary focus of 3 patients were in the distal portion of femur, and 2 patients were in the proximal portion of tibia. Three patients, whose chest X ray film were negative, were treated by amputation and chemotherapy. Two patients had isolated metastatic focus 1.5 cm in diameter in lung, were treated by amputation after 1 week of chemotherapy and then treated by lobectomy after 2 weeks of chemotherapy. After operation, the chemotherapy was carried out for 3 courses of treatment. The roentgenogram of chest and affected limb were taken once every two months. There were metastatic focuses found in the lung of 1 patient and in the distal portion of femur of 2 patients. One patient was operated on for 4 times. Up to now, 3 patients have been living for 5 years and 2 patients for 6 years after operation.


Disconnection in prosopagnosia and face processing.
Face perception is a function with significant complexity, reflected in cognitive models that propose a hierarchy of parallel and serial processing stages. Current neuroimaging data also show that face perception involves a core processing network of cortical modules, which are likely specialized for different functions involved in face processing. The core face processing network is further linked to an extended face processing network which is not solely involved in the perception of faces, but rather contains modules mediating the processing of semantic, biographic and emotional information about people. The segregation of these processes within discrete anatomic regions creates the potential for disconnection between regions to generate neuropsychological deficits involving faces. In this review we consider the types of disconnection possible both within the core face processing system and between the core and extended systems, the pattern of deficits that would be considered as evidence of such disconnections, the potential anatomy of lesions that would create them, and whether any cases exist that meet these criteria.


Incidence and prevalence of chlamydia, herpes, and viral hepatitis in a homeless adolescent population.
High rates of unprotected intercourse and illegal drug use have been reported among homeless adolescents. As a transient population with the potential to act as disease vectors from one location to another, incidence and prevalence of sexually transmitted infections in this population are of particular concern. To assess a homeless adolescent population for incidence and prevalence of Chlamydia trachomatis, herpes simplex virus type 2, hepatitis B virus, hepatitis C virus, HIV, and psychosocial correlates of the acquisition of sexually transmitted infections. Longitudinal with assessments at baseline, 3 months, and 6 months (n = 536; 319 males and 217 females). Baseline prevalence of C trachomatis was 4.17% for males and 6.30% for females. Prevalence of herpes simplex virus type 2 was 5.73% for males and 12.50% for females. Hepatitis B virus and hepatitis C virus prevalences were 3.60% and 5.0%, respectively. HIV seroprevalence was 0.3%. The incidence of sexually transmitted infections was significantly higher among females than among males (16.7% versus 9.8%) and was associated with inconsistent condom use and, for females, number of partners and sex with older partners. Incident hepatitis B virus and hepatitis C virus infection rates were 3.44% and 6.61%, respectively; both were associated with injection drug use. Among females, the incidence of herpes simplex virus type 2 (> 25%) and C trachomatis (12%) was relatively high. Inconsistent condom use was the primary factor associated with a significantly greater risk of incident sexually transmitted infections. This was especially true for females with multiple partners. Homeless adolescents also are at high risk for hepatitis B virus and hepatitis C virus infection, primarily associated with self-reported injection drug use.


Evaluation of protein A gene polymorphic region DNA sequencing for typing of Staphylococcus aureus strains.
Three hundred and twenty isolates of Staphylococcus aureus were typed by DNA sequence analysis of the X region of the protein A gene (spa). spa typing was compared to both phenotypic and molecular techniques for the ability to differentiate and categorize S. aureus strains into groups that correlate with epidemiological information. Two previously characterized study populations were examined. A collection of 59 isolates (F. C. Tenover, R. Arbeit, G. Archer, J. Biddle, S. Byrne, R. Goering, G. Hancock, G. A. Hébert, B. Hill, R. Hollis, W. R. Jarvis, B. Kreiswirth, W. Eisner, J. Maslow, L. K. McDougal, J. M. Miller, M. Mulligan, and M. A. Pfaller, J. Clin. Microbiol. 32:407-415, 1994) from the Centers for Disease Control and Prevention (CDC) was used to test for the ability to discriminate outbreak from epidemiologically unrelated strains. A separate collection of 261 isolates form a multicenter study (R. B. Roberts, A. de Lencastre, W. Eisner, E. P. Severina, B. Shopsin, B. N. Kreiswirth, and A. Tomasz, J. Infect. Dis. 178:164-171, 1998) of methicillin-resistant S. aureus in New York City (NYC) was used to compare the ability of spa typing to group strains along clonal lines to that of the combination of pulsed-field gel electrophoresis and Southern hybridization. In the 320 isolates studied, spa typing identified 24 distinct repeat types and 33 different strain types. spa typing distinguished 27 of 29 related strains and did not provide a unique fingerprint for 4 unrelated strains from the four outbreaks of the CDC collection. In the NYC collection, spa typing provided a clonal assignment for 185 of 195 strains within the five major groups previously described. spa sequencing appears to be a highly effective rapid typing tool for S. aureus that, despite some expense of specificity, has significant advantages in terms of speed, ease of use, ease of interpretation, and standardization among laboratories.


