Using Fourier Transform Near-Infrared Spectroscopy to Predict the Mechanical Properties of Thermally Modified Southern Pine Wood.
This study seeks to estimate the mechanical properties of thermally modified wood (TMW) by using near-infrared (NIR) spectroscopy to measure 80 samples in three-point bending tests. Near-infrared spectra collected from the transverse, radial, and tangential sections of wood, coupled with chemometric techniques, were used to predict the mechanical properties of southern pine wood, from which NIR models were constructed based on partial least squares and corresponding cross-validation. The coefficient of determination between NIR transverse section spectra, as well as two mechanical properties of wood samples, modulus of rupture (MOR) and modulus of elasticity (MOE), were above 0.92 and greater than values for other sections. Spectral data from the transverse sections were richer than data from other sections, and thus, a model based on transverse sections better predicts the mechanical properties of wood. A close relationship between the values for mechanical properties (MOE and MOR) and the NIR spectra of thermally modified southern pine wood can be demonstrated, which provides the potential to predict the mechanical properties of untreated and thermally modified wood.


Angiotensin-converting enzyme inhibitory activity of peptides derived from caprine kefir.
In this study, a potent angiotensin-converting enzyme (ACE)-inhibitory activity was found in a commercial kefir made from caprine milk. The low molecular mass peptides released from caseins during fermentation were mainly responsible for this activity. Sixteen peptides were identified by HPLC-tandem mass spectrometry. Two of these peptides, with sequences PYVRYL and LVYPFTGPIPN, showed potent ACE-inhibitory properties. The impact of gastrointestinal digestion on ACE-inhibitory activity of kefir peptides was also evaluated. Some of these peptides were resistant to the incubation with pepsin followed by hydrolysis with Corolase PP. The ACE-inhibitory activity after simulated digestion was similar to or slightly lower than unhydrolyzed peptides, except for peptide beta-casein f(47-52) (DKIHPF), which exhibited an activity 8 times greater after hydrolysis.


A method to construct a third-generation horseradish peroxidase biosensor: self-assembling gold nanoparticles to three-dimensional sol-gel network.
A novel method for fabrication of horseradish peroxidase biosensor has been developed by self-assembling gold nanoparticles to a thiol-containing sol-gel network. A cleaned gold electrode was first immersed in a hydrolyzed (3-mercaptopropyl)-trimethoxysilane (MPS) sol-gel solution to assemble three-dimensional silica gel, and then gold nanoparticles were chemisorbed onto the thiol groups of the sol-gel network. Finally, horseradish peroxidase (HRP) was adsorbed onto the surface of the gold nanoparticles. The distribution of gold nanoparticles and HRP was examined by atomic force microscopy (AFM). The immobilized horseradish peroxidase exhibited direct electrochemical behavior toward the reduction of hydrogen peroxide. The performance and factors influencing the performance of the resulting biosensor were studied in detail. The resulting biosensor exhibited fast amperometric response (2.5 s) to H2O2. The detection limit of the biosensor was 2.0 micromol L(-1), and the linear range was from 5.0 micromol L(-1) to 10.0 mmol L(-1). Moreover, the studied biosensor exhibited high sensitivity, good reproducibility, and long-term stability.


Global, regional, and national time trends in myocarditis-related mortality, 1990-2019: An age-period-cohort analysis.
The aim of this study was to analyze the tendency of myocarditis mortality in 204 countries and areas during the last three decades and its connection with age, epoch, and birth cohort. The Global Burden of Disease 2019 Study acquired a cause-specific myocarditis mortality estimate. The net drift, as well as the influence caused by age, period, and birth cohort, were evaluated by the age-period-cohort model. Additionally, we analyzed the tendency in research intensity and international collaboration across countries using 3,983 myocarditis-related publications from four periods during 1990-2019. During the last three decades, 101 of 204 countries and areas experienced an increase (net drifts ≥0.0%) or stagnant declines (≥-0.5%) in the death rate. In particular, increasing death rate was generally discovered in most countries whose Socio-demographic indexes (SDIs) are high and middle-high, such as the United States [net drift=2.11% (95% CI 1.71-2.51)] and Italy [2.65% (1.24-4.08)]. Countries with a higher number of deaths were more active in this field of study, such as the United States (237 publications), China (120), and Italy (73). The United States and Italy, whose total link strengths were 209 and 135, respectively, were more active in international collaborative studies. Despite the global decrease in myocarditis death rate during the last three decades, negative period and cohort effects and elevated mortality were discovered in numerous countries, especially in those whose SDIs were high, and the age distribution of deaths shifted from adolescent to middle-aged and older populations. We also observed a decline in myocarditis research in some countries with increased mortality.


Computer-based audit to detect and correct overutilization of laboratory tests.
We developed a computer-bases system to detect inappropriate use of the clinical laboratory and tested a program of physician education to reduce overutilization. We modified the hospital laboratory's computerized reporting system to identify medical patients with three or more determinations of lactic dehydrogenase (LDH) or calcium during the preceding seven days. We audited the charts of these patients, using explicit criteria, to determine whether multiple studies were justified. During the control period 51 per cent of the charts audited for multiple determinations of LDH revealed overutilization. During the study period, when physicians were notified if overutilization was found, 65 per cent of the charts showed overutilization. This difference was not significant. A simultaneous, undisclosed audit of calcium determinations also showed no change between the two periods. Therefore, this method is effective in detecting and measuring overutilization of the laboratory. It is a method which is easily adaptable to a hospital's computerized laboratory reporting system, and it can be applied without a computer. However, our program of notification and education of physicians is not effective in reducing overutilization. More effective methods of modifying physicians' use of laboratory tests need to be developed.


β-Amino-n-butyric Acid Regulates Seedling Growth and Disease Resistance of Kimchi Cabbage.
Non-protein amino acid, β-amino-n-butyric acid (BABA), has been involved in diverse physiological processes including seedling growth, stress tolerance and disease resistance of many plant species. In the current study, treatment of kimchi cabbage seedlings with BABA significantly reduced primary root elongation and cotyledon development in a dose-dependent manner, which adverse effects were similar to the plant response to exogenous abscisic acid (ABA) application. BABA was synergistically contributing ABA-induced growth arrest during the early seedling development. Kimchi cabbage leaves were highly damaged and seedling growth was delayed by foliar spraying with high concentrations of BABA (10 to 20 mM). BABA played roles differentially in in vitro fungal conidial germination, mycelial growth and conidation of necrotroph Alternaria brassicicola causing black spot disease and hemibiotroph Colletotrichum higginsianum causing anthracnose. Pretreatment with BABA conferred induced resistance of the kimchi cabbage against challenges by the two different classes of fungal pathogens in a dose-dependent manner. These results suggest that BABA is involved in plant development, fungal development as well as induced fungal disease resistance of kimchi cabbage plant.


Production of D-arabitol by Metschnikowia reukaufii AJ14787.
A potent producer of D-arabitol was isolated by screening of natural sources and identified as Metschnikowia reukaufii AJ14787. Resting cells of this strain can efficiently produce D-arabitol from D-glucose with a weight yield of more than 60%, and can also produce D-arabitol from several other types of sugars such as polyols, ketoses, and aldoses. To improve productivity, various culture conditions such as temperature and the concentrations of D-glucose and nitrogen sources were examined. Under optimal conditions, 206 g/l of D-arabitol was produced from D-glucose with a weight yield of 52% in 100 hours.


[The characters of AFP-producing early gastric cancer].
During the last decade, we have experienced 525 cases of gastric cancer. Within these, 195 were early gastric cancer (37.1%). Five and eight year survival rates were 86.9 and 77.2%. There were seven cases of recurrence, all of which were liver metastasis of submucosal cancers. Two combined with pulmonary metastasis. Three of the recurrent cases had serum AFP raised (greater than 20ng/ml) before or after partial gastrectomy. When these gastric specimens were reviewed, AFP positive cells were stained by PAP method. Compared with the AFP negative group of 168 early gastric cancers, invasion of lymphatic and venous vessels of the stomach and incidence of the liver metastasis were significantly higher in the stained group. 1.3 and 4.5 year survival rates of the cases (including ours) of AFP producing early gastric cancer, which had been reported in Japanese literatures, were 76.1, 45.7 and 22.9%, respectively. Liver metastasis was found in 7 of 12 cases (58.3%). It is clear that AFP producing early gastric cancer has the same tendency for liver metastasis as the AFP producing advance gastric cancer does. To prevent its recurrence, early diagnosis by PAP method for specimens with hepatic picture and aggressive adjuvant chemotherapy are mandatory.


[Effect of benzodiazepine tranquilizers on the ischemic focus and redistribution of blood flow in the ischemic myocardium].
It has been shown in experiments on dogs with acute coronary insufficiency (coronary artery constriction and electrical pacing of the right atrium) that the tranquilizers diazepam (0.1 and 0.3 mg/kg) and chlordiazepoxide (1.0 mg/kg) do not change the epicardial electrogram as compared to control. The drugs increase the ratio of the retrograde coronary circulation in the ligated coronary artery to the circulation in intact areas of the myocardium, that may evidence circulatory redistribution in favour of the affected myocardial area.


[A simple measuring device for monitoring radiation in phototherapy].
A simple low cost device is described for measuring the irradiation intensity used in phototherapy of hyperbilirubinemia in newborns. The spectral selectivity of the sensor is adapted to the most effective wavelength for phototherapy. The device can be calibrated in W/m2. A description of calibration is given. When fluorescent lamps adapted to phototherapy are used, the accuracy of the device can be compared to that of commercially manufactured units. The sensitivity is sufficient to measure differences of irradiance significant for the therapy. The device is suitable to quantify phototherapy of the newborn infant suffering from hyperbilirubinemia.


