Additional prognostic value of electrocardiographic left ventricular hypertrophy in traditional cardiovascular risk assessments in chronic kidney disease.
Left ventricular hypertrophy (LVH) is a common predictor of the cardiovascular prognosis in chronic kidney disease (CKD). However, whether or not electrocardiography-derived LVH (ECG-LVH) has prognostic value in patients with various degrees of CKD and improves the cardiovascular risk stratification based on traditional risk factors remains unclear. A total of 7206 participants at least 40 years of age who were free from cardiovascular events in a general population were followed for the incidence of cardiovascular events. CKD was confirmed by either the presence of a reduced estimated glomerular filtration rate (eGFR) (<60 ml/min per 1.73 m) or albuminuria, defined as a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g Cr. A total of 1886 (26.2%) had CKD, of which 1471 (78.0%) had a preserved eGFR (CKD stage 1-2). After an average 11.3 years of follow-up, the adjusted hazard ratio for the incidence of cardiovascular events significantly increased for ECG-LVH according to the Sokolow--Lyon voltage, Cornell voltage, or Cornell voltage product among participants with CKD (hazard ratio 1.47, P = 0.002), in contrast to those without CKD (hazard ratio 1.15, P = 0.210). The inclusion of any ECG-LVH parameters improved the accuracy of reclassification in any risk prediction model based on the eGFR, UACR, or Framingham 10-year risk score in the CKD participants (net reclassification improvement = 0.13-0.32, all P values <0.040). In patients with CKD stage 1-5, ECG-LVH is useful for predicting the risk of future cardiovascular events and adds prognostic information to traditional cardiovascular risk assessments.


Inactivation of virus in intravenous immunoglobulin G using solvent/detergent treatment and pasteurization.
The safety of plasma derived medicinal products, such as immunoglobulin, depends on viral inactivation steps that are incorporated into the production process. Several attempts have been made to validate the effectiveness of these inactivation methods against a range of physio-chemically diverse viruses. Treatment with solvent/detergent (S/D) and pasteurization (P) has been continuously used in our IgG production and these methods were analysed in this study as models of viral inactivation. Bovine Viral Diarrhoea Virus (BVDV), Herpes Simplex Virus (HSV) and Vesicular Stomatitis Virus (VSV) were employed as models of HCV, HBV and HIV respectively. Polio and Reo viruses also were used as stable viruses to chemical substances. The infectivity of a range of viruses before and after treatment with two methods of viral inactivation was measured by end point titration and their effectiveness expressed as Logarithmic Reduction Factors (LRF). Solvent/detergent treatment reduced the amount of enveloped viruses by 5-6 logs. The reduction factor was between 5-6 logs for all viruses used in the pasteurization process. A final log reduction factor was obtained as the sum of the two individual methods. Both inactivation methods have advantages and disadvantages with respect to their ability to inactivate viruses. Thus,combination of two robust virus inactivation steps, solvent/detergent and pasteurization, increases the safety margin of immunoglobulin preparations.


Temporal pole signal abnormality on MR imaging in temporal lobe epilepsy with hippocampal sclerosis: a fluid-attenuated inversion-recovery study.
To determine the frequency and regional involvement of temporal pole signal abnormality (TPA) in patients with hippocampal sclerosis (HS) using fluid-attenuated inversion-recovery (FLAIR) MR imaging, and to correlate this feature with history. Coronal FLAIR images of the temporal pole were assessed in 120 patients with HS and in 30 normal subjects, to evaluate gray-white matter demarcation. Ninety (75%) of 120 patients had associated TPA. The HS side made difference regarding the presence of TPA, with a left side prevalence (p=0.04, chi2 test). The anteromedial zone of temporal pole was affected in 27 (30%) out of 90 patients. In 63 (70%) patients the lateral zone were also affected. Patients with TPA were younger at seizure onset (p=0.018), but without association with duration of epilepsy. Our FLAIR study show temporal pole signal abnormality in 3/4 of patients with HS, mainly seen on the anteromedial region, with a larger prevalence when the left hippocampus was involved.


[Chemoprotective effect of the alkaloid extract of Melocactus bellavistensis against colon cancer induced in rats using 1,2-dimethylhydrazine].
To determine the toxicity and chemoprotective effect of the alkaloid extract of Melocactus bellavistensis against colon cancer induced in rats using 1,2-dimethylhydrazine (DMH). The alkaloid extract was obtained from the fleshy part of M. bellavistensis, and an acute toxicity test was then carried out on 30 mice of the Balb C57 strain. To assess its chemoprotective effect, colon cancer was induced in 45 Holtzman rats using DMH according to the following experimental design: one control group received 2 mL/kg sodium polysorbate, and four groups received 20 mg/kg DMH plus 0, 1, 5, or 10 mg/kg M. bellavistensis alkaloid extract. With a sample of 5 g of alkaloid extract, an LD50 greater than 1000 mg/mL was determined in the acute toxicity test. Histological indicators revealed that the 5 and 10 mg/kg doses had significant anti-tumor activity with 100% neoplasia inhibition against DMH- induced colon cancer in rats. Under experimental conditions, the alkaloid extract of M. bellavistensis has a chemoprotective effect against DMH-induced colon cancer in rats.


C1-Inhibitor Decreases the Release of Vasculitis-Like Chemotactic Endothelial Microvesicles.
The kinin system is activated during vasculitis and may contribute to chronic inflammation. C1-inhibitor is the main inhibitor of the kinin system. In this study, we investigated the presence of the kinin B1 receptor on endothelial microvesicles and its contribution to the inflammatory process. Compared with controls (n=15), patients with acute vasculitis (n=12) had markedly higher levels of circulating endothelial microvesicles, identified by flow cytometry analysis, and significantly more microvesicles that were positive for the kinin B1 receptor (P<0.001). Compared with microvesicles from wild-type cells, B1 receptor-positive microvesicles derived from transfected human embryonic kidney cells induced a significant neutrophil chemotactic effect, and a B1 receptor antagonist blocked this effect. Likewise, patient plasma induced neutrophil chemotaxis, an effect decreased by reduction of microvesicle levels and by blocking the B1 receptor. We used a perfusion system to study the effect of patient plasma (n=6) and control plasma (n=6) on the release of microvesicles from glomerular endothelial cells. Patient samples induced the release of significantly more B1 receptor-positive endothelial microvesicles than control samples, an effect abrogated by reduction of the microvesicles in the perfused samples. Perfusion of C1-inhibitor-depleted plasma over glomerular endothelial cells promoted excessive release of B1 receptor-positive endothelial microvesicles compared with normal plasma, an effect significantly decreased by addition of C1-inhibitor or B1 receptor-antagonist. Thus, B1 receptor-positive endothelial microvesicles may contribute to chronic inflammation by inducing neutrophil chemotaxis, and the reduction of these microvesicles by C1-inhibitor should be explored as a potential treatment for neutrophil-induced inflammation.


Bronchodilation test in allergic adolescents.
This study highlights the close link between upper and lower airways and the relevance of bronchodilation test in patients presenting with moderate-severe persistent allergic rhinitis and mild persistent asthma.


Effectiveness and versatility of biological prosthesis in transplanted patients.
To emphasize the effectiveness and versatility of prosthesis, and good tolerance by patients with incisional hernia (IH). From December 2001 to February 2016, 270 liver transplantations were performed at San Camillo Hospital. IH occurred in 78 patients (28.8%). IH usually appeared early within the first year post-orthotopic liver transplantation. In the first era, fascial defect was repaired by primary closure for defects smaller than 2.5 cm or with synthetic mesh for greater defects. Recently, we started using biological mesh (Permacol™, Covidien). We present a series of five transplanted patients submitted to surgery for abdominal wall defect correction repaired with biological mesh (Permacol™, Covidien). In our cases, the use of biological prosthesis (Permacol™, Covidien) have proven to be effective and versatile in repairing hernia defects of different kinds; patients did not suffer infections of the prosthesis and no recurrence was observed. Furthermore, the prosthesis remains intact even in the years after surgery. The cases that we presented show that the use of biological mesh (Permacol™, Covidien) in transplanted patients may be safe and effective, being careful in the management of perioperative immunosuppression and renal and graft function, although the cost of the product itself has been the main limiting factor and there is need for prospective studies for further evaluations.


Hitchhiking, collapse, and contingency in phage infections of migrating bacterial populations.
Natural bacterial populations are subjected to constant predation pressure by bacteriophages. Bacteria use a variety of molecular mechanisms to defend themselves from phage predation. However, since phages are nonmotile, perhaps the simplest defense against phage is for bacteria to move faster than phages. In particular, chemotaxis, the active migration of bacteria up attractant gradients, may help the bacteria escape slowly diffusing phages. Here we study phage infection dynamics in migrating bacterial populations driven by chemotaxis through low viscosity agar plates. We find that expanding phage-bacteria populations supports two moving fronts, an outermost bacterial front driven by nutrient uptake and chemotaxis and an inner phage front at which the bacterial population collapses due to phage predation. We show that with increasing adsorption rate and initial phage population, the speed of the moving phage front increases, eventually overtaking the bacterial front and driving the system across a transition from a regime where bacterial front speed exceeds that of the phage front to one where bacteria must evolve phage resistance to survive. Our data support the claim that this process requires phage to hitchhike with moving bacteria. A deterministic model recapitulates the transition under the assumption that phage virulence declines with host growth rate which we confirm experimentally. Finally, near the transition between regimes we observe macroscopic fluctuations in bacterial densities at the phage front. Our work opens a new, spatio-temporal, line of investigation into the eco-evolutionary struggle between bacteria and phage.


The Impact of Toxicities on First-Year Outcomes after Ex Vivo CD34+-Selected Allogeneic Hematopoietic Cell Transplantation in Adults with Hematologic Malignancies.
Factors that impact first-year morbidity and mortality in adults undergoing myeloablative allogeneic hematopoietic cell transplantation with ex vivo CD34+ selection have not been previously reported. We assessed all toxicities ≥ grade 3 from the start of conditioning to date of death, relapse, or last contact in 200 patients during the first year after transplantation, identifying 1885 individual toxicities among 17 organ-based toxicity groups. The most prevalent toxicities in the first year were of infectious, metabolic, hematologic, oral/gastrointestinal, hepatic, cardiac, and pulmonary etiologies. Renal complications were minimal. Grades II to IV and III and IV acute GVHD at day 100 were 11.5% and 3%, respectively. In separate multivariate models, cardiovascular, hematologic, hepatic, neurologic, pulmonary, and renal toxicities negatively impacted nonrelapse mortality (NRM) and overall survival during the first year. A higher-than-targeted busulfan level, patient cytomegalovirus seropositivity, and an Hematopoietic Cell Transplantation-Specific Comorbidity Index of ≥3 were associated with increased risk of NRM and all-cause death. Ex vivo CD34+ selection had a favorable 1-year OS of 75% and NRM of 17% and a low incidence of sinusoidal obstruction syndrome. These data establish a benchmark to focus efforts in reducing toxicity burden while improving patient outcomes.