The role of diacylglycerol in the exocytosis of the sperm acrosome. Studies using diacylglycerol lipase and diacylglycerol kinase inhibitors and exogenous diacylglycerols.
When ram spermatozoa were treated with Ca2+ and the ionophore A23187 to induce acrosomal exocytosis, a rise in diacylglycerol (DAG) mass was observed, concomitant with a rapid breakdown of [32P]P1-labelled phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-phosphate and a rise in [32P]Pi-labelled phosphatidate. Inclusion of the DAG lipase inhibitor RHC 80267 resulted in further but biphasic increases in DAG; there was an increasing accumulation of DAG with concentrations of RHC 80267 up to 10 microM, whereas higher concentrations produced lessening accumulation. Inclusion of RHC 80267 in the ionophore induction system also resulted in significant accelerations of the onset of exocytosis. In spermatozoa stimulated with Ca2+/A23187 and the DAG kinase inhibitor R59022, a similar increase in DAG levels together with stimulation of acrosomal exocytosis were observed. Preincubation of spermatozoa with sn-1-oleoyl-2-acetylglycerol, rac-1-oleoyl-2-acetylglycerol, sn-1,2-dioctanoylglycerol and sn-1,3-dioctanoylglycerol before treatment with Ca2+/A23187 resulted in a dose-dependent stimulation of exocytosis by all these isomers. Neomycin inhibited Ca2+/A23187-induced generation of DAG together with polyphosphoinositide breakdown, as well as acrosomal exocytosis. Inclusion of exogenous DAG, however, overcame the inhibitory effect of neomycin on exocytosis. Our results suggest that DAG has a key role in acrosomal exocytosis and that it acts as a messenger rather than as a substrate from which other active metabolites are generated. The lack of stereospecificity shown by the exogenous DAGs implies that DAG does not act by stimulating protein kinase C, but the metabolite's actual target in the sperm cell is as yet unclear.


Childhood Non-HDL Cholesterol and LDL Cholesterol and Adult Atherosclerotic Cardiovascular Events.
Although low-density lipoprotein cholesterol (LDL-C) remains the primary cholesterol target in clinical practice in children and adults, non-high-density lipoprotein cholesterol (non-HDL-C) has been suggested as a more accurate measure of atherosclerotic cardiovascular disease (ASCVD) risk. We examined the associations of childhood non-HDL-C and LDL-C levels with adult ASCVD events and determined whether non-HDL-C has better utility than LDL-C in predicting adult ASCVD events. This prospective cohort study included 21 126 participants from the i3C Consortium (International Childhood Cardiovascular Cohorts). Proportional hazards regressions were used to estimate the risk for incident fatal and fatal/nonfatal ASCVD events associated with childhood non-HDL-C and LDL-C levels (age- and sex-specific z scores; concordant/discordant categories defined by guideline-recommended cutoffs), adjusted for sex, Black race, cohort, age at and calendar year of child measurement, body mass index, and systolic blood pressure. Predictive utility was determined by the C index. After an average follow-up of 35 years, 153 fatal ASCVD events occurred in 21 126 participants (mean age at childhood visits, 11.9 years), and 352 fatal/nonfatal ASCVD events occurred in a subset of 11 296 participants who could be evaluated for this outcome. Childhood non-HDL-C and LDL-C levels were each associated with higher risk of fatal and fatal/nonfatal ASCVD events (hazard ratio ranged from 1.27 [95% CI, 1.14-1.41] to 1.35 [95% CI, 1.13-1.60] per unit increase in the risk factor z score). Non-HDL-C had better discriminative utility than LDL-C (difference in C index, 0.0054 [95% CI, 0.0006-0.0102] and 0.0038 [95% CI, 0.0008-0.0068] for fatal and fatal/nonfatal events, respectively). The discordant group with elevated non-HDL-C and normal LDL-C had a higher risk of ASCVD events compared with the concordant group with normal non-HDL-C and LDL-C (fatal events: hazard ratio, 1.90 [95% CI, 0.98-3.70]; fatal/nonfatal events: hazard ratio, 1.94 [95% CI, 1.23-3.06]). Childhood non-HDL-C and LDL-C levels are associated with ASCVD events in midlife. Non-HDL-C is better than LDL-C in predicting adult ASCVD events, particularly among individuals who had normal LDL-C but elevated non-HDL-C. These findings suggest that both non-HDL-C and LDL-C are useful in identifying children at higher risk of ASCVD events, but non-HDL-C may provide added prognostic information when it is discordantly higher than the corresponding LDL-C and has the practical advantage of being determined without a fasting sample.