Radiotracer investigations in pilot-scale soakers.
This paper describes a radiotracer investigation carried out to measure residence time distribution (RTD) of petroleum residues in pilot-scale soakers. The main objectives of the investigation were to evaluate the feasibility of using bromine-82 as dibromobiphenyl (DBBP) for tracing the petroleum residues (organic phase) as a radiotracer at elevated temperature and pressure, and to investigate the flow dynamics of the phase in the soaker at different operating and process conditions. The measured RTD was treated and mean residence times (MRTs) were determined. Tanks-in-series with backmixing model (TISBM) was used to simulate the measured RTD data. The results of model simulation indicated a high degree of backmixing in the soaker without baffles i.e. without sectionalizing the soaker. However, the introduction of perforated plates at various axial locations inside the soaker i.e. sectionalizing the soaker, reduces the extent of backmixing thus tending the flow towards plug flow.


Effects of elevated carbon dioxide environment on calcium metabolism in humans.
Chronic respiratory acidosis induced by an elevated carbon dioxide (CO2) environment should provoke hypercalciuria with related total body and subsequent bone calcium losses. We examined this hypothesis in four healthy male volunteers, who were exposed during a 25-d period to an 0.7% CO2 environment within a deep diving isolation chamber. Three months later the same subjects were reexamined during a second campaign being exposed to a 1.2% CO2 atmosphere. The subjects received a constant calcium intake (1.4 g.d-1) and vitamin D supplement (1000 IU.d-1) during both campaigns. Calcium balance (oral calcium intake minus urinary and fecal calcium output) was evaluated. Serum calcium concentrations and biomarkers of bone metabolism were measured, in order to evaluate bone turnover. Additionally, the response to an acute oral calcium load was examined as a sensitive measure of changes in calcium metabolism. Both, urinary calcium excretion (from 245 +/- 38 to 199 +/- 31 mg.d-1; mean +/- SE, 0.7% and 1.2%, respectively) and fecal calcium losses (from 1229 +/- 128 to 996 +/- 62 mg.d-1) were significantly reduced in the higher (1.2%) CO2 atmosphere. Although more calcium was retained in the body during the 1.2% than during the 0.7% CO2 campaign, serum calcium concentrations and biomarkers of bone formation were significantly lower in the higher CO2 campaign. Furthermore, bone resorption was slightly increased in the 1.2% experiment. Elevated CO2 atmosphere may dose-dependently preserve body calcium without a parallel improvement of bone substance.


Binding of pollutant aromatics on carbon nanotubes and graphite.
The semiempirical PM3 method with dispersive corrections (PM3-D) is used to predict the interaction energy of a number of aromatic pollutants with a graphene surface and with carbon nanotubes. It is found that the dispersive interactions are dominant in determining the magnitude of the interaction and that electron transfer between the adsorbate and the surface is small. Good agreement is found between the calculated interaction energies and the experimental affinities measured in an aqueous environment.


Nonequilibrium fluctuation-dissipation relations of interacting Brownian particles driven by shear.
We present a detailed analysis of the fluctuation-dissipation theorem (FDT) close to the glass transition in colloidal suspensions under steady shear using mode coupling approximations. Starting point is the many-particle Smoluchowski equation. Under shear, detailed balance is broken and the response functions in the stationary state are smaller at long times than estimated from the equilibrium FDT. An asymptotically constant relation connects response and fluctuations during the shear driven decay, restoring the form of the FDT with, however, a ratio different from the equilibrium one. At short times, the equilibrium FDT holds. We follow two independent approaches whose results are in qualitative agreement. To discuss the derived fluctuation-dissipation ratios, we show an exact reformulation of the susceptibility which contains not the full Smoluchowski operator as in equilibrium, but only its well defined Hermitian part. This Hermitian part can be interpreted as governing the dynamics in the frame comoving with the probability current. We present a simple toy model which illustrates the FDT violation in the sheared colloidal system.


Construction of a novel risk model based on the random forest algorithm to distinguish pancreatic cancers with different prognoses and immune microenvironment features.
Immune-related long noncoding RNAs (irlncRNAs) are actively involved in regulating the immune status. This study aimed to establish a risk model of irlncRNAs and further investigate the roles of irlncRNAs in predicting prognosis and the immune landscape in pancreatic cancer. The transcriptome profiles and clinical information of 176 pancreatic cancer patients were retrieved from The Cancer Genome Atlas (TCGA). Immune-related genes (irgenes) downloaded from ImmPort were used to screen 1903 immune-related lncRNAs (irlncRNAs) using Pearson's correlation analysis (R > 0.5; p < 0.001). Random survival forest (RSF) and survival tree analysis showed that 9 irlncRNAs were highly correlated with overall survival (OS) according to the variable importance (VIMP) and minimal depth. Next, Cox regression analysis was used to establish a risk model with 3 irlncRNAs (LINC00462, LINC01887, RP11-706C16.8) that was evaluated by Kaplan-Meier analysis, the areas under the curve (AUCs) of the receiver operating characteristics and the C-index. Additionally, we performed Cox regression analysis to establish the clinical prognostic model, which showed that the risk score was an independent prognostic factor (p < 0.001). A nomogram and calibration plots were drawn to visualize the clinical features. The Wilcoxon signed-rank test and Pearson's correlation analysis further explored the irlncRNA signatures and immune cell infiltration, as well as the immunotherapy response.


Job stress and major coronary events: results from the Job Stress, Absenteeism and Coronary Heart Disease in Europe study.
The intention of this study is to investigate the relationship of the demands/control/strain model with hard coronary events in an epidemiological, prospective, multicenter, European study. Six cohorts (Brussels, Ghent, Lille, Barcelona, Göteborg and Malmö) from four European countries (Belgium, France, Spain and Sweden) consisting of 21 111 middle-aged male subjects participated between 1993 and 1996 in the baseline survey of the Job Stress, Absenteeism and Coronary Heart Disease in Europe (JACE) study. The Karasek strain model of psychological demands (five items)/control (nine items) was used. During a mean follow-up of 40 months 185 acute coronary events or coronary deaths were observed. Age-adjusted hazard ratios (HRs) for developing an acute coronary event were 1.46 [CI 95% confidence interval (1.08-1.97)] for high against low psychological demands and 1.53 (95% CI 1.0-2.35) for strained (high demands plus low control) against relaxed (low demands plus high control) groups. After adjustment for standard cardiovascular risk factors the HR for developing a coronary event for those above or equal to the median against those below the median of psychological demands was 1.46 (95% CI 1.08-1.97) whereas the HR for strained against relaxed groups is 1.46 (95% CI 0.96-2.25). Sensitivity analyses confirmed the robustness of the results. In this European, multicenter, prospective, epidemiological study the Karasek job strain model was an independent predictor of acute coronary events, with the psychological demands scale emerging as the important component.


Impact of voluntary food fortification practices in Ireland: trends in nutrient intakes in Irish adults between 1997-9 and 2008-10.
Because of the discretionary nature of voluntary food fortification in the European Union, there is a need to monitor fortification practices and consumption of fortified foods in order to assess the efficacy and safety of such additions on an ongoing basis. The present study aimed to investigate the nutritional impact of changes in voluntary fortification practices in adults aged 18-64 years using dietary intake data from two nationally representative cross-sectional food consumption surveys, the North/South Ireland Food Consumption Survey (NSIFCS) (1997-9) and the National Adult Nutrition Survey (NANS) (2008-10). The supply of fortified foods increased between 1997-9 and 2008-10, resulting in a higher proportion of adults consuming fortified foods (from 67 to 82 ) and a greater contribution to mean daily energy intake (from 4.6 to 8.4%). The overall nutrient profile of fortified foods consumed remained favourable, i.e. higher in starch and dietary fibre and lower in fat and saturated fat, with polyunsaturated fat, sugars and Na in proportion to energy. Women, particularly those of childbearing age, remained the key beneficiaries of voluntary fortification practices in Ireland. Continued voluntary fortification of foods has increased protection against neural tube defect-affected pregnancy by folic acid and maintained the beneficial impact on the adequacy of Fe intake. Increased consumption of fortified foods did not contribute to an increased risk of intakes exceeding the tolerable upper intake level for any micronutrient. Recent increases in voluntary fortification of foods in Ireland have made a favourable nutritional impact on the diets of adults and have not contributed to an increased risk of adverse effects.


Efficacy Evaluation of Seed-Coating Compounds Against Cereal Cyst Nematodes and Root Lesion Nematodes on Wheat.
Cereal cyst nematodes (Heterodera avenae and H. filipjevi) and root lesion nematodes (Pratylenchus spp.) have been found to infect cereals in 16 provinces of China. To develop a nematicide that effectively controls nematodes, two novel chemical products, methylene bis thiocyanate (MBT) and MBT + thiamethoxam (MTT); four common pesticides, fipronil + chlorpyrifos (FIC), emamectin benzoate, imidacloprid, and Bacillus thuringiensis; and one fungicide, iprodione, were tested as seed coatings for the control of cereal cysts and root lesion nematodes from 2013 to 2015. Wheat seeds were treated with these seven seed coatings before sowing, and changes in the numbers of Heterodera spp. and Pratylenchus spp. were recorded during three different growth stages. Wheat yields were also compared after harvest. All treatments reduced the numbers of Pratylenchus in wheat and of cysts and eggs of Heterodera in the soil compared with the untreated control. Among the treatments, application of MTT or FIC was more effective than that of the other treatments for nematode control, and the other treatments had similar effects. The results of this study have demonstrated that MTT and FIC applied as seed treatments effectively reduce the number of cysts, inhibit the reproduction of Heterodera and Pratylenchus, and enhance wheat yields. MTT and FIC are thus suitable for controlling nematodes on wheat under natural field conditions.


Estimation of volatile emissions during the excavation of soil or waste.
A model is presented for estimating transient air emissions of volatile chemicals during excavation into a zone of contaminated soil or waste. Using measured in situ parameters, this model predicts the time-dependent increase in air emissions during the activity and the decay in air emissions once the excavation activity has ceased. The model compares favorably to air emission data taken during a full scale excavation.


Stability and beam divergence of multimode lasers with internal variable lenses.
A resonator with an internal lens can be characterized by its equivalent g-parameters which give the regions of stability if the lens has variable focal length. However, other properties are not given by this equivalence and have to be investigated by means of the resonator matrix method. Beam diameter, divergence angle, number of transversal modes, positions of beam waists, stability, and the correlations of these parameters with position and focal length of the internal lens are discussed. Regions of low sensitivity to variations of the focal length are evaluated and compared with experimental results. For some special resonator configurations numerical results are presented.