Colloidal-Bound Polyphosphates and Organic Phosphates Are Bioavailable: A Nutrient Solution Study.
Colloidal forms of Fe(III) minerals can be stabilized in solution by coatings of organic or poly-phosphate (P), which reduce the zeta-potential. This opens up a route toward the development of nanoforms of P fertilizers. However, it is unclear if such P forms are bioavailable. To address this question, spinach (Spinacia oleracea) was grown in nutrient solutions, at equal total P, using three different forms of P (orthophosphate = Pi; hexametaphosphate = HMP; myo-inositol hexaphosphate = IHP), free or bound to goethite/ferrihydrite colloids. After 10 days, P uptake was determined with a dose-response curve using colloid-free Pi as a reference treatment. The Pi concentration generating equal P uptake as in colloidal P treatments was used to calculate the relative bioavailability of colloidal P (RBAcolloid). The RBAcolloid was about 60% for Pi-loaded goethite, stabilized with natural organic matter. For HMP/IHP-Pi-loaded colloids, RBAcolloid ranged between 10 and 50%, in line with their higher sorption strength. In conclusion, colloidal organic P or poly-P can stabilize Fe(III) colloids in solution and can contribute to plant-available P. Soil experiments are required to assess their potential as nanofertilizers.


The experience of undertaking faculty practice.
The role of the nurse teacher in practice has been subject to scrutiny by nurse teachers and professional reviews (Clifford 1993, 1996, Crotty 1993, UKCC 1999, Aston et al. 2000). Two models that emerge from the literature to participate in practice are the liaison lecturer or the lecturer practitioner role. A further model of faculty practice is identifiable. Faculty practice has it origins in North America, the consequence of which is there is a dearth of English literature/research enabling analysis of the appropriateness of such a model in the United Kingdom. At a time when nurse educationalists are being encouraged to remain clinically competent it would seem pertinent to explore a further model. In this article the first experiences of faculty pr actice are explored. Key themes to emerge from this experience are gaining access and professional issues arising from the delivery of care, which would benefit from evaluation with Trust colleagues and patients.


Race, Space, and Cumulative Disadvantage: A Case Study of the Subprime Lending Collapse.
In this article, we describe how residential segregation and individual racial disparities generate racialized patterns of subprime lending and lead to financial loss among black borrowers in segregated cities. We conceptualize race as a cumulative disadvantage because of its direct and indirect effects on socioeconomic status at the individual and neighborhood levels, with consequences that reverberate across a borrower's life and between generations. Using Baltimore, Maryland as a case study setting, we combine data from reports filed under the Home Mortgage Disclosure Act with additional loan-level data from mortgage-backed securities. We find that race and neighborhood racial segregation are critical factors explaining black disadvantage across successive stages in the process of lending and foreclosure, controlling for differences in borrower credit scores, income, occupancy status, and loan-to-value ratios. We analyze the cumulative cost of predatory lending to black borrowers in terms of reduced disposable income and lost wealth. We find the cost to be substantial. Black borrowers paid an estimated additional 5 to 11 percent in monthly payments and those that completed foreclosure in the sample lost an excess of $2 million in home equity. These costs were magnified in mostly black neighborhoods and in turn heavily concentrated in communities of color. By elucidating the mechanisms that link black segregation to discrimination we demonstrate how processes of cumulative disadvantage continue to undermine black socioeconomic status in the United States today.


Clinical significance of an inflammation-based prognostic system for gastric cancer patients with a preoperative normal serum level of carcinoembryonic antigen.
To investigate the significance of the Glasgow Prognostic Score (GPS) for predicting the postoperative survival of gastric cancer (GC) patients with a normal preoperative serum level of carcinoembryonic antigen (CEA). Because CEA is a useful marker for prognostication of several types of cancer, some patients with GC have a normal CEA level. On the other hand, the GPS has been established as a valuable inflammation-based prognostic system for cancer patients. Among 650 patients who had undergone elective surgery for GC, 425 with a normal preoperative serum CEA level (≤5.0 ng/ml) were enrolled. Uni- and multivariate analyses were performed to evaluate the relationship of the GPS to overall survival. The Kaplan-Meier analysis and log rank test were used to compare the survival curves among patients with GPS 0, 1 and 2. Multivariate analysis using clinical characteristics selected from univariate analyses revealed that the GPS (0, 1/2) was associated with overall survival (hazard ratio=2.048; 95% C.I. (confidence interval)=1.002-4.185; p=0.049) along with age (≤70/>70) (years), sex, tumor type (3, 4, 5/0, 1, 2), lymph node metastasis (presence/absence) and platelet count (≤35/>35) (×10(4)/mm(3)). The Kaplan-Meier analysis and log rank test demonstrated that there were significant differences in overall survival among patients with GPS 0, 1 and 2 (p<0.001). Even if GC patients have a normal serum level of CEA, the GPS is able to predict their postoperative survival and classify such patients into three independent groups before surgery.


Some sources of nonsampling errors in African census and survey work: a review.
"The paper is a review of some of the more common sources of nonsampling errors in African census and survey work illustrated by some country experiences. [The author suggests] that development and sustainment of an ongoing Integrated System of Household Surveys under the auspices of the United Nations National Household Survey Capability Programme may go a long way toward monitoring and controlling these and other errors that arise in the said census and survey work." (summary in FRE)


Multi-Dielectric Brownian Dynamics and Design-Space-Exploration Studies of Permeation in Ion Channels.
This paper proposes a multi-dielectric Brownian dynamics simulation framework for design-space-exploration (DSE) studies of ion-channel permeation. The goal of such DSE studies is to estimate the channel modeling-parameters that minimize the mean-squared error between the simulated and expected "permeation characteristics." To address this computational challenge, we use a methodology based on statistical inference that utilizes the knowledge of channel structure to prune the design space. We demonstrate the proposed framework and DSE methodology using a case study based on the KcsA ion channel, in which the design space is successfully reduced from a 6-D space to a 2-D space. Our results show that the channel dielectric map computed using the framework matches with that computed directly using molecular dynamics with an error of 7%. Finally, the scalability and resolution of the model used are explored, and it is shown that the memory requirements needed for DSE remain constant as the number of parameters (degree of heterogeneity) increases.


Compact low temperature scanning tunneling microscope with in-situ sample preparation capability.
We report on the design of a compact low temperature scanning tunneling microscope (STM) having in-situ sample preparation capability. The in-situ sample preparation chamber was designed to be compact allowing quick transfer of samples to the STM stage, which is ideal for preparing temperature sensitive samples such as ultra-thin metal films on semiconductor substrates. Conventional spring suspensions on the STM head often cause mechanical issues. To address this problem, we developed a simple vibration damper consisting of welded metal bellows and rubber pads. In addition, we developed a novel technique to ensure an ultra-high-vacuum (UHV) seal between the copper and stainless steel, which provides excellent reliability for cryostats operating in UHV. The performance of the STM was tested from 2 K to 77 K by using epitaxial thin Pb films on Si. Very high mechanical stability was achieved with clear atomic resolution even when using cryostats operating at 77 K. At 2 K, a clean superconducting gap was observed, and the spectrum was easily fit using the BCS density of states with negligible broadening.


Visualization of Activity Landscapes and Chemogenomics Data.
Chemogenomics data are often difficult to analyze, given their large amounts, heterogeneity, and multi-dimensional nature. Network representations and other graphical methods are utilized to aid in data analysis. This review covers several recently introduced visualization methods for multi- or high-dimensional compound activity data that are designed for specific applications.


Quasi-harmonic thermoelasticity of palladium, platinum, copper, and gold from first principles.
We calculate the temperature-dependent elastic constants (ECs) of palladium, platinum, copper and gold within the quasi-harmonic approximation using a first-principles approach and evaluating numerically the second derivatives of the Helmholtz free-energy with respect to strain at the minimum of the free-energy itself. We find an overall good agreement with the experimental data although the anomalies of palladium and platinum reported at room temperature are not reproduced. The contribution of electronic excitations is also investigated: we find that it is non-negligible for theC44ECs of palladium and platinum while it is irrelevant in the other cases. Its effect is not sufficient to explain the details of the anomalies found by experiments, not even when, in the case of platinum, we take into account the electron-phonon interaction. Lastly, the effect of the exchange and correlation functional is addressed and it is found that it is important atT= 0 K, while all functionals give similar temperature dependencies.


Vibrational spectra and gas-phase structure of N-methyl-S,S-bis(trifluoromethyl)sulfimide, CH3N=S(CF3)2.
The molecular structure of N-methyl-S,S-bis(trifluoromethyl)sulfimide, CH3N=S(CF3)2, was determined by gas electron diffraction and quantum chemical calculations [B3LYP and MP2 with 6-31+G(2df,p) basis sets]. Furthermore, vibrational spectra, IR (gas) and Raman (liquid), were recorded. These spectra were assigned by comparison with analogous molecules and with calculated frequencies and intensities (HF, B3LYP, and MP2 with 6-311G basis sets). All experimental data and computational methods result in a single conformer with syn orientation of the CH3 group relative to the bisector of the two CF3 groups. The molecule possesses C1 symmetry, slightly distorted from CS symmetry. The N=S bond length in this compound [1.522(10) A] is longer than that in imidosulfur difluorides RN=SF2 [1.476(4) A - 1.487(5) A].


Photochemical and photobiological properties of ketoprofen associated with the benzophenone chromophore.
Irradiation of ketoprofen in neutral aqueous medium gave rise to 3-ethylbenzophenone as the major photoproduct. Its formation is justified via protonation of a benzylic carbanion or hydrogen abstraction by a benzylic radical. Minor amounts of eight additional compounds were isolated. Four of them are derived from the benzylic radical: 3-(1-hydroperoxyethyl)benzophenone, 3-(1-hydroxyethyl)benzophenone, 3-acetylbenzophenone and 2,3-bis-(3-benzoylphenyl)butane. The other four products involve initial hydrogen abstraction by the excited benzophenone chromophore of ketoprofen: 1,2-bis-(3-ethylphenyl)-1,2-diphenyl-1,2-ethanediol, 2-(3-benzoylphenyl)-1-(3-ethylphenyl)-1-phenylpropan-1-ol, alpha-(3-ethylphenyl)phenylmethanol, 1,2-bis-[3-(2-hydroxycarbonylethyl) phenyl]-1,2-diphenyl-1,2-ethanediol. The latter process was found to mediate the photoperoxidation of linoleic acid through a type I mechanism, as evidenced by the inhibition produced by the radical scavengers butylated hydroxyanisole and reduced glutathione. The major photoproduct, which contains the benzophenone moiety but lacks the propionic acid side chain, also photosensitized linoleic acid peroxidation. Because lipid peroxidation is indicative of cell membrane lysis, the above findings are highly relevant to explain the photobiological properties of ketoprofen.