How can we kill cancer cells: Insights from the computational models of apoptosis.
Cancer cells are widely known to be protected from apoptosis, a phenomenon that is a major hurdle to successful anticancer therapy. Over-expression of several anti-apoptotic proteins, or mutations in pro-apoptotic factors, has been recognized to confer such resistance. Development of new experimental strategies, such as in silico modeling of biological pathways, can increase our understanding of how abnormal regulation of apoptotic pathway in cancer cells can lead to tumour chemoresistance. Monte Carlo simulations are in particular well suited to study inherent variability, such as spatial heterogeneity and cell-to-cell variations in signaling reactions. Using this approach, often in combination with experimental validation of the computational model, we observed that large cell-to-cell variability could explain the kinetics of apoptosis, which depends on the type of pathway and the strength of stress stimuli. Most importantly, Monte Carlo simulations of apoptotic signaling provides unexpected insights into the mechanisms of fractional cell killing induced by apoptosis-inducing agents, showing that not only variation in protein levels, but also inherent stochastic variability in signaling reactions, can lead to survival of a fraction of treated cancer cells.


A Ln(III)-3-hydroxypyridine pH responsive probe optimized by DFT.
Differences in tissue pH can be diagnostic of cancer and other conditions that shift cell metabolism. Paramagnetic probes are promising tools for pH mapping in vivo using magnetic resonance spectroscopy (MRS) as they provide uniquely shifted MR signals that change with pH. Here, we demonstrate a 3-hydroxy-6-methylpyridyl coordinating group as a new pH-responsive reporter group for Ln(III) MRS probes. The pH response of the complex was observed by UV-Vis, fluorescence, and NMR spectroscopies, and modeled using DFT. These results provide insight into the observed pH-dependent NMR spectrum of the complex. The protonation state of the hydroxypyridine changes the coordinating ability of the ligand, affecting the dipolar field of the lanthanide and the chemical shift of nearby reporter nuclei. The favorable pH response and coordination properties of the 3-hydroxypyridyl group indicates its potential for further development as a dual responsive-reporter group. Incorporation into optimized scaffolds for MRS detection may enable sensitive pH-mapping in vivo.


Combined endoscopic and microsurgical approach for the drainage of a multisegmental thoracolumbar epidural abscess: illustrative case.
Spinal epidural abscess is a rare but serious infectious disease that can rapidly develop into a life-threatening condition. Therefore, the appropriate treatment is indispensable. Although conservative treatment is justifiable in certain cases, surgical treatment needs to be considered as an alternative early on because of complications such as (progressive) neurological deficits or sepsis. However, traditional surgical techniques usually include destructive approaches up to (multilevel) laminectomies. Such excessive approaches do have biomechanical effects potentially affecting the long-term outcomes. Therefore, minimally invasive approaches have been described as alternative strategies, including endoscopic approaches. The authors describe a surgical technique involving a combination of two minimally invasive approaches (endoscopic and microsurgical) to drain a multisegmental (thoracolumbar) abscess using the physical phenomenon of continuous pressure difference to minimize collateral tissue damage. The combination of minimally invasive approaches, including the endoscopic technique, may be an alternative in draining selected epidural abscesses while achieving a similar amount of abscess removal and causing less collateral approach damage in comparison with more traditional techniques.