Evolutionary Divergence in DNA Damage Responses among Fungi.
Cell cycle checkpoints and DNA repair pathways contribute to maintaining genome integrity and are thought to be evolutionarily ancient and broadly conserved. For example, in the yeast Saccharomyces cerevisiae and humans, DNA damage induces activation of a checkpoint effector kinase, Rad53p (human homolog Chk2), to promote cell cycle arrest and transcription of DNA repair genes. However, recent studies have revealed variation in the DNA damage response networks of some fungi. For example, Shor et al. (mBio 11:e03044-20, 2020, https://doi.org/10.1128/mBio.03044-20) demonstrate that in comparison to S. cerevisiae, the fungal pathogen Candida glabrata has reduced activation of Rad53p in response to DNA damage. Consequently, some downstream targets that contribute to S. cerevisiae genome maintenance, such as DNA polymerases, are transcriptionally downregulated in C. glabrata Downregulation of genome maintenance genes likely contributes to higher rates of mitotic failure and cell death in C. glabrata This and other recent findings highlight evolutionary diversity in eukaryotic DNA damage responses.


Clinical features and treatment outcome of Hispanic men with prostate cancer following external beam radiotherapy.
We retrospectively analyzed the clinical characteristics and outcomes of Hispanic men compared with other groups who underwent radiotherapy alone for localized or locally advanced prostate cancer. Between April 1987 and January 1998, 964 men who underwent full dose external beam radiotherapy alone for localized or locally advanced prostate cancer were included in the study. Patient medical records were reviewed for pertinent information. Of the 964 men 810 were non-Hispanic white, 54 were Hispanic and 86 were black Americans. The most significant difference among the groups was in the proportion of patients who presented with initial prostate specific antigen (PSA) greater than 20 ng/ml (22% of Hispanic vs 11% of white men, p = 0.0012). In addition, 17% of Hispanic men had a Gleason score of 8 or greater compared with 11% of white men (p = 0.0265). A greater proportion of Hispanic patients also had a less favorable posttreatment PSA nadir of greater than 1 ng/ml compared with white patients, (44% vs 26%, p = 0.0214), which may have translated into a trend toward a lower 5-year disease-free survival rate in Hispanics vs white men (52% vs 65%, p = 0.07). Hispanic men presented with higher PSA and higher grade prostate cancer than white men. Furthermore, a higher percent of Hispanic men had a PSA nadir of 1 ng/ml or greater after radiotherapy, which may have been responsible for their trend toward a decreased 5-year disease-free survival rate compared with white men. Improved screening and early detection may improve disease-free survival in Hispanic men with localized prostate cancer.


Adverse Drug Reactions in Critical Care Settings: A Systematic Review.
The prevalence of adverse drug reactions is reported to be high in critical care units. We conducted a systematic review to study the prevalence, drugs implicated, preventability, predictability, severity and determinants of adverse drug reactions in critical care settings. We searched MEDLINE, EMBASE, PROQUEST and OVID (January 1995 to June 2015) using pre-specified appropriate medical subject heading terms. Of 1552 studies, 34 studies were included for data extraction and synthesis. Overall, the prevalence of adverse drug reactions was 0.3% to 17% in paediatric intensive care units and 4.5% to 34.1% in adult intensive care units. The highest prevalence reported among critical care settings was 117.4 per 1000 patient days. The most common drug classes implicated were antimicrobials in the medical intensive care units, cardiovascular drugs and anticoagulants in the coronary care units, and analgesics and sedatives in the surgical care units. The prevalence of fatal and severe adverse drug reactions ranged from 0.9 to 19% and 5.7 to 28.6% respectively. The predictable and preventable adverse drug reactions ranged from 74.3 to 90.2% and 8.6 to 62.8% respectively. Only 8 studies reported patient outcomes. About 5.6% to 25.5% of patients died. There is wide variation in prevalence, characteristics and drug classes implicated in the occurrence of adverse drug reactions by type of intensive care unit. Findings of this study would help health care professionals to optimise pharmacotherapy in critical care settings.


Handling of thermal paper: Implications for dermal exposure to bisphenol A and its alternatives.
Bisphenol A (BPA) is an endocrine disrupting chemical used in a wide range of consumer products including photoactive dyes used in thermal paper. Recent studies have shown that dermal absorption of BPA can occur when handling these papers. Yet, regulatory agencies have largely dismissed thermal paper as a major source of BPA exposure. Exposure estimates provided by agencies such as the European Food Safety Authority (EFSA) are based on assumptions about how humans interact with this material, stating that 'typical' exposures for adults involve only one handling per day for short periods of time (<1 minute), with limited exposure surfaces (three fingertips). The objective of this study was to determine how individuals handle thermal paper in one common setting: a cafeteria providing short-order meals. We observed thermal paper handling in a college-aged population (n = 698 subjects) at the University of Massachusetts' dining facility. We find that in this setting, individuals handle receipts for an average of 11.5 min, that >30% of individuals hold thermal paper with more than three fingertips, and >60% allow the paper to touch their palm. Only 11% of the participants we observed were consistent with the EFSA model for time of contact and dermal surface area. Mathematical modeling based on handling times we measured and previously published transfer coefficients, concentrations of BPA in paper, and absorption factors indicate the most conservative estimated intake from handling thermal paper in this population is 51.1 ng/kg/day, similar to EFSA's estimates of 59 ng/kg/day from dermal exposures. Less conservative estimates, using published data on concentrations in thermal paper and transfer rates to skin, indicate that exposures are likely significantly higher. Based on our observational data, we propose that the current models for estimating dermal BPA exposures are not consistent with normal human behavior and should be reevaluated.


A simple technique for repositioning of the mandible by a surgical guide prepared using a three-dimensional model after segmental mandibulectomy.
Mandibular reconstruction is performed after segmental mandibulectomy, and precise repositioning of the condylar head in the temporomandibular fossa is essential for maintaining preoperative occlusion. In cases without involvement of soft tissue around the mandibular bone, the autopolymer resin in a soft state is pressed against the lower border of the mandible and buccal and lingual sides of the 3D model on the excised side. After hardening, it is shaved with a carbide bar to make the proximal and distal parts parallel to the resected surface in order to determine the direction of mandibular resection. On the other hand, in cases that require resection of soft tissue around the mandible such as cases of a malignant tumor, right and left mandibular rami of the 3D model are connected with the autopolymer resin to keep the preoperative position between proximal and distal segments before surgical simulation. The device is made to fit the lower border of the anterior mandible and the posterior border of the mandibular ramus. The device has a U-shaped handle so that adaptation of the device will not interfere with the soft tissue to be removed and has holes to be fixed on the mandible with screws. We successfully performed the planned accurate segmental mandibulectomy and the precise repositioning of the condylar head by the device. The present technique and device that we developed proved to be simple and useful for restoring the preoperative condylar head positioning in the temporomandibular fossa and the precise resection of the mandible.


Trans-10,cis-12 conjugated linoleic acid suppresses the desaturation of linoleic and alpha-linolenic acids in HepG2 cells.
The objective of this study was to determine the effects of cis-9,trans-11 and trans-10,cis-12 CLA on the fatty acid desaturation in a human hepatoma cell line, HepG2. Therefore, experiments were conducted in which HepG2 cells were incubated with various concentrations of those fatty acids and the concentrations of fatty acids in various lipid fractions of HepG2 cells were determined. In the presence of linoleic acid as substrate, cells treated with 25 micromol/L of trans-10,cis-12 CLA had lower ratios of dihomo-gamma-linoleic acid to linoleic acid and of arachidonic acid to linoleic acid in phospholipids than control cells; with alpha-linolenic acid as substrate, they had a lower ratio of eicosapentaenoic acid to alpha-linolenic acid in phospholipids than control cells. Cells treated with cis-9,trans-11 CLA did not differ in these ratios from control cells. Cells treated with trans-10,cis-12 CLA had also a markedly lower ratio of monounsaturated fatty acids (MUFA) to saturated fatty acids (SFA) in lipids than control cells; cells treated with cis-9,trans-11 CLA had a slightly lower MUFA:SFA ratio than control cells. These findings suggest that trans-10,cis-12 CLA suppresses Delta9-, Delta6- and Delta5-desaturation in HepG2 cells; cis-9,trans-11 CLA slightly reduces Delta9-desaturation but does not inhibit Delta6- and Delta5-desaturation. Moreover, HepG2 cells treated with 100 micromol/L of trans-10,cis-12 CLA released larger amounts of 6-keto-prostaglandin F(1alpha) and prostaglandin F(2alpha) than control cells. Treatment of cells with cis-9,trans-11 CLA did not alter the release of these eicosanoids compared with control cells. In conclusion, this study suggests that trans-10,cis-12 CLA has significant effects on the metabolism of essential fatty acids in HepG2 cells, whereas cis-9, trans-11 CLA does not have any effect in this respect.


New strategy in synthetic biology: from enzyme inhibition and natural products synthesis to PET imaging by 6pi-azaelectrocyclization.
While elucidating the inhibitory mechanism of a hydrolytic enzyme by aldehyde-containing natural products, we discovered a reaction involving a rapid 6pi-azaelectrocyclization of azatrienes generated from aldehyde with lysine residues. The electrocyclic reaction of the 1-azatriene system, a cyclization precursor, exhibited a substituent effect. Structure-reactivity studies showed that azaelectrocyclization, which usually proceeds in low yield at high temperatures, produced a quantitative yield in less than 5 min at room temperature. Asymmetric chiral piperidine synthesis and a one-pot library synthesis of pyridines on solid-supports were applied to synthesize pyridine/indole alkaloid-type natural products. Additionally, we developed lysine-based labeling of biomolecules based on the rapid 6pi-azaelectrocyclization. Both DOTA as a metal chelating agent (either for MRI, PET, or other radiopharmaceutical purposes, e.g., SPECT with gamma emitters) as well as fluorescent groups were introduced efficiently and selectively into lysine residues within 10 min at concentrations as low as 10(-8) m. The DOTA-labeled somatostatin and glycoproteins were then radiometallated with (68)Ga to observe the receptor-mediated accumulation of somatostatin in pancreatic tissue. Furthermore, microPET visualized the oligosaccharide dependent circulatory residence of glycoproteins for the first time.