High-Intensity Exercise Reduces Cardiac Fibrosis and Hypertrophy but Does Not Restore the Nitroso-Redox Imbalance in Diabetic Cardiomyopathy.
Diabetic cardiomyopathy refers to the manifestations in the heart as a result of altered glucose homeostasis, reflected as fibrosis, cellular hypertrophy, increased oxidative stress, and apoptosis, leading to ventricular dysfunction. Since physical exercise has been indicated as cardioprotective, we tested the hypothesis that high-intensity exercise training could reverse the cardiac maladaptations produced by diabetes. For this, diabetes was induced in rats by a single dose of alloxan. Diabetic rats were randomly assigned to a sedentary group or submitted to a program of exercise on a treadmill for 4 weeks at 80% of maximal performance. Another group of normoglycemic rats was used as control. Diabetic rat hearts presented cardiomyocyte hypertrophy and interstitial fibrosis. Chronic exercise reduced both parameters but increased apoptosis. Diabetes increased the myocardial levels of the mRNA and proteins of NADPH oxidases NOX2 and NOX4. These altered levels were not reduced by exercise. Diabetes also increased the level of uncoupled endothelial nitric oxide synthase (eNOS) that was not reversed by exercise. Finally, diabetic rats showed a lower degree of phosphorylated phospholamban and reduced levels of SERCA2 that were not restored by high-intensity exercise. These results suggest that high-intensity chronic exercise was able to reverse remodeling in the diabetic heart but was unable to restore the nitroso-redox imbalance imposed by diabetes.


Pediatric living donor liver transplant in a recipient with biliary atresia and portal vein duplication-How did we manage it?
Portal vein malformations might occur during the embryonic period, as a consequence of abnormal remodeling of vitelline veins during embryonic life. Patients suffering from biliary atresia are particularly prone to have vascular malformations; although being the most frequent indication for liver transplantation in the pediatric age, portal vein duplication has not been so far associated with biliary atresia, and to the best of our knowledge, there is no-written evidence describing how to manage it when it is first diagnosed while performing a pediatric liver transplant. Therefore, we present a recent case from our group, describing the intraoperative diagnosis of a double portal system in a patient with biliary atresia and failed Kasai. We aim to describe its surgical management, understanding that it is a real challenge to find them unexpectedly during the surgical procedure in the setting of cirrhosis and portal hypertension, particularly in small patients; therefore, by reporting this case, we aim to make readers aware about the chance of finding it, and how to managed it, to include this approach as part of the surgical armamentarium.


Pre-implantation genetic diagnosis and pre-implantation genetic screening: two years experience at a single center.
Indications for preimplantation genetic diagnosis (PGD)/preimplantation genetic screening (PGS) cycles and clinical outcomes were evaluated at CHA Gangnam Medical Center. This is retrospective cohort study. All patients (n=336) who went through in vitro fertilization (IVF)-PGD/PGS cycles (n=486) between January 2014 and December 2015 were included in Fertility Center of CHA Gangnam Medical Center. Patients underwent IVF-PGD/PGS with 24-chromosome screening. Patients with euploid embryos had transfer of one or 2 embryos in a fresh cycle with any subsequent frozen embryo transfer (ET) cycle. Compared implantation, clinical pregnancy, ongoing pregnancy, and early abortion rates were the main outcome measures. The most common indication for PGD/PGS was recurrent spontaneous abortion (n=160). The chromosome rearrangement cases (n=116) included 24 Robertsonian translocations, 60 reciprocal translocations, 3 inversions, 2 deletions, 4 additions, and 23 mosaicisms. PGS cases rather than the PGD cases showed higher implantation rates (26.4% vs. 20.3%), ongoing pregnancy rates (19.5% vs. 16.4%), and clinical pregnancy rates (28.6% vs. 23.3%). Implantation rates (30.3% vs. 23.7%), clinical pregnancy rates (39.2% vs. 25.2%), and ongoing pregnancy rates (25.7% vs. 17.5%) were significant higher in the blastocyst evaluation group than cleavage stage evaluation group. This was the largest study of PGD/PGS for 2 years at a single center in Korea. The pregnancy outcomes of PGD cases are slightly lower than PGS cases. It was confirmed again that success rate of PGD/PGS is higher if biopsy was done at blastocyst than cleavage stage.


Common and rare GCH1 variants are associated with Parkinson's disease.
GCH1 encodes the enzyme guanosine triphospahte (GTP) cyclohydrolase 1, essential for dopamine synthesis in nigrostriatal cells, and rare mutations in GCH1 may lead to Dopa-responsive dystonia (DRD). While GCH1 is implicated in genomewide association studies in Parkinson's disease (PD), only a few studies examined the role of rare GCH1 variants in PD, with conflicting results. In the present study, GCH1 and its 5' and 3' untranslated regions were sequenced in 1113 patients with PD and 1111 controls. To examine the association of rare GCH1 variants with PD, burden analysis was performed. Three rare GCH1 variants, which were previously reported to be pathogenic in DRD, were found in five patients with PD and not in controls (sequence Kernel association test, p = 0.024). A common haplotype, tagged by rs841, was associated with a reduced risk for PD (OR = 0.71, 95% CI = 0.61-0.83, p = 1.24 × 10-4), and with increased GCH1 expression in brain regions relevant for PD (www.gtexportal.org). Our results support a role for rare, DRD-related variants, and common GCH1 variants in the pathogenesis of PD.


Comparative investigation on the mutagenicities of organophosphate, phthalimide, pyrethroid and carbamate insecticides by the Ames and lactam tests.
The Salmonella lactam test is a newly developed method for detecting genotoxins. This technique is based on the ability of DNA damaging agents to reverse expression of the beta-lactamase gene, an important gene that enables microbes to resist beta-lactam antibiotics. A construct p-SELECT Control DNA plasmid containing a beta-lactamase gene site was constructed in many mutant forms, including point and frameshift mutants. These mutant constructs were introduced into Salmonella tester strains whose mutagenicity is based on their ability to reverse expression of the beta-lactamase gene. Fourteen pesticides were evaluated for genotoxicity using our newly developed Salmonella typhimurium strains JK947 and JK3, which are useful for detecting base substitution mutations. Six pesticides, namely allethrin, captan, folpet, monocrotophos, acephate and carbofuran, proved highly mutagenic in strain JK947, while the first four pesticides were more weakly mutagenic in strain JK3. In comparison, results from the Ames test show strain JK947 to be more sensitive to these pesticides than strains TA100 and TA1535. Strains TA98 and JK1 proved insensitive to allethrin, captan, folpet, acephate, carbofuran and monocrotophos. Among the many advantages of the lactam test are: large numbers of cells can treated and the test is operationally simple and inexpensive; revertant colonies form faster in the lactam test (16 h) than in the Ames test (48 h); the lactam test can detect mutagens present in biological specimens contaminated by histidine and biotin, samples that may give false positive results in the Ames test.


An integrated data analysis tool for improving measurements on the MST RFP.
Many plasma diagnostics contain complementary information. For example, the double-foil soft x-ray system (SXR) and the Thomson Scattering diagnostic (TS) on the Madison Symmetric Torus both measure electron temperature. The complementary information from these diagnostics can be combined using a systematic method based on integrated data analysis techniques, leading to more accurate and sensitive results. An integrated data analysis tool based on Bayesian probability theory was able to estimate electron temperatures that are consistent with both the SXR and TS diagnostics and more precise than either. A Markov Chain Monte Carlo analysis to increase the flexibility of the tool was implemented and benchmarked against a grid search method.


Angiotensin-converting enzyme genotype and arterial oxygen saturation at high altitude in Peruvian Quechua.
The I-allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with performance benefits at high altitude (HA). In n = 142 young males and females of largely Quechua origins in Peru, we evaluated 3 specific hypotheses with regard to the HA benefits of the I-allele: (1) the I-allele is associated with higher arterial oxygen saturation (Sa(O(2))) at HA, (2) the I-allele effect depends on the acclimatization state of the subjects, and (3) the putative I-allele effect on Sa(O(2)) is mediated by the isocapnic hypoxic ventilatory response (HVR, l/min(1)/% Sa(O(2))(1)). The subject participants comprised two different study groups including BLA subjects (born at low altitude) who were lifelong sea-level residents transiently exposed to hypobaric hypoxia (<24 h) and BHA subjects (born at HA) who were lifelong residents of HA. To control for the possibility of population stratification, Native American ancestry proportion (NAAP) was estimated as a covariate for each individual using a panel of 70 ancestry-informative molecular markers (AIMS). At HA, resting and exercise Sa(O(2)) was strongly associated with the ACE genotype, p = 0.008 with approximately 4% of the total variance in Sa(O(2)) attributed to ACE genotype. Moreover, I/I individuals maintained approximately 2.3 percentage point higher Sa(O(2)) compared to I/D and D/D. This I-allele effect was evident in both BLA and BHA groups, suggesting that acclimatization state has little influence on the phenotypic expression of the ACE gene. Finally, ACE genotype was not associated with the isocapnic HVR, although HVR had a strong independent effect on Sa(O(2)) (p = 0.001). This suggests that the I-allele effect on Sa(O(2)) is not mediated by the peripheral control of breathing, but rather by some other central cardiopulmonary effect of the ACE gene on the renin-angiotensin-aldosterone system (RAAS).


A Validation Study of the Spanish Version of the Hypersexual Behavior Inventory (HBI): Paper-and-Pencil Versus Online Administration.
Hypersexuality is a problematic behavior characterized by the combination of an excessive sexual desire and the pathological inability to control it. This study presents the psychometric properties of the Spanish paper-and-pencil and online versions of the Hypersexual Behavior Inventory (HBI), one of the most popular scales to assess this issue. A total of 2,250 participants (1,070 men) completed a translated version of the HBI (1,450 in paper-and-pencil; 800 online). The exploratory factor analysis yielded three factors that explained 67.53% of total variance for the HBI paper-and-pencil version. This factor structure was confirmed in the HBI online version through confirmatory factor analysis (CFA). Factorial, structural, scalar and error variance-invariance according to gender was also confirmed through multigroup CFA. Reliability of the total score and subscales ranged between .89 and .96. Likewise, correlations with other related scales were positive and significant (r between .511 and .743). Temporal stability one year after the first application was .77 (paper-and-pencil format) and .68 (online version). These results support the reliability and validity of the HBI and justify its use in the assessment of hypersexuality in Spanish-speaking countries.