Laparoscopic and open abdominal staging for early-stage ovarian cancer: our experience, systematic review, and meta-analysis of comparative studies.
The aim of this study was to analyze perioperative and long-term survival outcomes after either laparoscopic or open abdominal staging for apparent early-stage ovarian cancer. Data of consecutive women with early-stage ovarian cancer undergoing comprehensive laparoscopic staging between 2003 and 2010 were matched with a historical cohort of patients undergoing open surgery. Five-year survival outcomes were analyzed using the Kaplan-Meier method. In addition, a systematic review of the literature and meta-analysis of comparative studies was performed A total of 35 women undergoing staging via laparoscopy were compared with a cohort of 32 patients undergoing open surgery. Baseline characteristics were similar between groups. Spillage occurred in 6 and 4 patients in laparoscopic and open group, respectively (P = 0.59). Patients undergoing laparoscopy experienced longer operative time (P < 0.001), shorter hospital stay (P = 0.03), and lower postoperative complication rate (3% vs 28%; P = 0.005) than patients undergoing staging via open surgery. The median (range) follow-up period was 64 (37-106) and 100 (61-278) months for case and control, respectively (P < 0.001). Five-year disease-free survival (P = 0.12, log-rank test) and overall survival (P = 0.26, log-rank test) were not influenced by surgical approach. Pooled analyses of the literature results corroborate our results suggesting an improvement of perioperative results in the laparoscopic group in comparison with the open abdominal one. In comparison with open surgery, laparoscopy did not influenced spillage (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.35-1.73) and upstaging rate (OR, 0.7; 95% CI, 0.38-1.27). No between-group differences in survival were observed (OR, 0.5; 95% CI, 0.21-1.21). Laparoscopy upholds open surgery in long-term oncologic control, reducing morbidity.


Mendelian randomisation: a tool for assessing causality in observational epidemiology.
Detection and assessment of the effect of a modifiable risk factor on a disease with view to informing public health intervention policies are of fundamental concern in aetiological epidemiology. In order to have solid evidence that such a public health intervention has the desired effect, it is necessary to ascertain that an observed association or correlation between a risk factor and a disease means that the risk factor is causal for the disease. Inferring causality from observational data is difficult, typically due to confounding by social, behavioural, or physiological factors which are difficult to control for and particularly difficult to measure accurately. A possible approach to inferring causality when confounding is believed to be present but unobservable, as it may not even be fully understood, is based on the method of instrumental variables and is known under the name of Mendelian randomisation if the instrument is a genetic variant. While testing for the presence of a causal effect using this method is generally straightforward, point estimates of such an effect are only obtainable under additional parametric assumptions. This chapter introduces the concept and illustrates the method and its assumptions with simple real-life examples. It concludes with a brief discussion on pitfalls and limitations.


Functional Ag-EDTA-modified MnO2 nanocoral reef for rapid removal of hazardous copper from wastewater.
A novel MnO2@EDTA-Ag nanocoral reef was constructed via a simplified redox reaction followed by EDTA and Ag nanoparticles impregnation to capture hazardous copper (II) from wastewater. A comprehensive characterization of the synthesized materials was conducted. The morphology of MnO2@EDTA-Ag in the form of a nanocoral reef was constructed of two-dimensional nanoplatelets and nanorod-like nanostructures. The optimal adsorption conditions proposed by the Plackett-Burman design (PBD) that would provide a removal % of 99.95 were pH 5.5, a contact time of 32.0 min, a Cu(II) concentration of 11.2 mg L-1, an adsorbent dose of 0.05 g, and a temperature of 40.3 °C. The loading of Ag nanoparticles onto MnO2@EDTA improved the adsorption capability of MnO2@EDTA-Ag. Additionally, the recyclability of MnO2@EDTA-Ag nanocoral reef was maintained at 80% after three adsorption-desorption cycles, and there was no significant change in the XRD analysis before and after the recycling process, implying its stability. It was found that nanocoral reef-assisted EDTA formed a chelation/complexation reaction between COO- groups and C-N bonds of EDTA with Cu(II) ions. In addition, X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) analysis proved the synergistic effect of the electrostatic interaction and chelation/complexation was responsible for the removal mechanism of Cu(II). Also, the results demonstrated no significant variation in MnO2@EDTA-Ag removal efficiency for all the tested real water samples, revealing its efficacy in wastewater treatment. Therefore, the current study suggests that MnO2@EDTA-Ag has substantial potential to be used as a feasible adsorbent for probable hazardous metals remediation.