Systemic anticoagulation and prevention of hemodialysis catheter malfunction.
Although chronic anticoagulation is commonly prescribed to prevent thrombosis and malfunction of hemodialysis tunneled cuffed catheters (TCC), there are only limited data regarding its efficacy. The aim of this prospective study was to evaluate whether anticoagulation with adjusted-dose warfarin targeting an international normalized ratio (INR) of 1.5-2.0 is associated with improved catheter outcome in long-term patients at high risk of TCC malfunction. Among the 65 patients included in the study, 35 were considered at high risk (i.e., patients with a history of previous TCC thrombosis requiring catheter replacement and/or with TCC malfunction occurring within 2 weeks after catheter insertion in the absence of mechanical problems) and were prescribed warfarin, whereas 30 low-risk patients did not receive anticoagulation. During follow-up, TCC malfunction, defined as the need for inversion of catheter lines and/or recombinant tissue-type plasminogen activator infusion, was observed in 61.5% of patients. Among patients receiving warfarin, 19 (54.3%) achieved adequate anticoagulation (i.e., > 80% of follow-up INR values and INR value at the time of malfunction within target range). Anticoagulation was considered inadequate in 16 patients (45.7%). Malfunction-free catheter survival at 9 months was 47.1% in patients with adequate anticoagulation compared with 8.1% in patients with inadequate anticoagulation (p = 0.01). This difference remained statistically significant after adjustment for aspirin intake. These results suggest that achieving adequate anticoagulation with target INR 1.5-2.0 may prevent TCC malfunction and improve catheter outcome.


ESI-MS Study of the Interaction of Potential Oxidovanadium(IV) Drugs and Amavadin with Model Proteins.
In this study, the binding to lysozyme (Lyz) of four important VIV compounds with antidiabetic and/or anticancer activity, [VIVO(pic)2(H2O)], [VIVO(ma)2], [VIVO(dhp)2], and [VIVO(acac)2], where pic-, ma-, dhp-, and acac- are picolinate, maltolate, 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate, and acetylacetonate anions, and of the vanadium-containing natural product amavadin ([VIV(hidpa)2]2-, with hidpa3- N-hydroxyimino-2,2'-diisopropionate) was investigated by ElectroSpray Ionization-Mass Spectrometry (ESI-MS). Moreover, the interaction of [VIVO(pic)2(H2O)], chosen as a representative VIVO2+ complex, was examined with two additional proteins, myoglobin (Mb) and ubiquitin (Ub), to compare the data. The examined vanadium concentration was in the range 15-150 μM, i.e., very close to that found under physiological conditions. With pic-, dhp-, and hidpa3-, the formation of adducts n[VIVOL2]-Lyz or n[VIVL2]-Lyz is favored, while with ma- and acac- the species n[VIVOL]-Lyz are detected, with n dependent on the experimental VIV/protein ratio. The behavior of the systems with [VIVO(pic)2(H2O)] and Mb or Ub is very similar to that of Lyz. The results suggested that under physiological conditions, the moiety cis-VIVOL2 (L = pic-, dhp-) is bound by only one accessible side-chain protein residue that can be Asp, Glu, or His, while VIVOL+ (L = ma-, acac-) can interact with the two equatorial and axial sites. If the VIV complex is thermodynamically stable and does not have available coordination positions, such as amavadin, the protein cannot interact with it through the formation of coordination bonds and, in such cases, noncovalent interactions are predicted. The formation of the adducts is dependent on the thermodynamic stability and geometry in aqueous solution of the VIVO2+ complex and affects the transport, uptake, and mechanism of action of potential V drugs.


The origin of low mass stars.
Recent evidence indicates that most low mass stars in the Galaxy (< 5 M [symbol: see text]) form alongside massive stars in clusters embedded in giant molecular clouds. Once their parental gas is removed, the fate of these clusters is to disperse and blend into the field population of the galactic disk. The distribution of stellar masses in the solar neighborhood, called the Initial Mass Function, is discussed in the context of the origin of low mass stars. Arguments based on the production rate of field stars are presented that point to giant molecular clouds as the primary birth sites for low mass stars. The role of observations of molecular clouds at millimeter and infrared wavelengths in confirming this picture is reviewed. Millimeter-wave observations have revealed that molecular clouds consist of low-density gas interspersed with high-density cores. Near-infrared images of these clouds indicate that stars form preferentially in these cores, with the number of young stars roughly scaling with the mass of the core. Molecular-line and near-infrared observations which characterize star formation in the nearest giant molecular cloud complex in Orion are presented. The implications for the Sun forming in a cluster environment are briefly discussed.


Dysregulated expression of microRNA-150 in human papillomavirus-induced lesions of K14-HPV16 transgenic mice.
High-risk human papillomavirus (HPV) infection is one of the major causes of infection-related cancers worldwide. MicroRNAs (miRNAs) are a family of non-coding RNAs (ncRNAs), whose dysregulated levels may cause an aberrant expression of genes involved in oncogenic pathways and consequently lead to cancer development. This is the case of the miRNA-150 (miR-150), whose expression in HPV-induced lesions remains unclear and the present work aims to clarify it. We employed K14-HPV16 mice, which express the early genes of HPV16 in basal keratinocytes, leading to the development of hyperplastic and dysplastic skin lesions and squamous cell carcinomas, and are a representative model of HPV-induced cancers. In order to evaluate the expression of miR-150 in HPV-induced lesions, we performed qPCR in wild-type mice (HPV-/-) and in skin lesions of K14-HPV16 transgenic mice (HPV+/-). Matched skin samples were analyzed histologically. 24-26weeks-old HPV+/- mice showed diffuse epidermal hyperplasia and focal dysplasia in a hyperplastic background (31.8% incidence), but 28-30weeks-old HPV+/- mice presented higher incidence of dysplasia (100.0%). MiR-150 was upregulated in HPV+/- mice when compared with HPV-/- mice (p<0.001). MiR-150 was also overexpressed in diffuse dysplastic lesions when compared with hyperplastic lesions (p=0.005). The present results suggest that miR-150 is overexpressed in HPV-induced lesions in this model and its expression seems to increase with lesion progression, along the process of multi-step carcinogenesis.


Involvement of the anterior portion of the subacromial-subdeltoid bursa in the painful shoulder.
The purpose of our study was to verify that increased widening of the anterior portion of the subacromial-subdeltoid bursa is associated with anteromedial shoulder pain. Bursography, sonography, and CT were performed in six cadaver shoulders and compared with anatomic sections in neutral position and while the humerus was extended and internally rotated. For the clinical study, the width of the anterior portion of the bursa was measured in both positions in both shoulders of 27 patients referred because of shoulder pain and in eight asymptomatic volunteers. Pain was coded as absent, experienced in the anteromedial portion of the shoulder, or experienced elsewhere but not anteromedially, and we compared the pain scores between shoulder positions. In all cadaver shoulders, when compared with CT scans and anatomic sections, sonography showed the morphology of the bursa, its relationships with surrounding structures, and morphologic changes associated with position. In volunteers, the mean width of the bursa was 0.74 +/- 0.05 and 0.93 +/- 0.09 mm (p = 0.013), respectively, in neutral and stress position. In patients, the same values were 0.70 +/- 0.07 and 0.81 +/- 0.14 mm (p = 0.286) in the asymptomatic side and 1.20 +/- 0.11 and 1.75 +/- 0.23 mm (p < 0.001) in the symptomatic side, respectively. The bursa was wider in patients experiencing pain anteromedially than in those who experienced pain elsewhere and volunteers (p = 0.002 and < 0.001, respectively), and the bursa was wider in symptomatic shoulders than in asymptomatic shoulders (p < 0.001). Widening of the anterior portion of the subacromial-subdeltoid bursa is associated with anteromedial shoulder pain and the clinical syndrome of coracoid impingement.


Analysis of Risk Factors for Infusion-Related Reactions Following Rituximab Administration in Patients with Desensitization before Renal Transplantation.
Infusion-related reactions (IRRs) are the major side effects of rituximab administration. Although several studies have reported predictive markers for IRRs in patients with malignancies, there are no such reports for patients without malignancies. Accordingly, we aimed to clarify the predictive markers for rituximab-induced IRRs in renal transplant recipients. This retrospective study included 116 inpatients aged ≥18 years who received an initial dose of 150 mg/m2 of rituximab for desensitization before renal transplantation with loxoprofen and diphenhydramine before rituximab infusion between June 2007 and February 2022. Overall, 45 patients were evaluated and 71 patients were excluded in this study. IRRs were observed in 12 (26.7%) patients. The proportion of men in the IRRs group was significantly higher than that in the non-IRRs group (p = 0.023). Additionally, body weight, body surface area (BSA), and body mass index (BMI) were significantly higher in the IRRs group than in the non-IRRs group (body weight, p = 0.0058; BSA, p = 0.0051; BMI, p = 0.017). Their cutoff values for predicting rituximab-induced IRRs, based on the receiver-operating characteristic curve, were 74.850 kg, 1.910 m2 and 24.164 kg/m2, respectively. In conclusion, the male sex, high actual body weight, BSA, and BMI may be new predictive markers for rituximab-induced IRRs in renal transplant recipients. Therefore, clinicians should carefully monitor patients who receive rituximab before renal transplantation and present with the predictive markers.