Increase in lymphogranuloma venereum cases in South Florida.
The purpose of the study was to evaluate the clinic prevalence and clinical characteristics of patients with LGV since 2007 when active clinic surveillance started. We review all the reports of rectal Chlamydia trachomatis and LGV testing of those samples. Chlamydia trachomatis LGV DNA was detected by Nucleic Acid Amplification/ompA gene sequencing. Medical records of all patients with LGV were reviewed. Prevalence of rectal CT among tested individuals was relatively stable during the study period: 2007 (15%), 2008 (15%), 2009 (12%) and 2010 (14%). Eight cases of LGV were identified during the study period, one in 2009 and seven in 2010. All individuals were male and all except one had sex with only men. Most of them were also infected with HIV (62.5%). We concluded that this is the first report of LGV cases in South Florida and shows a rapid increase in the number of cases in the last year.


Lack of effects for dietary exposure of bisphenol A during in utero and lactational periods on reproductive development in rat offspring.
The potential for health effects on humans with exposure to bisphenol A (BPA) has raised concerns, and the adverse effects of low-dose exposure to BPA on reproduction have been controversial. The purpose of the present study was to investigate the effects of low-dose exposure to BPA on reproductive development in F(1) rat offspring. Pregnant female Sprague-Dawley rats (F(0)) were fed a diet containing low doses of BPA (0, 0.33, 3.3, or 33 ppm) from gestational day (GD) 6 through postnatal day (PND) 21. The weanlings (F(1)) from all dose groups were fed a normal diet ad libitum after weaning and then were subjected to necropsy at 5 weeks or 3 months of age. No BPA-related changes were observed in body weight or weight of any of the major reproductive organs in F(1) males and females. Epididymis weight was significantly lower only in 3-month-old F(1) males exposed to 33 ppm BPA. Anogenital distance (AGD), the ratio of AGD to the cube root of body weight, and relative ovary weight were significantly lower in 5-week-old F(1) females exposed to 3.3 and 33 ppm BPA, but significant differences were not observed in 3-month-old females. There were no BPA-related effects on cauda epididymal sperm motility in 3-month-old F(1) males. Plasma reproductive steroid hormone concentrations were not altered among groups in either sex. These outcomes indicate that low-dose exposure to BPA in the diet does not adversely affect reproductive development in F(1) rat offspring.


Cryptosporidium infection in an adult mouse model. Independent roles for IFN-gamma and CD4+ T lymphocytes in protective immunity.
Cryptosporidium is a protozoan parasite that can cause chronic life-threatening diarrhea in immunocompromised persons. Host immune responses are poorly understood, an impediment to development of effective therapy. In mice, normal adult BALB/c animals resist infection whereas chronic symptomatic cryptosporidiosis develops in adult nude mice and in neonatally infected BALB/c mice treated with anti-CD4 mAb. To define further the immune defects that allow mice to be infected with Cryptosporidium, adult BALB/c mice were treated with cytolytic anti-CD4 or anti-CD8 or with neutralizing anti-IFN-gamma or anti-IL-2 mAb. Chronic infection, manifested by continuous shedding of sparse but statistically significant numbers of oocysts, occurred with anti-CD4 +/- anti-CD8 mAb treatment although anti-CD8 mAb treatment alone did not allow infection. Treatment with anti-IFN-gamma mAb greatly enhanced oocyst shedding but infection was self-limited. Treatment with a combination of anti-CD4 and anti-IFN-gamma mAb permitted both chronic infection and shedding of large numbers of oocysts. Furthermore mice treated initially with anti-CD4 mAb showed a substantial increase in oocyst shedding when later treated with anti-IFN-gamma mAb; and mice treated initially with both mAbs showed a decline in oocyst shedding when anti-IFN-gamma mAb was stopped. Anti-IFN-gamma mAb treatment of congenitally athymic adult BALB/c mice led to an approximately a 75-fold increase in oocyst shedding. Treatment of adult BALB/c mice with anti-IL-2 mAb did not permit Cryptosporidium infection. These results suggest that redundant immunologic mechanisms limit Cryptosporidium infection such that both CD4+ cells and IFN-gamma are required to prevent initiation of infection whereas either alone can limit the extent (IFN-gamma) or duration (CD4+ T cells) of infection. They also suggest that production of IFN-gamma by a non-T cell contributes to host immunity.


Heart valve operations in solid organ recipients: an 18-year single-center experience.
We retrospectively analyzed the outcome of heart valve operations in solid organ recipients, who were referred for operation to our institution. Over an 18-year period, 23 heart (group 1) and 16 renal (group 2) transplant recipients in New York Heart Association (NYHA) classes III and IV underwent valve operation. The mean interval from the time of transplantation to cardiac surgery was 77.9 months with a mean follow-up time of 34.6 months in group 1 and 87.2 months with a mean follow-up time of 39.2 months in group 2. Group 1 underwent tricuspid valve replacement (n=12), tricuspid valve reconstruction (n=7), aortic valve replacement (AVR, n=3), and mitral valve replacement (MVR, n=1). In group 2, mechanical valve replacement was performed in 14 patients (9 AVR, 3 MVR, 2 AVR and MVR) and tricuspid or mitral valve reconstruction in two patients. There was no operative death. During hospitalization, multiorgan failure due to sepsis was the main cause of mortality (2 in both groups). In the mean follow-up period of 41.2 months, there were four late non-cardiac-related deaths in group 1. Currently 29 surviving transplant recipients (16 heart, 69.6% and 13 renal, 81.3%) are in NYHA classes I and II. In heart and renal recipients, valve operations can be performed effectively and safely with acceptable mortality, low cardiac morbidity, and excellent clinical results, although infection is the most serious complication.


The Effect of Crosslinking Degree of Hydrogels on Hydrogel Adhesion.
The development of adhesive hydrogel materials has brought numerous advances to biomedical engineering. Hydrogel adhesion has drawn much attention in research and applications. In this paper, the study of hydrogel adhesion is no longer limited to the surface of hydrogels. Here, the effect of the internal crosslinking degree of hydrogels prepared by different methods on hydrogel adhesion was explored to find the generality. The results show that with the increase in crosslinking degree, the hydrogel adhesion decreased significantly due to the limitation of segment mobility. Moreover, two simple strategies to improve hydrogel adhesion generated by hydrogen bonding were proposed. One was to keep the functional groups used for hydrogel adhesion and the other was to enhance the flexibility of polymer chains that make up hydrogels. We hope this study can provide another approach for improving the hydrogel adhesion generated by hydrogen bonding.


Antibody formation to trehalose-6,6'-dimycolate (cord factor) of Mycobacterium tuberculosis.
A complex of trehalose-6, 6'-dimycolate (cord factor) and methylated bovine serum albumin was prepared, and its effect on the toxicity of cord factor in mice was studied. Either the active immunization with cord factor-methylated bovine serum albumin complex or the passive transfer of sera of rabbits vaccinated with the complex protected mice against the toxic action of cord factor. The antisera of mice and rabbits and gamma globulin fraction of rabbit antiserum demonstrated a precipitin reaction with an aqueous emulsion of cord factor. The reactivity of anticord factor was totally lost by treatment with 2-mercaptoethanol. The antigenic determinant group of cord factor was alpha-d-trehalose. Cord factor-anticord factor complex was devoid of activity to induce in vitro swelling and inhibition of respiratory and phosphorylative activity of mouse liver mitochondria. These results suggest that vaccination with cord factor-methylated bovine serum albumin complex induced the production of antibody to cord factor in mouse and rabbit serum which binds to cord factor and neutralizes its toxic activity either in vivo or in vitro.


2-Methoxyestradiol improves the apoptosis level in keloid fibroblasts through caspase-dependent mechanisms in vitro.
Apoptosis is a form of programmed cell death that occurs in multicellular organisms. Fibroblasts are the main cellular ingredients in keloid tissue, which has a relatively low apoptosis level. A natural metabolite of estradiol, 2-Methoxyestradiol (2ME2) exerts a pro-apoptotic effect on tumor cells. In this study, the expression levels of key factors in the apoptosis pathway and the expression level of the proliferating cell nuclear antigen (PCNA) were measured to assess the levels of apoptosis and proliferation in both normal skin fibroblasts and keloid fibroblasts. Twelve samples were obtained from 12 patients: 6 keloid patients and 6 non-keloid patients. All 12 of the patients were randomly selected from the Department of Plastic Surgery at Peking Union Medical College Hospital from June 2016 to December 2016. After cell culture, fibroblasts were divided into the following 6 groups: normal skin fibroblasts (S); keloid fibroblasts (K); keloid fibroblasts treated with 2ME2 (2ME2); keloid fibroblasts treated with DMSO (DMSO); keloid fibroblasts treated with the caspase inhibitor Ac-DEVD-CHO (IN); and keloid fibroblasts treated with both Ac-DEVD-CHO and 2ME2 (IN+2ME2). Fibroblasts at up to passage 3 were used for analysis. Cell activity was measured by the cell counting kit-8. TUNEL staining was used to observe the cell apoptotic morphology. The key apoptosis factors (caspase-3, caspase-8, caspase-9, Bcl-2, Bax, and cytochrome-c) and PCNA expression levels were detected by immunofluorescence analysis and Western blotting. A certain concentration of 2ME2 was also used in group S to evaluate the toxicity. Compared with that in the other groups, 2ME2 significantly inhibited cell activity and led to apoptotic appearance of fibroblasts. In protein analysis, 2ME2 remarkably increased the expression of apoptosis factors and decreased the PCNA expression. Apoptosis levels were reduced by both the caspase inhibitor and 2ME2; thus indicating that the pro-apoptosis effect of 2ME2 was achieved through a caspase-dependent mechanism in keloid fibroblasts. Toxicity assessment showed that 2ME2 had a very low influence on normal skin fibroblasts. 2ME2, considered to be a new promising type of chemotherapy drug, exerts a pro-apoptosis effect by regulating the caspase family and an anti-proliferation effect towards keloid fibroblasts, and it presents low toxicity towards normal fibroblasts in vitro.