Olanzapine in the treatment of pathological gambling: a negative randomized placebo-controlled trial.
Pathological gambling is associated with bipolar disorder and dopamine dysfunction. Olanzapine is a second-generation antipsychotic with mood-stabilizing properties and antagonistic activity at several dopamine receptors. The purpose of this study was to evaluate olanzapine in the treatment of pathological gambling. In this 12-week, single-center, randomized, double-blind, placebo-controlled, flexible-dose (2.5-15 mg/day) trial, 42 outpatients with pathological gambling by DSM-IV-TR criteria received olanzapine (N = 21) or placebo (N = 21). The primary outcome measure was the Pathological Gambling Adaptation of the Yale-Brown Obsessive Compulsive Scale (PG-YBOCS). The primary analysis of efficacy was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the effect measure. Subjects were enrolled from June 2, 2000, through November 28, 2005. Compared with placebo, olanzapine was associated with a similar rate of reduction in total scores on the PG-YBOCS scale, as well as in gambling episodes/week, hours gambled/week, and Clinical Global Impressions-Severity of Illness scale scores. The mean (SD) olanzapine daily dose at endpoint evaluation was 8.9 (5.2) mg/day. Eleven subjects (52%) receiving olanzapine and 6 (29%) receiving placebo discontinued prematurely; 3 subjects receiving olanzapine and 2 receiving placebo discontinued because of adverse events. Events causing olanzapine discontinuation were pneumonia, sedation, and hypomania. Olanzapine was not superior to placebo in the short-term treatment of pathological gambling. It was also associated with a high discontinuation rate. ClinicalTrials.gov identifier NCT00438776 (http://www.clinicaltrials.gov).


Validated registry of pre-dialysis chronic kidney disease: description of a large cohort.
Chronic diseases account for the majority of deaths in Brazil. These include hypertension (SAH) and diabetes mellitus (DM), which are the main causes of chronic kidney disease (CKD). This study aimed to validate the data of an electronic health record and to point out characteristics of the profile of these users in relation to clinical quality indicators for a pre-dialytic CKD. Retrospective cohort, August/2010 to December/2014. Included users > 18 years, with at least two queries. Variables analyzed: sociodemographic, underlying disease, main medications and main clinical indicators of control. A descriptive analysis was performed and the percentage of users was evaluated in the goals at admission and at the end of the study. Exported, converted and validated data of 1,977 users with average follow-up time of 21 months. Of these, 51.4% were men, 58% were > 64 years of age and 81.6% were overweight. The main medications in use were diuretics (82.9%), BRAT (62%), Statin (60.7%) and ACE inhibitors (49.9%). The percentage of users with a decline in the glomerular filtration rate was 33.7%. Regarding glycated hemoglobin, users with CKD and DM, 36% were within the initial goal and 52.1% of the final. Blood pressure was at the target for admission at 34.3% and 49.8% at the end of follow-up. Validated data are of vital importance for health managers to monitor users. The population of this study is predominantly elderly, obese, requiring multi-professional care to slow the progression of the disease and decrease morbidity and mortality.


Assembly of hepatitis E vaccine by 'in situ' growth of gold clusters as nano-adjuvants: an efficient way to enhance the immune responses of vaccination.
Vaccine-based immunotherapy plays an integral role in the development of present and future clinical therapies. Despite the success, there is still a great need to improve the efficiency and safety of vaccines. Nanoparticles have been widely used for improving the efficacy of vaccines by encapsulating the vaccines or using nanoparticles as immune adjuvants. However, the methods for the preparation of nanoparticles are complex with a relatively low encapsulation efficiency of protein vaccine inside the nanocarriers and/or undefined physiochemical properties. Here, we report a new method of preparation of a vaccine by the "in situ" growth of gold clusters in the hepatitis E vaccine (HEVA). The gold cluster grafted HEVA (HEVA/Au) can be easily obtained and there is no loss of HEVA during the preparation process. More importantly, the "in situ" prepared HEVA/Au can not only enhance its immune responses in vivo, but also reduce the potential toxicity of HEVA. Furthermore, the intrinsic fluorescence of gold clusters enables the HEVA to be traceable, which may open a way to track the dynamic behavior of vaccines and further help to optimize an individual therapeutic regimen for immunotherapy.