Theoretical study of the decomposition of formamide in the presence of water molecules.
Formamide (NH2CHO, FM) has been considered an active key precursor in prebiotic chemistry on early Earth. Under certain conditions such as dry lagoons, FM can decompose to produce reactants that lead to formation of more complex biomolecules. Specifically, FM decomposition follows many reactive channels producing small molecules such as H2, CO, H2O, HCN, HNC, NH3, and HNCO with comparable energy barriers in the range of 73-82 kcal/mol. Due to the likely presence of water on prebiotic Earth and the intrinsic presence of water following FM decomposition, we explore the effects of water oligomers, (H2O)n with n = 1-3, on its dehydration, dehydrogenation, and decarbonylation reactions using quantum chemical computations. Geometries are optimized using MP2/aug-cc-pVxZ calculations (x = D,T), and relative energies are evaluated using coupled-cluster theory CCSD(T) with the aug-cc-pVxZ basis sets (x = D, T, Q). Where possible the coupled-cluster energies are extrapolated to the complete basis set limit (CBS). Water classically acts as an efficient bifunctional catalyst for decomposition. With the presence of one water molecule, the dehydration pathway leading to HCN is favored. When two and three water molecules are involved, dehydration remains energetically favored over other channels and attains an energy barrier of ~30 kcal/mol.


Coping with physical and psychological symptoms: a qualitative study of advanced lung cancer patients and their family caregivers.
Advanced lung cancer patients have high rates of multiple physical and psychological symptoms, and many of their family caregivers experience significant distress. However, little is known about strategies that these patients and their family caregivers employ to cope with physical and psychological symptoms. This study aimed to identify strategies for coping with various physical and psychological symptoms among advanced, symptomatic lung cancer patients and their primary family caregivers. Patients identified their primary family caregiver. Individual semi-structured qualitative interviews were conducted with 21 advanced, symptomatic lung cancer patients and primary family caregivers. Thematic analysis of interview data was framed by stress and coping theory. Patients and caregivers reported maintaining a normal routine and turning to family and friends for support with symptom management, which often varied in its effectiveness. Whereas support from health-care professionals and complementary and alternative medicine were viewed favorably, reactions to Internet and in-person support groups were mixed due to the tragic nature of participants' stories. Several cognitive coping strategies were frequently reported (i.e., changing expectations, maintaining positivity, and avoiding illness-related thoughts) as well as religious coping strategies. Results suggest that advanced lung cancer patients and caregivers may be more receptive to cognitive and religious approaches to symptom management and less receptive to peer support. Interventions should address the perceived effectiveness of support from family and friends.


Homicidal hanging.
We report a case of homicide by hanging of a 29-year-old woman that was committed by her husband, who nearly escaped from justice. We offer some reflections on the rarity of this method of mechanical asphyxia in cases of homicide, and on the difficulties in the diagnosis of the medico-legal etiology of these situations. We also offer a short review of similar cases in the medico-legal literature.


Clinical outcomes of radiofrequency ablation for solitary T1aN0M0 versus T1bN0M0 papillary thyroid carcinoma: a propensity-matched cohort study.
To conduct a cohort study comparing the treatment outcomes of radiofrequency ablation (RFA) therapy for solitary T1aN0M0 (T1a) versus T1bN0M0 (T1b) papillary thyroid carcinoma (PTC). This retrospective analysis comprised 310 patients with low-risk PTC undergoing RFA classified into T1a (n = 272) and T1b (n = 38) groups according to the tumor size. A comparative analysis between the two groups was conducted for the volume reduction ratio (VRR), volume, local tumor progression (LTP), and recurrence-free survival (RFS) before and after 1:2 propensity score matching (PSM). Cox analysis was conducted to examine the influence of several variables, including T1b, on recurrence following RFA for PTC. The total VRR was 99.99 ± 0.11% throughout the median follow-up duration of 26 months, and the overall incidence of LTP was 2.58% (8/310). No irrecoverable complications occurred after RFA. The variations between the T1a and T1b groups following PSM were insignificant in terms of volume (p = 0.574), VRR (p = 0.574), complete disappearance rate (p = 0.210), LTP incidence (p = 1.000), and RFS rate (p = 0.610). The correlation between T1b and LTP continued to be insignificant (p = 0.686). No distant metastasis or delayed surgery occurred. The presence of T1b did not influence the patients' prognoses following RFA for T1N0M0 PTC. After appropriate patient selection and adequate preoperative assessment, RFA has the potential to serve as an effective therapy for individuals with T1a and T1b PTC.


In vivo production of neuraminidase by Pasteurella haemolytica A1 in goats after transthoracic challenge.
Nine goats were injected transthoracically with Pasteurella haemolytica A1 to determine if an extracellular bacterial enzyme, neuraminidase, was produced in vivo during infection with this organism. The principal group of goats (n = 9) each received 1 ml of 7.25 x 10(5) live P. haemolytica A1 cells in polyacrylate beads transthoracically in the left lung on days 0 and 21. Six goats were used as negative controls and received 0.3 g of polyacrylate beads subcutaneously in the right flank on days 0 and 21. Serum was obtained from all animals on days -4, 3, 7, 14, 21, 24, and 32. Preimmune serum from all animals showed no detectable antibody to P. haemolytica A1 neuraminidase in an enzyme neutralization assay. None of the sera from the negative control animals possessed a significant antibody concentration in response to the P. haemolytica A1 neuraminidase. On day 32, serum samples from the nine infected animals possessed enzyme neutralizing activity that ranged from 62% to 100%. Anti-neuraminidase antibody could be detected as early as day 14 by the enzyme neutralization assay. These data demonstrate that the enzyme neuraminidase is produced in vivo during an active P. haemolytica A1 lobar infection.


Small region of Rtf1 protein can substitute for complete Paf1 complex in facilitating global histone H2B ubiquitylation in yeast.
Histone modifications regulate transcription by RNA polymerase II and maintain a balance between active and repressed chromatin states. The conserved Paf1 complex (Paf1C) promotes specific histone modifications during transcription elongation, but the mechanisms by which it facilitates these marks are undefined. We previously identified a 90-amino acid region within the Rtf1 subunit of Paf1C that is necessary for Paf1C-dependent histone modifications in Saccharomyces cerevisiae. Here we show that this histone modification domain (HMD), when expressed as the only source of Rtf1, can promote H3 K4 and K79 methylation and H2B K123 ubiquitylation in yeast. The HMD can restore histone modifications in rtf1Δ cells whether or not it is directed to DNA by a fusion to a DNA binding domain. The HMD can facilitate histone modifications independently of other Paf1C subunits and does not bypass the requirement for Rad6-Bre1. The isolated HMD localizes to chromatin, and this interaction requires residues important for histone modification. When expressed outside the context of full-length Rtf1, the HMD associates with and causes Paf1C-dependent histone modifications to appear at transcriptionally inactive loci, suggesting that its function has become deregulated. Finally, the Rtf1 HMDs from other species can function in yeast. Our findings suggest a direct and conserved role for Paf1C in coupling histone modifications to transcription elongation.


[Acute renal failure after cesarean section as a consequence of hematoma of the retropubic space of Retzius].
Acute renal failure is rare postoperative complication of cesarean section. Postrenal acute renal failure is corectible ant it shoud be done immediately in order to avoid secundary destruction of renal parenchim. Surgical techniques shoud be directed to achieve adequat haemostasis, espetialy at low transverse Pfannenstiel incision, as well as in tender manipuliating with tissues to prevent unnecessery formation of dead space and tissues devitalisation. Authors are presenting the case of acute renal failure after cesarean section as a consequence of hematoma of the retropubic space of Retzius and way of treatment.


High-Performance Polymers Sandwiched with Chemical Vapor Deposited Hexagonal Boron Nitrides as Scalable High-Temperature Dielectric Materials.
Polymer dielectrics are the preferred materials of choice for power electronics and pulsed power applications. However, their relatively low operating temperatures significantly limit their uses in harsh-environment energy storage devices, e.g., automobile and aerospace power systems. Herein, hexagonal boron nitride (h-BN) films are prepared from chemical vapor deposition (CVD) and readily transferred onto polyetherimide (PEI) films. Greatly improved performance in terms of discharged energy density and charge-discharge efficiency is achieved in the PEI sandwiched with CVD-grown h-BN films at elevated temperatures when compared to neat PEI films and other high-temperature polymer and nanocomposite dielectrics. Notably, the h-BN-coated PEI films are capable of operating with >90% charge-discharge efficiencies and delivering high energy densities, i.e., 1.2 J cm-3 , even at a temperature close to the glass transition temperature of polymer (i.e., 217 °C) where pristine PEI almost fails. Outstanding cyclability and dielectric stability over a straight 55 000 charge-discharge cycles are demonstrated in the h-BN-coated PEI at high temperatures. The work demonstrates a general and scalable pathway to enable the high-temperature capacitive energy applications of a wide range of engineering polymers and also offers an efficient method for the synthesis and transfer of 2D nanomaterials at the scale demanded for applications.


The role of reactive oxygen intermediates in the intracellular fate of Leptospira interrogans in the macrophages of different hosts.
Pathogenic species of Leptospira cause leptospirosis, a global zoonotic disease. Our previous work showed that leptospires survive and replicate in human macrophages but are killed in murine macrophages. However, the mechanism responsible for the different intracellular fates of leptospires within the macrophages of different hosts remains unclear. The present study demonstrates that infection with Leptospira interrogans caused significant up-regulation of reactive oxygen species (ROS) and superoxide in J774A.1 cells but did so to a lesser extent in THP-1 cells. The up-regulation of ROS and superoxide was significantly inhibited by the NADPH oxidase inhibitor apocynin. The damaged leptospires and remnants of leptospires within membrane-bound vacuoles were significantly inhibited by apocynin in J774A.1 cells but were less inhibited in THP-1 cells. In addition, apocynin significantly prevented damage to leptospires and the co-localization of L. interrogans with lysosomes in J774A.1 cells but did so to a lesser extent in THP-1 cells. Furthermore, the relative fluorescence intensity levels of intracellular leptospires and the viability of the intracellular leptospires increased in apocynin pretreated J774A.1 and THP-1 cells after 2 h of infection. The present study, based on our previous findings, further demonstrated that ROS contributed substantially to the bactericidal ability of mouse macrophages to kill intracellular leptospires. However, ROS did not contribute as much in human macrophages, which partially explains the different intracellular fates of L. interrogans in human and mouse macrophages.