[Functional analysis of autophagy-related gene Atg6 in planarian central nervous system regeneration].
Autophagy-related gene 6 (Atg6) plays an essential role in autophagy, and loss of its function impairs neurogenesis. Planarian is a good model for the study of the central nervous system (CNS) regeneration. It can regenerate a new head de novo in 1 week following decapitation. Therefore, functional analysis of Atg6 in planarian CNS regeneration is very important for understanding of autophagy in the regulation of neurogenesis. In this work, we reported the molecular characteristics of Atg6 in Dugesia japonica (DjAtg6) for the first time and examined its function by RNAi. The full-length cDNA of DjAtg6 is 1366 bp encoding 423 amino acids. The deduced amino sequence of DjAtg6 contains the coil-coil domain and β-α-repeated autophagy-specific domain shared by ATG6/Beclin 1 family. Following amputation before and after the pharynx, DjAtg6 transcripts increased and were mainly distributed in the newly regenerated brain structure. RNAi-DjAtg6 delayed planarian head regeneration with a small size of brain, and decreased the expression levels of neural-related genes. In addition, our results revealed that RNAi-DjAtg6 did not affect the stem cell proliferation, but down-regulated the cell migration-related genes mmp1 and mmp2. Furthermore, RNAi-mmp1 and RNAi-mmp2 delayed planarian head regeneration. Therefore, our results suggest that DjAtg6 is important for planarian CNS regeneration. The abnormal CNS regeneration caused by RNAi-DjAtg6 may be related to cell migration, but the detailed mechanism needs to be further investigated.


Fluoroquinolone susceptibility testing of Salmonella enterica: detection of acquired resistance and selection of zone diameter breakpoints for levofloxacin and ofloxacin.
Fluoroquinolones (e.g., ciprofloxacin) have become a mainstay for treating severe Salmonella infections in adults. Fluoroquinolone resistance in Salmonella is mostly due to mutations in the topoisomerase genes, but plasmid-mediated quinolone resistance (PMQR) mechanisms have also been described. In 2012, the Clinical and Laboratory Standards Institute (CLSI) revised the ciprofloxacin interpretive criteria (breakpoints) for disk diffusion and MIC test methods for Salmonella. In 2013, the CLSI published MIC breakpoints for Salmonella to levofloxacin and ofloxacin, but breakpoints for assigning disk diffusion results to susceptible (S), intermediate (I), and resistant (R) categories are still needed. In this study, the MICs and inhibition zone diameters for nalidixic acid, ciprofloxacin, levofloxacin, and ofloxacin were determined for 100 clinical isolates of nontyphi Salmonella with or without resistance mechanisms. We confirmed that the new levofloxacin MIC breakpoints resulted in the highest category agreement (94%) when plotted against the ciprofloxacin MICs and that the new ofloxacin MIC breakpoints resulted in 92% category agreement between ofloxacin and ciprofloxacin. By applying the new MIC breakpoints in the MIC zone scattergrams for levofloxacin and ofloxacin, the following disk diffusion breakpoints generated the least number of errors: ≥28 mm (S), 19 to 27 mm (I), and ≤18 mm (R) for levofloxacin and ≥25 mm (S), 16 to 24 mm (I), and ≤15 mm (R) for ofloxacin. Neither the levofloxacin nor the ofloxacin disk yielded good separation of isolates with and without resistance mechanisms. Further studies will be needed to develop a disk diffusion assay that efficiently detects all isolates with acquired resistance to fluoroquinolones.


A mathematical musculoskeletal shoulder model for proactive ergonomic analysis.
Occupational shoulder musculoskeletal injuries and disorders are common. Generally available shoulder work analysis tools do not offer insight into specific muscle load magnitudes that may indicate increased risk, nor do they address many concerns germane to job analysis. To address these issues, a biomechanical model of the shoulder was developed to include several critical components: the systematic inclusion of kinematic and kinetic effects, population scalability, geometric realism, an empirical glenohumeral constraint, and integration with digital ergonomics analysis software tools. This unique combination of features in a single model was explored through examination of both experimental and simulated data with the developed analysis tool. The utility of the model is discussed together with a review of its specific strengths and weaknesses, and the potential for its future use in proactive ergonomic analyses and workplace simulations.


Changes in the appearance and treatment of deep sternal infections.
The Department of Thoracic Surgery at the University Hospital, Linköping, Sweden, has actively followed up infectious complications of cardiac surgery since 1989. The aim of this study was to investigate whether changes occurred during the 1990s in the appearance and the management of deep infections. This was done by studying patients undergoing surgical revision of infected wounds. We studied 42 patients during 1990-94 and 49 during 1997-98 (total number of operations in these periods, 3075 and 1646, respectively). Pre-operative and intra-operative variables were recorded for the two patient populations. The proportion of cardiac surgery procedures followed by a surgical revision for an infection in the sternal wound increased between the two periods (1.4% vs. 3.0%). Variables associated with the surgical procedures preceding the infection remained unchanged. In the later period, treatment was started earlier (64 vs. 24 days), and the length of antibiotic treatment was decreased (115 vs. 72 days). The incidence of osteomyelitis of the sternal bone was lower (61% vs. 27%). It appears that as the proportion of patients undergoing surgical revision increased, management of the infections became more effective, with aggressive surgical and antibiotic treatment policies and shorter treatment periods. This indicates that in order to evaluate the overall impact of measures designed to reduce infections after cardiac surgery, not only the incidence of infection needs to be followed up but other factors also need to be taken into account.


We'll fight it as long as we can: coping with the onset of Alzheimer's disease.
The onset of dementia places major demands on coping resources, and the development of adaptive coping strategies is crucial in optimizing well-being and minimizing excess disability. Understanding how people with early-stage dementia naturally attempt to adjust and cope is an important starting point in developing interventions that can enhance self-efficacy and adaptive coping. This study aimed to identify and conceptualize the coping strategies used by people with early-stage Alzheimer's disease (AD). Twelve participants with early-stage Alzheimer's and their partners were each interviewed separately on two occasions, and interpretative phenomenological analysis was used to identify themes within their accounts. The ways in which participants tried to adjust fell into two groups reflecting the same continuum, running from self-protective to integrative responding, that characterized reactions, explanations, and emotional responses. Attempts at holding on and compensating were essentially self-protective, and reflected attempts to maintain a sense of self and normality. Developing a fighting spirit and coming to terms reflected attempts to confront the threats head on, view them as a challenge, and respond in a way that balanced struggle with acceptance in order to integrate the changes within the self. Most participants described strategies in the self-protective categories, while fewer gave accounts that fell into the integrative categories. On the basis of the themes identified in the participants' accounts, key areas in which early intervention may facilitate the development of adaptive coping strategies are identified. The results provide a useful foundation for further developing interventions that can assist in enhancing well-being and self-esteem in early-stage AD.


An intersectional approach to social determinants of stress for African American men: men's and women's perspectives.
Stress is a key factor that helps explain racial and gender differences in health, but few studies have examined gendered stressors that affect men. This study uses an intersectional approach to examine the sources of stress in African American men's lives from the perspectives of African American men and important women in their lives. Phenomenological analysis was used to examine data from 18 exploratory focus groups with 150 African American men, ages 30 years and older, and eight groups with 77 African American women. The two primary sources of stress identified were seeking to fulfill socially and culturally important gender roles and being an African American man in a racially stratified society. A central focus of African American men's daily lives was trying to navigate chronic stressors at home and at work and a lack of time to fulfill roles and responsibilities in different life domains that are traditionally the responsibility of men. Health was rarely mentioned by men as a source of stress, though women noted that men's aging and weathering bodies were a source of stress for men. Because of the intersection of racism and economic and social stressors, men and women reported that the stress that African American men experienced was shaped by the intersection of race, ethnicity, age, marital status, and other factors that combined in unique ways. The intersection of these identities and characteristics led to stressors that were perceived to be of greater quantity and qualitatively different than the stress experienced by men of other races.


Cancer stem cells: The potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells.
One major obstacle in cancer therapy is chemoresistance leading to tumor recurrence and metastasis. Cancer stem cells, in particular glioblastoma stem cells, are highly resistant to chemotherapy, radiation, and immune recognition. In case of immune recognition, several survival mechanisms including, regulation of autophagy, proteases, and cell surface major histocompatibility complex class I molecules, are found in glioblastoma stem cells. In different pathways, cathepsins play a crucial role in processing functional proteins that are necessary for several processes and proper cell function. Consequently, strategies targeting these pathways in glioblastoma stem cells are promising approaches to interfere with tumor cell survival and will be discussed in this review.


Successful removal of metallic foreign body in the neck-mediastinum via the parapharyngeal space approach.
Neck-mediastinum foreign body (FB) is a common emergency in otorhinolaryngology head and neck surgery departments, and it can be lethal. We present a case of an uncommon foreign body in the neck-mediastinum. The FB was metallic and about 12 cm long. A 74-year-old male accidentally swallowed a metallic FB that lodged in his throat for > 3 days. The intake of the object was associated with smoking a peace pipe, and was an indication for surgery. Aerodermectasia was observed in the neck upon physical examination, and a high-density foreign body was found in the neck-mediastinum through cervicothoracic computed-tomography (CT) scan. Electronic laryngoscopy showed a white pseudo-membrane adhering to the surface of the bilateral piriform fossa in the right laryngeal vestibule, and the root of the tongue, and mucosa were swollen. Cervicothoracic CT revealed dense shadows in the neck-mediastinum. However, electronic laryngoscopy showed no FB in the larynx or piriform fossa. The metal FB was removed by surgery via the parapharyngeal space approach instead of endoscopy. After preoperative assessment and preparation, we successfully removed the metal FB from the neck-mediastinum via the parapharyngeal space approach. The patient was doing well at one-month follow-up. Neck-mediastinum FB is an emergency but rare case necessitating otorhinolaryngology head and neck surgery. It can easily lead to mediastinal and lung infection; given its location in the body, it may lead to aortic arch rupture if not handled promptly.


Platelet-Lymphocyte Ratio as a Useful Predictor of the Therapeutic Effect of Neoadjuvant Chemotherapy in Breast Cancer.
The peripheral blood platelet-lymphocyte ratio (PLR) has been proposed as an indicator for evaluating systemic inflammatory responses in cancer-bearing patients. While some reports suggest a correlation between PLR and prognosis, few studies have examined the relationship between PLR and sensitivity to chemotherapy. We conducted a study on whether PLR could serve as a predictor of the therapeutic effects of neoadjuvant chemotherapy (NAC). PLR was evaluated in 177 breast cancer patients treated with the NAC 5-fluorouracil, epirubicin and cyclophosphamide, followed by weekly paclitaxel and subsequent curative surgery. The correlation between PLR and prognosis, and between PLR and the efficacy of NAC, were evaluated retrospectively. The low PLR group had significantly more patients > 56 years old (p = 0.001) and postmenopausal women (p = 0.001) than the high PLR group. The low PLR group also had a higher pathologic complete response (pCR) rate (p = 0.019). On examining the correlation with prognosis, the low-PLR group was found to have significantly longer disease-free survival (p = 0.004) and overall survival (p = 0.032) than the high PLR group. Multivariate analysis also revealed that lymph node metastasis (p = 0.043, hazard ratio = 4.40) and a high PLR (p = 0.005, hazard ratio = 2.84) were independent, unfavorable prognostic factors. For patients with breast cancer treated with NAC, a low PLR indicated high chemotherapy sensitivity, suggesting that PLR could serve as a predictive marker of the therapeutic effect of NAC.