Granular presence of terminin is the marker to distinguish between the senescent and quiescent states.
We have previously identified statin, a nonproliferating-cell-specific nuclear protein of 57,000 dalton whose presence can be used to distinguish between growing and nongrowing cells. In this report we identify another protein, terminin, whose presence (by immunofluorescence microscopy) can be used to distinguish between temporarily and permanently growth-arrested cells. Thus terminin is a marker to separate the senescent from the quiescent state. By means of an unique monoclonal antibody (mAb1.2), the presence of terminin is recognized as granules in the cytoplasm of in vitro aged fibroblasts; these granules are not found in serum-starved, contact-inhibited, growing or transformed fibroblasts, except for those cells experiencing the initiation of apoptosis due to long-term deprivation of nutrients. Preliminary histochemical studies show that terminin is also found in the superficial epithelial layer of the esophagus, where terminal differentiation is followed by apoptosis and sloughing off into the lumen. Biochemical characterization by Western blot shows the terminin antibody recognizing a protein of 84 kilodalton (kDa) in growing and quiescent cells, whereas in senescent cells a protein of 57 kDa is recognized; this result suggests that a senescence-dependent protease may cleave the 84 kDa protein to 57 kDa. This proteolytic action seems to render the specific antigenic epitope exposed in its native state and accessible to the terminin antibody by immunofluorescence microscopy. It is this product of posttranslational modification in the form of a cytoplasmic 57 kDa protein that is the marker distinguishing between senescence and quiescence.


Risk-Based Critical Concentrations of Legionella pneumophila for Indoor Residential Water Uses.
Legionella spp. is a key contributor to the United States waterborne disease burden. Despite potentially widespread exposure, human disease is relatively uncommon, except under circumstances where pathogen concentrations are high, host immunity is low, or exposure to small-diameter aerosols occurs. Water quality guidance values for Legionella are available for building managers but are generally not based on technical criteria. To address this gap, a quantitative microbial risk assessment (QMRA) was conducted using target risk values in order to calculate corresponding critical concentrations on a per-fixture and aggregate (multiple fixture exposure) basis. Showers were the driving indoor exposure risk compared to sinks and toilets. Critical concentrations depended on the dose response model (infection vs clinical severity infection, CSI), risk target used (infection risk vs disability adjusted life years [DALY] on a per-exposure or annual basis), and fixture type (conventional vs water efficient or "green"). Median critical concentrations based on exposure to a combination of toilet, faucet, and shower aerosols ranged from ∼10-2 to ∼100 CFU per L and ∼101 to ∼103 CFU per L for infection and CSI dose response models, respectively. As infection model results for critical L. pneumophila concentrations were often below a feasible detection limit for culture-based assays, the use of CSI model results for nonhealthcare water systems with a 10-6 DALY pppy target (the more conservative target) would result in an estimate of 12.3 CFU per L (arithmetic mean of samples across multiple fixtures and/or over time). Single sample critical concentrations with a per-exposure-corrected DALY target at each conventional fixture would be 1.06 × 103 CFU per L (faucets), 8.84 × 103 CFU per L (toilets), and 14.4 CFU per L (showers). Using a 10-4 annual infection risk target would give a 1.20 × 103 CFU per L mean for multiple fixtures and single sample critical concentrations of 1.02 × 105, 8.59 × 105, and 1.40 × 103 CFU per L for faucets, toilets, and showers, respectively. Annual infection risk-based target estimates are in line with most current guidance documents of less than 1000 CFU per L, while DALY-based guidance suggests lower critical concentrations might be warranted in some cases. Furthermore, approximately <10 CFU per mL L. pneumophila may be appropriate for healthcare or susceptible population settings. This analysis underscores the importance of the choice of risk target as well as sampling program considerations when choosing the most appropriate critical concentration for use in public health guidance.


Power of protein/tRNA functional assembly against aberrant aggregation.
Understanding the mechanisms of protein oligomerization and aggregation is a major concern for biotechnology and medical purposes. However, significant challenges remain in determining the mechanism of formation of these superstructures and the environmental factors that can precisely modulate them. Notably the role that a functional ligand plays in the process of protein aggregation is largely unexplored. We herein address these issues with an original flavin-dependent RNA methyltransferase (TrmFO) used as a protein model since this protein employs a complex set of cofactors and ligands for catalysis. Here, we show that TrmFO carries an unstable protein structure that can partially mis-unfold leading to either formation of irregular and nonfunctional soluble oligomers endowed with hyper-thermal stability or large amorphous aggregates in the presence of salts. Mutagenesis confirmed that this peculiarity is an intrinsic property of a polypeptide and it is independent of the flavin coenzyme. Structural characterization and kinetic studies identified several regions of the protein that enjoy conformational changes and more particularly pinpointed the N-terminal subdomain as being a key element in the mechanisms of oligomerization and aggregation. Only stabilization of this region via tRNA suppresses these aberrant protein states. Although protein chaperones emerged as major actors against aggregation, our study emphasizes that other powerful mechanisms exist such as the stabilizing effect of functional assemblies that provide an additional layer of protection against the instability of the proteome.