SIRT1 deacetylates TopBP1 and modulates intra-S-phase checkpoint and DNA replication origin firing.
SIRT1, the mammalian homolog of yeast Sir2, is a founding member of a family of 7 protein and histone deacetylases that are involved in numerous biological functions. Previous studies revealed that SIRT1 deficiency results in genome instability, which eventually leads to cancer formation, yet the underlying mechanism is unclear. To investigate this, we conducted a proteomics study and found that SIRT1 interacted with many proteins involved in replication fork protection and origin firing. We demonstrated that loss of SIRT1 resulted in increased replication origin firing, asymmetric fork progression, defective intra-S-phase checkpoint, and chromosome damage. Mechanistically, SIRT1 deacetylates and affects the activity of TopBP1, which plays an essential role in DNA replication fork protection and replication origin firing. Our study demonstrated that ectopic over-expression of the deacetylated form of TopBP1 in SIRT1 mutant cells repressed replication origin firing, while the acetylated form of TopBP1 lost this function. Thus, SIRT1 acts upstream of TopBP1 and plays an essential role in maintaining genome stability by modulating DNA replication fork initiation and the intra-S-phase cell cycle checkpoint.


Screening for cognitive impairment in patients with acute stroke.
Formal assessment of cognitive impairment is rare in acute stroke, yet. It was the goal to utilize easy-to-apply established screening tests to assess cognitive impairment from any cause in patients with acute ischemic stroke. 209 consecutive patients (69.8 +/- 13.3 years, mean +/- SD; 117 male, 92 female) admitted to an acute stroke unit, which serves as a community stroke center, and diagnosed as having acute cerebral ischemia from any cause were investigated within 24 h of stroke onset and in part followed up after 3 months. Orientation and aphasia were assessed with the ADAScog subscales orientation and aphasia, verbal memory with Buschke's Memory Impairment Screen, and concentration/working memory with a letter sorting test. On admission, 74.6% were impaired on the Memory Impairment Screen, 77.0% on the letter sorting test, 45.0 and 24.9% on the ADAScog subscales aphasia and orientation. Results of the Memory Impairment Screen and letter sorting test were similar at the follow-up after 3 months. Formal brief assessment of cognitive deficits with tests not requiring motor capabilities in unselected patients with an acute cerebral ischemic event reveals widespread deficits. This needs to be considered when obtaining informed consent from the patients and instructing them. Routine formalized screening may thus improve care for patients with acute stroke. Patients with impairment on admission should be followed up, diagnosed concerning preexisting or poststroke dementia with a more extensive workup and eventually treated.


Finite Element Analysis of Bone Stress in the Posterior Mandible Using Regular and Short Implants, in the Same Context, with Splinted and Nonsplinted Prostheses.
The aim of this study was to compare the bone stress generated by rehabilitation using regular and short-length Morse taper implants (11 and 5 mm, respectively) in the same context and allied with splinted (SP) and nonsplinted (NSP) prostheses in the posterior area of the mandible using finite element analysis. Three-dimensional geometric models using regular implants (Ø4 × 11 mm) and short implants (Ø4 × 5 mm) were simulated with a left posterior mandible that had the first premolar tooth and all teeth posterior to that premolar removed. The four experimental groups were as follows: Group 1 NSP (two regular implants and one short implant rehabilitated with nonsplinted prostheses), Group 1 SP (two regular implants and one short implant rehabilitated with splinted prostheses), Group 2 NSP (one regular implant and two short implants rehabilitated with nonsplinted prostheses), and Group 2 SP (one regular implant and two short implants rehabilitated with splinted prostheses). Oblique forces were simulated in molars (365 N) and premolars (200 N). Qualitative and quantitative analyses of the minimum principal stress in bone were performed using the ANSYS Workbench software, version 10.0. The splinted prostheses decreased the stress to the surrounding bone of short implants. Moreover, they also decreased the stress on the surrounding bone adjacent to the tooth. However, the splinted prostheses generated higher stress in the coverage of the surrounding bone for regular intermediate implants and prominently in the bone at the implant cervical region, at the edge crest, compared with the individualized groups. The benefits in the use of splinted prostheses are notable for the preservation of the bone surrounding the short implants and tooth; however, it is necessary to evaluate each clinical situation because, in this context, the regular implants are at higher stress than the individualized implants.


LNA and alpha-L-LNA: towards therapeutic applications.
LNA and alpha-L-LNA are promising candidates for the development of efficient oligonucleotide-based therapeutic agents. Here, we report dose-dependent inhibition of HIV-1 Tat-dependent trans activation by a 12-mer chimeric alpha-L-LNA/DNA oligomer. This oligomer exhibits a dose-dependency similar to that of the corresponding 12-mer chimeric LNA/2'-O-Me-RNA oligomer. In addition, we show that incorporation of alpha-L-LNA or LNA monomers into each of the two binding arms of a "10-23" DNAzyme markedly increases cleavage of the target RNA.


Quality control in haemoglobinometry with special reference to the stability of haemiglobincyanide reference solutions.
In haemoglobinometry grave errors are still being made even though an internationally accepted standardized method is available for the determination of the haemoglobin content of blood. Up to the present only haemiglobincyanide reference solutions have been available on a wide scale to check the measuring stage of the standardized haemiglobincyanide method. These reference solutions are shown to remain stable, under proper storage conditions, for more than 10 years. Concentrated haemoglobin solutions have become available recently, offering the possibility to control the dilution and conversion steps of the haemiglobincyanide method. Such a solution is shown to remain stable, under proper storage conditions, for at least a year. Using both haemiglobincyanide reference solutions and concentrated haemoglobin solutions, as well as having the possibility of checking the cyanide content of the reagent used, an acceptable intra-laboratory control program may now be set up.


Aneurysmal bone cysts: treatment with direct percutaneous Ethibloc injection: long-term results.
To assess the efficacy and long-term results of Ethibloc treatment in aneurysmal bone cysts (ABC). Thirteen patients with ABC were treated with direct percutaneous Ethibloc injection. Four patients had only one injection and the other nine patients from two to four injections. No severe complications were observed; in two patients a local leakage of Ethibloc from the cyst into the soft tissues occurred but it was temporary and the consequent inflammation self-healed without residua and sequelae. Imaging follow-up lasted from 6 to 67 months and included conventional radiology (CR) and magnetic resonance imaging (MRI), both used in the presurgical phase. All images demonstrated a remarkable shrinkage of the cystic lesion and bone cortex thickening. In all patients, circumscribed areas of lucency persisted at radiography, corresponding to residual cystic areas without fluid-fluid levels at MRI. Pain, which was present in all the patients before treatment, was relieved within a month. According to our experience, direct percutaneous Ethibloc injection is effective in the treatment of ABC and can be recommended as the first-choice treatment. Due to its higher sensitivity MRI must be included either in the pretreatment phase to study the multilocular structure or in the imaging follow-up to evaluate the efficacy of Ethibloc in persistently non-responsive areas.


Construction and Validation of Two Hepatocellular Carcinoma-Progression Prognostic Scores Based on Gene Set Variation Analysis.
Background: Liver hepatocellular carcinoma (LIHC) remains a global health challenge with a low early diagnosis rate and high mortality. Therefore, finding new biomarkers for diagnosis and prognosis is still one of the current research priorities. Methods: Based on the variation of gene expression patterns in different stages, the LIHC-development genes (LDGs) were identified by differential expression analysis. Then, prognosis-related LDGs were screened out to construct the LIHC-unfavorable gene set (LUGs) and LIHC-favorable gene set (LFGs). Gene set variation analysis (GSVA) was conducted to build prognostic scoring models based on the LUGs and LFGs. ROC curve analysis and univariate and multivariate Cox regression analysis were carried out to verify the diagnostic and prognostic utility of the two GSVA scores in two independent datasets. Additionally, the key LCGs were identified by the intersection analysis of the PPI network and univariate Cox regression and further evaluated their performance in expression level and prognosis prediction. Single-sample GSEA (ssGSEA) was performed to understand the correlation between the two GSVA enrichment scores and immune activity. Result: With the development of LIHC, 83 LDGs were gradually upregulated and 247 LDGs were gradually downregulated. Combining with LIHC survival analysis, 31 LUGs and 32 LFGs were identified and used to establish the LIHC-unfavorable GSVA score (LUG score) and LIHC-favorable GSVA score (LFG score). ROC curve analysis and univariate/multivariate Cox regression analysis suggested the LUG score and LFG score could be great indicators for the early diagnosis and prognosis prediction. Four genes (ESR1, EHHADH, CYP3A4, and ACADL) were considered as the key LCGs and closely related to good prognosis. The frequency of TP53 mutation and copy number variation (CNV) were high in some LCGs. Low-LFG score patients have active metabolic activity and a more robust immune response. The high-LFG score patients characterized immune activation with the higher infiltration abundance of type I T helper cells, DC, eosinophils, and neutrophils, while the high-LUG score patients characterized immunosuppression with the higher infiltration abundance of type II T helper cells, TRegs, and iDC. The high- and low-LFG score groups differed significantly in immunotherapy response scores, immune checkpoints expression, and IC50 values of common drugs. Conclusion: Overall, the LIHC-progression characteristic genes can be great diagnostic and prognostic signatures and the two GSVA score systems may become promising indices for guiding the tumor treatment of LIHC patients.


Conformational Behaviour of Azasugars Based on Mannuronic Acid.
A set of mannuronic-acid-based iminosugars, consisting of the C-5-carboxylic acid, methyl ester and amide analogues of 1deoxymannorjirimicin (DMJ), was synthesised and their pH-dependent conformational behaviour was studied. Under acidic conditions the methyl ester and the carboxylic acid adopted an "inverted" 1 C4 chair conformation as opposed to the "normal" 4 C1 chair at basic pH. This conformational change is explained in terms of the stereoelectronic effects of the ring substituents and it parallels the behaviour of the mannuronic acid ester oxocarbenium ion. Because of this solution-phase behaviour, the mannuronic acid ester azasugar was examined as an inhibitor for a Caulobacter GH47 mannosidase that hydrolyses its substrates by way of a reaction itinerary that proceeds through a 3 H4 transition state. No binding was observed for the mannuronic acid ester azasugar, but sub-atomic resolution data were obtained for the DMJ⋅CkGH47 complex, showing two conformations-3 S1 and 1 C4 -for the DMJ inhibitor.