Integrated nanoliter systems.
Microfluidic chip platforms for manipulating liquid volumes in the nanoliter range are slowly inching their way into mainstream genomic and proteomic research. The principal challenge faced by these technologies is the need for high-throughput processing of increasingly smaller volumes, with ever higher degrees of parallelization. Significant advances have been made over the past few years in addressing these needs through electrokinetic manipulation, vesicle encapsulation and mechanical valve approaches. These strategies allow levels of integration density and platform complexity that promise to make them into serious alternatives to current robotic systems.


[The new National Guidelines System in Italy: a first evaluation].
The so-called Gelli-Bianco Law (L 24/2017) recognizes the central role of Guidelines as far as decision-making in the health sector is concerned and establishes the Italian National Guidelines System (SNLG) as a "safe harbor", notwithstanding the specificities of each real-world case. The Italian National Center for Clinical Excellence, Quality and Security (CNEC) is responsible for the creation and the development of the SNLG. After considering the many issues revolving around the creation of shared Guidelines, both on the national and international level, we present here the activities of the SNLG to date, together with an evaluation of how the new rules and practices around the creation of National Guidelines have been received. We also provide a series of recommendations for scientific societies on how best to produce Guidelines in their own field and how to submit them to the SNLG.


(2E)-3-(3-Bromo-4-meth-oxy-phen-yl)-1-(4-fluoro-phen-yl)prop-2-en-1-one.
In the title compound, C(16)H(12)BrFO(2), the dihedral angle between the aromatic rings is 23.75 (12)° and the dihedral angle between the prop-2-en-1-one fragment and the fluorobenzene ring is 20.9 (2)°. In the crystal, only van der Waals interactions occur.


Owner perceptions and management of the adverse behavioural effects of fireworks on companion animals: an update.
Aims: To provide updated results on the adverse behavioural effects of fireworks on companion animals in New Zealand, measures that owners use to mitigate these effects, and opinions on a ban on the sale of fireworks. Method: A cross-sectional survey of companion animal owners in New Zealand was conducted between 2 November and 5 December 2016 using an online survey. The survey was modelled after a similar study conducted in 2006. Owners were asked to provide information on the types and severity of behaviours observed in their animals that were frightened by fireworks, what they did for their frightened animals and whether they would support a ban on the sale of fireworks. Results: There were 4,293 respondents who completed the online survey and they owned 15,871 companion animals, of which 11,750 (74.4%) were frightened of fireworks. For the 7,464 fearful animals with individual data available, the most commonly reported adverse behaviours were hiding (5,287; 70.8%), shivering (4,058; 54.3%) and cowering (3,324; 44.5%). Owners reported that 345 animals had been physically injured as the result of fireworks. Of 3,682 owners with frightened animals, 2,649 (71.9%) had not sought help or treatment for their animal. Frightened animals were mostly kept inside (3,479/7,464; 46.%) or comforted (2,112/7,464; 28.2%). Of all 4,325 respondents, 3,631 (84.0%) were supportive of a ban on the private sale of fireworks, with 370 (8.6%) against and 315 (7.3%) undecided. Owners with ≥1 animal that was fearful towards fireworks were more likely to support a ban (3,137/3,412; 91.9%) than owners whose animals were not afraid (466/561; 83.1%) (OR = 2.32; 95% CI = 1.80-2.98). Conclusion and Clinical Relevance: Among respondents to this survey, many owners of companion animals reported that their animals were adversely affected by fireworks, but few of them sought advice about strategies to mitigate the impacts. The majority of respondents supported a ban on the private sale of fireworks. Campaigns to raise public awareness of treatment strategies for managing fear behaviours during anticipated fireworks displays may be beneficial.


APOE and cytokines as biological markers for recovery of prevalent delirium in elderly medical inpatients.
Delirium frequently occurs in the context of infection and other inflammatory conditions associated with elevated levels of cytokines. Cytokines used therapeutically can induce symptoms of delirium as an adverse effect. We hypothesized that a causal relationship might exist between delirium and cytokine production during illness. Further, we speculated that the APOE genotype of patients might influence their rate of recovery from delirium given that APOE is associated with amyloid deposition, increased susceptibility to exogenous neurotoxins, and can affect the immune response. A cohort of 164 acutely ill patients, 70 years or older, admitted to an elderly medical unit were studied within 3 days of hospital admission and re-assessed twice weekly until their discharge, to identify and follow the clinical course of delirium. The APOE genotype and the level of circulating cytokines were determined for 116 and 60 patients respectively. Prevalent delirium was significantly (p < 0.05) associated with a previous history of dementia, age, illness severity, disability and low levels of circulating IGF-I. Recovery was significantly associated (p < 0.05) with lack of APOE 4 allele and higher initial IFN-gamma. A model incorporating gender, APOE epsilon 4 status and IGF-I levels predicted recovery or not from delirium in 76.5% of cases, with a sensitivity 0.77 and specificity 0.75. A relationship between delirium with APOE genotype, IFN-gamma, and IGF-I, but not with IL-6, IL-1, TNF-alpha, and LIF was found. A predictive model of recovery was derived from gender, APOE status, and IGF-I levels. This model needs replication with further studies.


Crystal structure of T4-lysozyme generated from synthetic coding DNA expressed in Escherichia coli.
The polypeptide produced by expressing a chemically synthesized gene coding for the amino-acid sequence of T4-lysozyme has been crystallized and subjected to X-ray diffraction. The crystal structure has been refined to a standard R-factor of 0.191 for data between 8 and 2 A resolution. The refined model is essentially the same as the well-known structure of wild-type T4-lysozyme determined previously by Matthews et al. (1987). Some small changes in the C-terminal region, which is important in maintaining the folded structure, have been noted. In addition to confirming that the synthetic gene product is very close to the wild type, this structure provides a benchmark for protein engineering experiments on the folding and the catalytic activity of this molecule by the method of gene synthesis.


[Treatment results in brain metastases with primary irradiation and after surgery and postoperative irradiation].
61 patients with cerebral metastases were treated between 1977 and 1982, 32 out of them were operated and postoperatively irradiated, 29 only irradiated. The irradiations were given for curative purposes. Sixteen patients were alive at the date of December 31, 1982. The survival times calculated with the method of Kaplan-Mayer were 10 months after surgery and irradiation and 5 months after irradiations alone. In case of metastases of the mammary carcinoma, surgery with irradiation seems to be an especially effective method, as is suggested by the median survival time of 35 months and the total absence of local recurrences. In most of the other cases, too, the prolonged survival time was accompanied by a good quality of life which lasted for a considerable period of time. Younger patients had a longer survival time than older patients. The results of a high-dosed therapy with several daily fractions, namely 60 Gy within 17 days or 1825 ret NSD, respectively, were not (yet) better than those of conventional fractionation and dosage with 50 to 60 Gy in 5 to 6 weeks or 1572 to 1768 ret NSD, respectively. However, the value of this method was the same, its advantage lying in the shorter treatment time. Only in patients over 60 years, above all if they had received a total-brain irradiation with this method, we think to have seen a more frequent development of psychosyndromes. (The calculation of the survival times includes all cases, even patients who died during or shortly after radiotherapy).


Involvement of the prostatic steroid-binding protein in the transfer of ligand to the dioxin receptor.
The prostatic steroid-binding protein (PSP) represents a highly abundant protein in the rat prostate which binds carcinogens reversibly and with high affinity. The biological role of PSP and the toxicological implications of the carcinogen-protein interaction are unclear. In this report, we have attempted to examine a possible role of PSP in the transfer of ligands to the dioxin receptor. PSP was purified from the rat ventral prostate and labeled in vitro with 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin (dioxin). Dioxin-labeled PSP was then incubated with rat liver cytosol in the presence or absence of a 200-fold excess of nonradioactive competitor, 2,3,7,8-tetrachlorodibenzofuran. After 2 h of incubation, a complete in vitro transfer of ligand from PSP to the rat hepatic dioxin receptor was observed, as assessed by velocity sedimentation analysis of specific dioxin binding. These results indicate that a high abundance carcinogen-binding protein, such as PSP, may be of importance in the cellular transfer of dioxin receptor ligands, thereby eliciting a receptor-mediated biochemical and/or toxic response.


Basicity of nucleophilic carbenes in aqueous and nonaqueous solvents-theoretical predictions.
The complete basis set method CBS-QB3 was used in conjunction with the CPCM solvation model to predict both the absolute and relative pKa's of 12 nucleophilic carbenes in dimethyl sulfoxide (DMSO), acetonitrile (MeCN), and water. Average absolute pKa values in DMSO ranged from 14.4 +/- 0.16 for 3-methylthiazol-2-ylidene (12) to 27.9 +/- 0.23 in the case of bis(dimethylamino)carbene (11), while values in MeCN were determined to be between 25.7 +/- 0.16 (12) and 39.1 +/- 0.25 (11). Relative pKa calculations yielded similar results. Calculations in aqueous solution gave pKa's between 21.2 +/- 0.2 (12) and 34.0 +/- 0.3 (11). Excellent agreement between calculated and experimental pKa's was obtained for the few cases where experimental numbers are available, confirming that this theoretical approach may be used to calculate highly accurate pKa values.


Action Research on Development and Application of Internet of Things Services in Hospital.
Services based on the Internet of Things (IoT) technologies have emerged in various business environments. To enhance health service quality and maximize benefits, this study applied an IoT technology based on NFC and iBeacon as an omni-channel service for patient care in hospitals. Application of the IoT technology based on NFC and iBeacon was conducted in a general hospital during August 2015 through June 2016, and the development and evaluation results were aligned to an action research framework. The five phases in the action research included diagnosing, planning action, taking action, evaluating action, and specifying learning phases. During the first two phases, problems of functional operations in a hospital were diagnosed and eight service models were designed by using iBeacon and NFC to solve the problems. Service models were applied to the hospital by installing beacons, wearable beacons, beacon scanners, and NFC tags during the third phase. During the fourth and fifth phases, the roles and benefits of stakeholders participating in the service models were evaluated, and issues and knowledge of the whole application process were derived and summarized from technological, economic, social and legal perspectives, respectively. From an action research perspective, IoT-based healthcare services were developed and verified. IoT-based services enable the hospital to acquire lifelog data for precision medicine and ultimately be able to go one step closer to precision medical care. The derived service models could provide patients more enhanced healthcare services and improve the work efficiency and effectiveness of the hospital.


High school students' body weight control: differences between athletes and non-athletes.
Due to chronic dissatisfaction with body weight in youth, efforts to lose weight often lead to pathological dietary behaviours. Regular and heavy sports activity may contribute to the optimization of body weight, not only by elevating the energy utilization but also by increasing the health consciousness and the tendency to self-monitor. Research generally finds a beneficial role of extracurricular sports activity in body weight control. Therefore, we aim to analyze how regular, heavy sports activity (more precisely, competitive sports) may contribute to body weight control among two groups of youth: athletes and non-athletes. Our study was carried out using 347 adolescents; among them there were 91 athletes and 259 controls. The subjects completed self-administered questionnaires concerning their body weight control and dietary habits. We found that girls were less satisfied with their body weight and reported dieting more frequently with a greater emphasis on healthy dieting than boys. Sport influenced these strong gender differences only regarding healthy dieting, young male athletes laid a larger emphasis on healthy diets than their non-athlete counterparts, therefore their attitude became similar to that of female athletes and non-athletes. We conclude that despite the normal weight in high school students, episodes of dieting that might contribute to eating disorders were quite frequent. This was not influenced by the students' extracurricular sports activity. A greater monitoring of male athletes' and their friend's diet draw attention to the need for developing health education programs specific to boys.


Triggering receptor expressed on myeloid cells and 5'adenosine monophosphate-activated protein kinase in the inflammatory response: a potential therapeutic target.
The events in the cellular and molecular signaling triggered during inflammation mitigate tissue healing. The metabolic check-point control mediated by 5'-adenosine monophosphate-activated protein kinase (AMPK) is crucial for switching the cells into an activated state capable of mediating inflammatory events. The cell metabolism involved in the inflammatory response represents a potential therapeutic target for the pharmacologic management of inflammation. Areas covered: In this article, a critical review is presented on triggering receptor expressed on myeloid cell (TREM) receptors and their role in the inflammatory responses, as well as homeostasis between different TREM molecules and their regulation. Additionally, we discussed the relationship between TREM and AMPK to identify novel targets to limit the inflammatory response. Literature search was carried out from the National Library of Medicine's Medline database (using PubMed as the search engine) and Google Scholar and identified relevant studies up to 30 March 2016 using inflammation, TREM, AMPK, as the key words. Expert commentary: The prevention of phenotype switching of immune cells during inflammation by targeting AMPK and TREM-1 could be beneficial for developing novel management strategies for inflammation and associated complications.


Inhibitory effect of calcitonin on growth hormone response to growth hormone releasing hormone in acromegaly.
1. A neuroendocrine role for calcitonin (CT) has been suggested by the finding of CT receptors in the hypothalamus. We have recently shown that salmon calcitonin (sCT) inhibits growth hormone releasing hormone (GHRH)-induced GH secretion in man by a mechanism apparently independent of changes in peripheral cortisol, glucose, calcium or parathyroid hormone levels. 2. We have further investigated the inhibitory action of sCT on GH secretion by studying the effects of sCT (100 MRC units, im) or placebo on basal and GHRH (1-29) NH2 (50 micrograms, iv) stimulated GH secretion in 6 acromegalic patients with active disease. 3. Basal GH levels were not altered by sCT administration (placebo: 136 +/- 99 micrograms/l vs sCT: 99 +/- 53 micrograms/l). However, the GH response to GHRH was decreased by sCT. The area under the curve was significantly smaller when patients were treated with sCT compared to placebo controls (placebo: 77202 +/- 57036 vs sCT: 64828 +/- 51909 micrograms min-1 l-1; P less than 0.02). No changes in glucose or calcium levels were observed. 4. These results demonstrate that sCT decreases GHRH-induced GH secretion in acromegalic patients. Although the mechanism of action of sCT on GH secretion is unknown, our results indicate that the inhibitory effect of this peptide on GH secretion is also observed in patients harboring pituitary adenomas.


Could poly(A) align the splicing sites of messenger RNA precursors?
In general, poly(A)-mRNA appears to be derived from larger nuclear RNA precursors. The maturation of these precursors involves excision of sequences of variable length from within the molecule and splicing of the remaining structural and coding sequences. The mechanism by which this process occurs is not known. It does not appear to operate solely through the recognition of a defined primary sequence or through the formation of a consistent secondary structure. We propose an alternative model in which poly(A) facilitates the splicing event by promoting the formation of triple-stranded structures within the mRNA precursor.


T helper 1 inhibitor TAK-603 inhibits IFN-gamma and IL-12 production with no effect on IL-18: an observation in sarcoidosis patients.
Sarcoidosis is immunologically characterized by highly enhanced Th1 responses in active stage. TAK-603 is a new quinoline derivative, which selectively suppresses Th1 cytokine production. Thus, the present study was designed to investigate whether TAK-603 ameliorates excess IFN-gamma production in active sarcoidosis. We evaluated inhibitory effects of TAK-603 on IFN-gamma, IL-12 and IL-18 production in stimulated bronchoalveolar lavage (BAL) fluid cells and peripheral blood mononuclear cells (PBMCs) of sarcoidosis patients and healthy subjects. TAK-603 inhibited IFN-gamma production in stimulated BAL fluid cells and PBMCs of sarcoidosis patients and healthy subjects. TAK-603 inhibited IL-12 production in stimulated BAL fluid cells of sarcoidosis patients and healthy subjects. TAK-603 tended to inhibit IL-12 production in stimulated PBMCs of sarcoidosis patients and healthy subjects. However, TAK-603 did not affect IL-18 production in stimulated BAL fluid cells and PBMCs. TAK-603 did not affect TNF-alpha production in stimulated BAL fluid cells of sarcoidosis patients. TAK-603 inhibited IL-12 production in stimulated blood monocytes of healthy subjects, whereas IL-18 was increased by treatment with TAK-603. TAK-603 inhibited IFN-gamma production in PHA-stimulated blood T lymphocytes of healthy subjects with stimulation of IL-12 or a combination of IL-12 and IL-18. TAK-603 did not increase IL-10 or TGF-beta1 production in LPS-stimulated BAL fluid cells of sarcoidosis patients. TAK-603 inhibits IFN-gamma production in activated T lymphocytes and IL-12 production in activated monocytes/macrophages independently of increased production of IL-10 and TGF-beta1. TAK-603 may ameliorate excess IFN-gamma production and be a therapeutic tool for refractory sarcoidosis.


Five Genes Associated With Survival in Patients With Lower-grade Gliomas Were Identified by Information-theoretical Analysis.
Understanding of the molecular events associated with progression and survival differences in patients with lower-grade gliomas (LGGs) is still unclear. The comparison of findings across studies using different datasets and methods is essential for a new molecular-based classification system. The aim of the study was to identify biomarkers for prognostic classification of patients with LGGs, and furthermore to lay a foundation for future development of targeted therapies for LGGs. Using information-theoretic and statistical approaches, we analyzed mRNA expression data for 18,413 genes from LGG samples in order to identify candidate biomarkers for survival. The candidate genes were then evaluated for their potential as prognostic biomarkers using multivariable Cox regression analyses that adjusted for the effects of age and grade. WEE1, EMP3, E2F7, CD58 and NSUN7 genes were identified as candidate biomarkers of LGGs and their high expression was associated with significantly shorter survival. The hazard ratios for mortality were 5.02 (95% CI=3.40-7.40) for WEE1, 5.45 (95% CI=3.63-8.18) for EMP3, 4.49 (95% CI=3.03-6.66) for E2F7, 4.77 (95% CI=3.22-7.06) for CD58 and 4.38 (95% CI=2.97-6.47) for NSUN7. In addition, the expression pattern of these genes, associated with shorter survival in LGGs, was also observed in glioblastoma multiforme. Identification of genes associated with poor outcomes will provide insights into novel biological mechanisms that may lead to improvement in progression and survival for patients with LGGs.


Development of chitosan/poly-γ-glutamic acid/pluronic/curcumin nanoparticles in chitosan dressings for wound regeneration.
The hydrophobic polyphenol curcumin has anti-inflammatory, antimicrobial, and wound-healing properties that warrant its pharmacological consideration. We report a curcumin nanoparticle with a tripolymeric composite that can be used as a delivery device for wound healing. The present composite nanoparticles were prepared with three biocompatible polymers of chitosan, poly-γ-glutamic acid, and pluronic using a simple ionic gelation technology. Pluronic was used to enhance the solubility of curcumin in chitosan/poly-γ-glutamic acid nanoparticles, leading to the incorporation of chitosan/poly-γ-glutamic acid/pluronic/curcumin nanoparticles into chitosan membranes, and reduced inflammation and bacterial infection during wound regeneration. Nanoparticles were of 193.1 ± 8.9 nm and had a zeta potential of 20.6 ± 2.4 mV. Moreover, in vitro analyses indicated controlled curcumin release in a simulated skin tissue model. Subsequent in vivo studies show that chitosan wound dressing containing chitosan/poly-γ-glutamic acid/pluronic/curcumin nanoparticles promoted neocollagen regeneration and tissue reconstruction. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 81-90, 2017.


Observations of feeding practices of US parents of young children with Down syndrome.
Parental behaviours influence food acceptance in young children, but few studies have measured these behaviours using observational methods, especially among children with Down syndrome (CWDS). The overall goal of this study was to understand parent feeding practices used during snack time with young CWDS (N = 111, aged 11-58 months). A coding scheme was developed to focus on feeding practices used by parents of CWDS from a structured home-use test involving tasting variously textured snack products. Behavioural coding was used to categorise parental feeding practices and quantify their frequencies (N = 212 video feeding sessions). A feeding prompt was coded as successful if the child ate the target food product or completed the prompt within 20 s of the prompt being given without a refusal behaviour. CWDS more frequently consumed the test foods and completed tasks in response to Autonomy-Supportive Prompts to Eat (49.3%), than to Coercive-Controlling Prompts to Eat (24.2%). By exploring the parent-CWDS relationship during feeding, we can identify potentially desirable parent practices to encourage successful feeding for CWDS. Future research should build upon the knowledge gained from this study to confirm longitudinal associations of parent practices with child behaviours during feeding.