Disseminated CMV and Tuberculosis Infection with Osseous Metaplasia in a Presumable Crohn's Patient: Case Report.
Associations of different pathologies are not uncommon in every day practice, but association of disseminated infections like cytomegalovirus infection and tuberculosis are quite rare and hard to diagnose. Both are infections which appear frequently in immunocompromised patients and have unfavorable prognosis. We present a case of a 62 year old male with a history of Crohn's disease and tuberculosis which presented with symptoms of relapse and infection. He was treated with immunosuppressive medication and cortisol for the past 6 weeks. Cytomegalovirus (CMV) infection was serologically confirmed. In evolution, he suffered from gastrointestinal hemorrhage and died afterwards due to the hemorrhage and pulmonary infections. Histology confirmed the CMV modification in the lungs and intestines, but also highlighted active and disseminated tuberculosis (TB), bronchopneumonia, osseous metaplasia, hyaline membranes, numerous TB abscesses in the intestinal wall and specific CMV and TB modifications in the liver. The trigger for such important and serious infections remains unclear, for the cause can be represented by the Crohn's disease per se or only by the immunosuppressive treatment. Also, CMV can trigger modifications in immune system and patients with immune-mediated diseases have an increased risk for TB reactivation.


gp78: a multifaceted ubiquitin ligase that integrates a unique protein degradation pathway from the endoplasmic reticulum.
The endoplasmic reticulum (ER) is the site for maturation of proteins destined for the secretory pathway. Failure in maturation leads to production of misfolded proteins that are eliminated through the ER-associated degradation (ERAD) pathway. ERAD is a complex process that includes misfolded protein recognition, retrotranslocation to the cytosol, ubiquitination and proteasomal degradation. gp78 is an E3 ubiquitin ligase that integrates these ERAD steps by nucleating a unique degradation machine, which uses the p97/VCP-Npl4 complex for retrotranslocation instead of the wellknown p97/VCP-Ufd1-Npl4 complex. A growing list of substrates have been identified for gp78, which highlights the importance of gp78-mediated ERAD in essential physiological pathways and pathological processes.


[Villous adenoma of Vater's papilla. Problems in diagnosis and therapy].
Adenomas of the ampulla of Vater are rare tumors which cause the same diagnostic problems as adenomas of the colon and rectum. From 1984 to 1991 we treated 5 patients with adenomas of the ampulla of Vater verified by endoscopy and biopsy. All 5 patients underwent transduodenal papillectomy and reimplantation of the common bile duct and pancreatic duct with intraoperative frozen section examination of the specimen. In 2 out of the 5 cases, the definitive diagnosis was invasive carcinoma undetected by frozen section examination. Both patients subsequently underwent partial duodenopancreatectomy with preservation of the pylorus. In one of our patients villous adenoma was detected six years after the insertion of a biliary endoprosthesis for alveolar echinococcus infiltrating the bifurcation of the hepatic ducts, a finding which raises the question as to an etiologic role of long-time biliary duct stenting. We discuss the diagnostic problems of the adenoma-carcinoma sequence and the therapeutic options.


Mass determination of human immunoglobulin IgM using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Monoclonal human immunoglobulin IgM has been analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Using a matrix of sinapinic acid with a laser wavelength of 355 nm, positive ions with 2 to 6 charges were observed in the mass spectra. Two major molecular species were present. The molecular weights estimated from the multiply-charged signals were found to decrease systematically with decrease in the charge state of the ion. This effect was determined to stem from the non-linear influence of the initial kinetic energy of desorption on the final kinetic energy of the multiply-charged species. A method of successive approximations, with the molecular weights and desorption velocities of the analytes as variables, was used to correct for these non-linearities. Mean molecular weights for the two IgM species were found to be 939,000 +/- 2000 and 982,000 +/- 2000 Da. An initial desorption velocity of 565 +/- 10 ms/s was determined for both.


Stillbirth rates and their association with swine leucocyte antigen class II haplotypes in Microminipigs.
Microminipig (MMP) is a miniature pig with an extra small body size for experimental use. In the present study, the occurrence of stillbirths and their genetic association with swine leukocyte antigen (SLA) class II haplotypes were evaluated in a population of MMPs. The occurrences of stillbirth and genetic association with SLA class II haplotypes using 483 stillborn and 2,246 live piglets, and their parents were compared among the three groups of newborn piglet litters; an all stillborn (AS) group consisting of only stillborn piglet litters, a partial stillborn (PS) group consisting of stillborn and live piglet litters, and an all alive (AA) group consisting of only live piglet litters. The incidence of stillborn piglets was 483/2,729 (17.7%). Distributions of litter sizes, numbers of stillborn piglets in a litter, parities, and gestation periods were distinct among the three groups. The frequencies of low resolution haplotype (Lr)-0.7 or Lr-0.23 were higher in the AS group than in the PS or AA groups. In sires, the frequency of Lr-0.7 associated with the AS group was significantly higher in the AS group than with the AA group. In dams, the frequency of Lr-0.23 was significantly higher in the AS group than in the PS or AA groups, whereas the frequency of Lr-0.7 was not significantly different. The incidence of stillborn piglets in MMPs appears to be higher than those in other pig breeds. Several traits related with stillbirths such as the number of stillborn piglets and parities of the AS group were different from those of the PS and AA groups. Specific SLA class II haplotypes were associated significantly with a high incidence of stillbirths and could be used as genetic markers to adopt breeding strategies to lower the rate of stillbirth in MMPs.


Inhibitory effects of acetylsalicylic acid on exocrine pancreatic carcinogenesis.
We investigated short (6 months) and long (12 months) term inhibitory effects of low (200 ppm) and high (400 ppm) dosages of acetylsalicylic acid (aspirin) on exocrine pancreatic carcinogenesis. It is known that exocrine pancreatic carcinogenesis can be detected by the presence of atypical acinar cell foci (AACF) in pancreas. We investigated possible inhibitory effects of acetylsalicylic acid in an azaserine-treated rat model. AACF were produced in rats by injection with azaserine according to previous studies. Our findings showed that the number, volume and diameter of pancreatic AACF were reduced after acetylsalicylic acid application. These observations suggest that acetylsalicylic acid may exert a protective effect against neoplastic development of pancreatic acinar cells in azaserine injected rats. Our findings corroborate reports in the literature concerning the effects of aspirin in reducing neoplastic development.


Modified polyriboinosinic-polyribocytidylic acid complex: modulation of toxicity for rabbits by alterations in components.
In an earlier study the physiological effects encountered in humans of a modified complex of polyriboinosinic acid-polyribocytidylic acid [poly(I)-poly(C)] with carboxymethylcellulose and poly-L-lysine [poly(ICLC) (9S)], namely, the induction of high titers of serum interferon along with fever and hypotension, were reproduced in rabbits. In the present studies, also in rabbits, we evaluated effects of complexes with homopolymer polyribonucleotide sedimentation coefficients decreasing from 9S to 6S and 4S. Modified complexes of carboxymethylcellulose and poly-L-lysine with decreasing molecular weights were also tested. In several studies diphenhydramine and indomethacin were administered concomitantly. These experiments showed that at a daily intravenous dose of 0.2 mg/kg the various preparations of poly(I)-poly(C) (9S) and poly(I)-poly(C) (6S) induced falls in blood pressure, but stabilized complexes of poly(I)-poly(C) (4S) did not. Alterations in the molecular weights of carboxymethylcellulose and poly-L-lysine n the modified complex and the concomitant administration of diphenhydramine did not influence the occurrence or severity of untoward reactions. In rabbits, poly(ICLC) (4S) along with indomethacin induced high titers of serum interferon without fever or hypotension.


Modulation of boradiazaindacene emission by cation-mediated oxidative PET.
[reaction: see text] Bright green boradiazaindacene fluorescence is quenched by an oxidative photoinduced electron transfer (PET) from the excited state fluorophore to the bipyridyl unit complexed to metal cations. The closed shell diamagnetic cation Zn(II) is one of the most effective quenchers of fluorescence in this system, demonstrating that the quenching is not simply related to the facilitated intersystem crossing. The molecule also acts as a NOR logic gate with two chemical inputs, TFA and Zn(II).


Recurrent symptoms after ventricular pacing in unexplained syncope.
We report clinical and hemodynamic data in two cases of recurrent syncope. Both patients received permanent demand ventricular pacing (VVI) for unexplained syncope. Both patients experienced recurrent syncope after pacemaker implantation. They later underwent 60 degrees head-up tilt testing, initially noninvasively and then with hemodynamic profile. A vasovagal response to tilt occurred with bradycardia and was complicated by the onset of ventricular pacing and retrograde atrioventricular conduction (RAVC) with hemodynamic deterioration and rapid reproduction of syncope. Limited intracardiac electrophysiological study (EPS) excluded atrioventricular (AV) conduction disease, sinus node disease, and carotid sinus syndrome, and confirmed RAVC. Both patients were upgraded to dual chamber pacing, DDI mode, with 50/80 rate hysteresis. One patient was asymptomatic at repeat tilt testing; the other experienced continued symptoms due to the vasodepressor component of vasovagal syncope. Cardiac pacing alone is ineffective treatment for this phenomenon, and no proven therapy is presently available. Ventricular pacing applied to patients with unexplained syncope may lead to an increase in or continuation of symptoms rather than an amelioration. There is a need for full investigation of such patients, which must include tilt testing, to allow for the most accurate diagnosis possible and guide the most appropriate therapy.