The morphological effects of chenodeoxycholic acid on human gastric mucosa.
Morphology of human gastric mucosa was examined by light microscopy before and after exposure to suspensions of chenodeoxycholic acid tablets. During gastroscopy with a flexible instrument the gastric mucosa of eight control subjects without gastric disease was biopsied. In five other patients the chenodeoxycholic acid tablet suspension was instilled immediately after control biopsies of mucosa. Subsequent biopsies were collected after 10-15 min exposure to the suspension. Surface mucosal cells regularly showed development of clear cytoplasmic vacuoles, marked cytoplasmic condensations, and pyknosis of the nuclei. Appreciable changes in relative cytoplasmic staining density, loss of intactness of cells, and loss of surface mucous cell granules were observed less frequently. Thus, exposure of gastric mucosa to chenodeoxycholic acid tablet suspensions may be associated with histological changes in surface mucosal cells.


Aspirin in the Food and Drug Administration Adverse Event Reporting System: Missing Demographics and Underreporting.
Background The U.S. Food and Drug Administration (FDA) Adverse Event (AE) Reporting System (FAERS) is a global passive surveillance repository requiring mandatory updates by pharmaceutical manufacturers. Oral antiplatelet agents (OAAs) including aspirin (acetylsalicylic acid [ASA]) are broadly used to prevent thrombosis, at the expense of extra bleeding risks. However, the OAA filing quality and their comparative patterns in FAERS are unknown. We assessed completeness of original annual FAERS reports for OAA with special attention on ASA. Methods We extracted AE cases co-reported with OAA including ASA, clopidogrel, prasugrel, ticagrelor, vorapaxar, or their combination. The 2015 FAERS cases were examined based on OAA distribution, suspected causative role, missing gender or age, and most common AEs after ASA. Results A total of 1,187,729 reports qualified the inclusion criteria. The majority ( n = 1,121,989) of the reports contain no reference of OAA, while 65,730 reports contain reference of at least one OAA, including 47,900 ASA cases. Therapy with ASA was heavily (>50%) underreported when used with prasugrel or ticagrelor, but still dominant (72.8%) among OAAs, followed by clopidogrel (18.7%), prasugrel (4.1%), ticagrelor (3.6%), and anecdotal vorapaxar (0.05%). Despite current recommendations, some (0.73%) reports contain multi-OAAs. The primary role of ASA in AE reporting was seldom (<1%), followed by clopidogrel (2.9%), prasugrel (3.7%), and highest for ticagrelor (9.3%). Missing gender after OAA was not common (<10%), but age was missing in approximately 25% of reports. Bleeding was the most frequent AE associated with ASA. Conclusion The quality of reporting for OAA in general and ASA in particular can be improved by stricter FDA rules, better surveillance, and enforcements. Heavy ASA underreporting during dual antiplatelet therapy and missed demographic variables challenge outcome research capacities for establishing drug interactions in FAERS.


Combined femoral-obturator-sciatic nerve block has superior postoperative pain score and earlier ambulation as compared to spinal anaesthesia for arthroscopic anterior cruciate ligament reconstruction.
Peripheral nerve blocks can be a suitable alternative to central neuraxial blockage, as the sole anaesthetic agent for better early postoperative outcomes, decreased hospital stay and earlier mobilisation after anterior cruciate ligament reconstruction (ACLR) surgery. The purpose of this study was to compare consciousness during the procedure, pain during early postoperative period (< 7 days), and perioperative outcomes following ACLR using combined sciatic, femoral, and obturator nerve blocks compared to the spinal anaesthesia. This was a prospective case-control study including patients between 18 and 55 years of age, with anterior cruciate ligament (ACL) injury confirmed clinically and radiologically and undergoing ACLR. Patients were allocated in the two groups alternatively, group 1 included patients who received combined nerve blocks, and group 2 included patients who received spinal anaesthesia for the surgery. The sensory effect, motor effect, adequacy of anaesthesia, perioperative analgesic use, duration of stay, postoperative pain (visual analogue scale 0-10 cm) and functional outcomes were noted. There were 60 patients in each group. A total of seven patients in group 1 (11%) and two patients in group 2 (3%) needed conversion to general anaesthesia (n.s.). In group 1, out of 53 patients who underwent surgery, 26 patients had no perception of surgery in the joint, 17 patients had perception of manipulation of the knee joint, 4 patients had sense of touch, and 6 patients had sensation of pain in the knee (VAS scale less than 3). In group 2, out of 58 patients, 42 patients had no perception of surgery, 12 had a perception of manipulation of the knee joint, 2 had sense of touch, and 2 had sensation of pain in the knee. Blockage of sensory effect was significantly better in group 2 (p = 0.0001). However, the motor effect was comparable between the two groups (n.s.). Group 1 had significantly better pain scores 6, 12, and 18 h after the surgery. Moreover, patients in group 1 also had faster ambulation (mean difference of 5.5 h, p = 0.0001) and reduced hospital stay (mean difference of 8.4 h, p = 0.0001). Combined sciatic, femoral, and adductor canal block is an effective sole anaesthetic modality for ACLR. The sensory effect was inferior when compared to spinal anaesthesia but sufficient for the procedure without the need for supplementation with any other anaesthetic modality. Patients receiving this combined nerve block had lesser early postoperative pain scores, earlier ambulation, and shorter hospital stay as compared to the spinal anaesthesia. Level 3.


Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism.
The human genome contains at least 17 genes that are members of the aldehyde dehydrogenase (ALDH) superfamily. These genes encode NAD(P)(+)-dependent enzymes that oxidize a wide range of aldehydes to their corresponding carboxylic acids. Aldehydes are highly reactive molecules that are intermediates or products involved in a broad spectrum of physiologic, biologic, and pharmacologic processes. Aldehydes are generated during retinoic acid biosynthesis and the metabolism of amino acids, lipids, carbohydrates, and drugs. Mutations in several ALDH genes are the molecular basis of inborn errors of metabolism and contribute to environmentally induced diseases.


Construction of database for three-dimensional human tooth models and its ability for education and research--Carious tooth models -.
To construct a human teeth database which is freely available to researchers and students, three-dimensional human tooth models were generated in a previous study, by means of micro-CT, from 35 human teeth extracted during orthodontic treatment. In this study, X-ray images of 55 extracted human teeth were acquired using three-dimensional micro-CT at a resolution of 50x50x50 microm, and then visualized using a numerical data visualization software. These carious tooth models provided insight into the morphology and progression of carious defects as well as a rare insight into the morphology of carious tooth pulp, therefore rendering them as a useful tool and efficient method for dental students' learning. Moreover, these three-dimensional models could be simultaneously observed and used by many students and researchers at any one time, which was a superior advantage than having only one actual tooth for learning and study by many.


Human Papillomavirus Genotype Distribution in Invasive Cervical Cancer in Pakistan.
Few studies have assessed the burden of human papillomavirus (HPV) infection in Pakistan. We aim to provide specific information on HPV-type distribution in invasive cervical cancer (ICC) in the country. A total of 280 formalin-fixed paraffin-embedded tissue blocks were consecutively selected from Shaukat Khanum Memorial Cancer Hospital and Research Centre (Lahore, Pakistan). HPV-DNA was detected by SPF10 broad-spectrum PCR followed by DNA enzyme immunoassay and genotyping by LiPA25. HPV-DNA prevalence was 87.5% (95%CI: 83.0-91.1), with 96.1% of cases histologically classified as squamous cell carcinoma. Most of the HPV-DNA positive cases presented single infections (95.9%). HPV16 was the most common type followed by HPV18 and 45. Among HPV-DNA positive, a significantly higher contribution of HPV16/18 was detected in Pakistan (78.4%; 72.7-83.3), compared to Asia (71.6%; 69.9-73.4) and worldwide (70.8%; 69.9-71.8) and a lower contribution of HPVs31/33/45/52/58 (11.1%; 7.9-15.7 vs. 19.8%; 18.3-21.3 and 18.5%; 17.7-19.3). HPV18 or HPV45 positive ICC cases were significantly younger than cases infected by HPV16 (mean age: 43.3, 44.4, 50.5 years, respectively). A routine cervical cancer screening and HPV vaccination program does not yet exist in Pakistan; however, the country could benefit from national integrated efforts for cervical cancer prevention and control. Calculated estimations based on our results show that current HPV vaccine could potentially prevent new ICC cases.


FoxO1 gene confers genetic predisposition to acute anterior uveitis with ankylosing spondylitis.
Recent studies have shown that a decrease of regulatory T (Treg) cells may contribute to the activity of acute anterior uveitis (AAU) and ankylosing spondylitis (AS). A number of immunogenetic factors including IL2RA, miR-27a, miR-182, and FoxO1 are associated with Treg cell function. In this study, we investigated the association between polymorphisms of these genes and AAU with or without AS in a Chinese Han population. Using PCR-restricted fragment length polymorphism (RFLP) assay, a two-stage association study was performed in 680 AAU patients with or without AS and 1280 controls. Gene expression was quantified by real-time PCR. In the first stage study, an association analysis of 10 single nucleotide polymorphisms (SNPs) was performed in 230 AAU patients with AS, 240 AAU patients without AS, and 650 controls. The results showed significantly increased frequencies of the FoxO1/rs2297626 AA genotype and A allele in AAU patients with AS (AA genotype: P = 6.23 × 10(-5), odds ratio [OR] = 1.86; A allele: P = 2.17 × 10(-4), OR = 1.53). No significant association of the other 9 SNPs with AAU with or without AS was observed. In the second stage study, an association analysis of FoxO1/rs2297626 was performed in 210 AAU patients with AS and 630 controls. The second stage and combined studies confirmed the association of FoxO1/rs2297626 with AAU with AS (AA genotype: P = 3.45 × 10(-8), OR = 1.85; A allele: P = 1.55 × 10(-7), OR = 1.55). This study suggests that FoxO1, but not miR-27a, miR-182, and IL2RA, contributes to the genetic susceptibility of AAU with AS, but none of the tested polymorphisms confer risk to AAU without AS.


Practical method of assessing local and global impacts for risk-based decision making: a case study of metal degreasing processes.
For risk-based decision making, local and global impacts should be considered simultaneously. In metal degreasing processes, various cleansing agents are used and a significant amount of such cleansing agents is released into the environment. An appropriate measure of reducing chemical risk associated with industrial cleaning processes should be implemented on the basis of evaluation results representing the local and global impacts. In this study, we assessed metal degreasing processes using a chlorinated solvent with an open-top washing machine and four alternative scenarios, namely, improving the settings of the machine (two cases), changing the local ventilation system, and installing a recovery system using activated carbon. The applied methods are plant-specific risk and life cycle assessments. Specifically in the risk assessment, detailed process data available for decision makers are utilized to evaluate occupational and neighborhood risks. The results of this case study indicate a tradeoff relationship between the local and global impacts in metal degreasing. Through the discussions on the practicability of the integration of the local and global impacts into actual decision making, we conclude that the way to use, select, or integrate risk and life cycle assessments should be analyzed systematically as the situation demands at decision making.