Route-dependent stereoselective pharmacokinetics of tramadol and its active O-demethylated metabolite in rats.
The effects of route of administration on the stereoselective pharmacokinetics of tramadol (T) and its active metabolite (M1) were studied in rats. A single 20 mg/kg dose of racemic T was administered through intravenous, intraperitoneal, or oral route to different groups of rats, and blood and urine samples were collected. Samples were analyzed using chiral chromatography, and pharmacokinetic parameters (mean +/- SD) were estimated by noncompartmental methods. Following intravenous injection, there was no stereoselectivity in the pharmacokinetics of T. Both enantiomers showed clearance values (62.5 +/- 27.2 and 64.4 +/- 39.0 ml/min/kg for (+)- and (-)-T, respectively) that were equal or higher than the reported liver blood flow in rats. Similar to T, the area under the plasma concentration-time curves (AUCs) of M1 did not exhibit stereoselectivity after intravenous administration of the parent drug. However, the systemic availability of (+)-T was significantly (P < 0.05) higher than that of its antipode following intraperitoneal (0.527 +/- 0.240 vs. 0.373 +/- 0.189) and oral (0.307 +/- 0.136 vs. 0.159 +/- 0.115) administrations. The AUC of the M1 enantiomers, on the other hand, remained mostly nonstereoselective regardless of the route of administration. Pharmacokinetic analysis indicated that the stereoselectivity in the pharmacokinetics of oral T is due to stereoselective first pass metabolism in the liver and, possibly, in the gastrointestinal tract. The direction and extent of stereoselectivity in the pharmacokinetics of T and M1 in rats were in agreement with those previously reported in humans, suggesting that the rat may be a suitable model for enantioselective studies of T pharmacokinetics.


Correlation of gamma-catenin expression with good prognosis in medulloblastomas.
Medulloblastoma is a malignant cerebellar tumor of childhood and is difficult to cure due to frequent cerebrospinal fluid dissemination. Amplification of the c-myc gene (4%) and messenger (mRNA) overexpression (50%) are known to be adverse prognostic indicators. Because mRNA overexpression cannot be explained by gene amplification alone, mechanisms other than gene amplification are postulated. Molecules on the Wnt signal pathway in primary tumors were examined. Immunohistochemical and cytogenetic examinations of beta- and gamma-catenin, c-myc, N-myc, and cyclin D1 in 24 primary medulloblastomas were conducted, and their clinical relevance was evaluated. Cytoplasmic/membranous staining of beta- and gamma-catenin was detected in 19 (79%) and nine (37%) cases, respectively, and nuclear expression of cyclin D1 and c-myc was detected in six (25%) and 21 (83%) cases, respectively. The expression levels of gamma-catenin in Western blot analysis and immunohistochemistry were similar. By differential polymerase chain reaction, c-myc and N-myc were amplified separately in two large cell/anaplastic medulloblastomas. No cyclin D1 amplification, or beta- or gamma-catenin mutations were found. Kaplan-Meier analysis revealed no dissemination at diagnosis (Chang Grade M0) and gamma-catenin expression was correlated with good prognosis (p = 0.0002 and 0.003, respectively). Expression of gamma-catenin was also significant in the M0 group (p = 0.022). Expression of cyclin D1 showed a trend toward adverse outcome (p = 0.057) and all patients in whom cyclin D1 expression was found died of disease. Expression of gamma-catenin is of great prognostic value and its immunohistochemistry may be useful for further stratification of treatment. Cyclin D expression may have the potential to be an adverse prognostic indicator.


Reversed lateralization of temporal activation during speech production in thought disordered patients with schizophrenia.
Formal thought disorder is a core symptom of schizophrenia. It is associated with a reversed lateralization of the superior temporal cortex volume, an area that is implicated in lexical retrieval. We investigated the neural correlates of word retrieval during continuous speech in patients with formal thought disorder using functional magnetic resonance imaging (fMRI). Blood oxygenation level dependent (BOLD) contrast was measured with fMRI while six patients with schizophrenia and six healthy control subjects spoke about seven Rorschach inkblots for 3 min each. Subjects produced varying amounts of speech during each run. In a within subject design, the number of words produced was correlated with the BOLD contrast in the two runs in each participant who showed the highest variance of speech output. In control subjects, the amount of speech produced was mainly correlated with activation in the left superior temporal gyrus. In the patient group, the main correlations were in the right superior temporal gyrus. During the production of continuous speech, patients with formal thought disorder showed a reversed laterality of activation in the superior temporal cortex. This is consistent with findings of perturbed hemispheric interaction in schizophrenia, particularly in patients with formal thought disorder.


Multiple type-B response regulators mediate cytokinin signal transduction in Arabidopsis.
Type-B Arabidopsis thaliana response regulators (ARRs) are transcription factors that function in the final step of two-component signaling systems. To characterize their role in plant growth and development, we isolated T-DNA insertions within six of the genes (ARR1, ARR2, ARR10, ARR11, ARR12, and ARR18) from the largest subfamily of type-B ARRs and also constructed various double and triple combinations of these mutations. Higher order mutants revealed progressively decreased sensitivity to cytokinin, including effects on root elongation, lateral root formation, callus induction and greening, and induction of cytokinin primary response genes. The triple mutant arr1,10,12 showed almost complete insensitivity to cytokinin under many of the assay conditions used. By contrast, no significant change in the sensitivity to ethylene was found among the mutants examined. These results indicate that there is functional overlap among the type-B ARRs and that they act as positive regulators of cytokinin signal transduction.


Optimization of Naphthyridones into Selective TATA-Binding Protein Associated Factor 1 (TAF1) Bromodomain Inhibitors.
Bromodomain containing proteins and the acetyl-lysine binding bromodomains contained therein are increasingly attractive targets for the development of novel epigenetic therapeutics. To help validate this target class and unravel the complex associated biology, there has been a concerted effort to develop selective small molecule bromodomain inhibitors. Herein we describe the structure-based efforts and multiple challenges encountered in optimizing a naphthyridone template into selective TAF1(2) bromodomain inhibitors which, while unsuitable as chemical probes themselves, show promise for the future development of small molecules to interrogate TAF1(2) biology. Key to this work was the introduction and modulation of the basicity of a pendant amine which had a substantial impact on not only bromodomain selectivity but also cellular target engagement.


MRI of subendocardial perfusion deficits in isolated left ventricular noncompaction.
Ventricular noncompaction is a rare unclassified cardiomyopathy due to intrauterine arrest of compaction of the loose interwoven meshwork. It is characterized by markedly irregular endocardial surfaces with prominent trabeculations and intertrabecular recesses. Patients are asymptomatic or present with depressed ventricular function, ventricular arrhythmia, and systemic embolism. Areas of restricted myocardial perfusion have been previously documented by scintigraphy and positron emission tomography. This report documents a case of isolated left ventricular noncompaction with subendocardial perfusion deficits on MRI.


A randomized, placebo-controlled, double-blind, prospective clinical trial of silicone gel in prevention of hypertrophic scar development in median sternotomy wound.
Hypertrophic scarring caused by sternotomy is prevalent among Asians. The effectiveness of silicone gel in scar prevention may influence the decision of surgeons and patients regarding its routine use during the postoperative period. The authors conducted a randomized, placebo-controlled, double-blind, prospective clinical trial. The susceptibility to scar development varied among patients; therefore, sternal wounds were divided into the upper half and the lower half. Two types of coded gel prepared by an independent pharmacist were used on either half. Thus, selection and assessment biases and confounders were eliminated. One hundred wounds in 50 patients were randomized into two arms, 50 control and 50 silicone gels. The median age was 61 years and there were 34 men and 16 women. Ethnic distribution was 28 Malays, 18 Chinese, and four Indians. No side effect caused by the silicone gel was noted. Ninety-eight percent of patients had moderate to good compliance. The incidence of sternotomy scar was 94 percent. At the third month postoperatively, the silicone gel wounds were scored lower when compared with the control wounds. The differences were statistically significant in all parameters, including pigmentation (p = 0.02), vascularity (p = 0.001), pliability (p = 0.001), height (p = 0.001), pain (p = 0.001), and itchiness (p = 0.02). The effect of silicone gel in prevention of hypertrophic scar development in sternotomy wounds is promising. There are no side effects and patients' compliance is satisfactory. This study may popularize the use of silicone gel in all types of surgery to minimize the formation of hypertrophic scars in the early postoperative period.


TP53 R273C Mutation Is Associated With Poor Prognosis in LGG Patients.
Purpose: With the progress of cancer immunotherapy, hotspot mutations of common oncogenes and tumor suppressors are becoming new potential therapeutic targets. TP53 R273C mutation is one of the hotspot mutations of TP53, and it has a higher frequency in low-grade glioma (LGG). However, the function of this mutation and its prognostic significance in LGG are not still clear. Methods: To address this question, RNA sequencing, clinical, and SNP data of LGG patients from the TCGA database were downloaded. The Kaplan-Meier (KM) method was used for survival analysis. Immune cell populations in this cohort were assessed via the MCP counter and CIBERSORT. DNA damage/repair scores were calculated by GSVA analysis. WGCNA was conducted to identify genes related to TMB. Results: In the context of IDH1/2 mutation, LGG patients with TP53 R273C mutation had worse prognosis than other mutation types and wild types. This conclusion is still valid in LGG patients who had received chemotherapy or radiotherapy. Considering the 1p19q codeletion status, it was found that patients with both R273C mutation and 1p19q non-codeletion had the worst prognosis. Further analysis showed that LGG patients with TP53 R273C mutation had higher M2 macrophage infiltration and tumor mutation burden (TMB) than that of TP53 wild-type LGG patients, and higher TMB indicates poor prognosis in LGG patients. Furthermore, we identified genes which could be associated with higher M2 macrophage infiltration and TMB in LGG patients with TP53 R273C mutation. Conclusion: The study indicates that TP53 R273C mutation is very likely oncogenic and may be used as an indicator of the prognosis of LGG.


The Study of Active Monitoring in Sweden (SAMS): a randomized study comparing two different follow-up schedules for active surveillance of low-risk prostate cancer.
Only a minority of patients with low-risk prostate cancer needs treatment, but the methods for optimal selection of patients for treatment are not established. This article describes the Study of Active Monitoring in Sweden (SAMS), which aims to improve those methods. SAMS is a prospective, multicentre study of active surveillance for low-risk prostate cancer. It consists of a randomized part comparing standard rebiopsy and follow-up with an extensive initial rebiopsy coupled with less intensive follow-up and no further scheduled biopsies (SAMS-FU), as well as an observational part (SAMS-ObsQoL). Quality of life is assessed with questionnaires and compared with patients receiving primary curative treatment. SAMS-FU is planned to randomize 500 patients and SAMS-ObsQoL to include at least 500 patients during 5 years. The primary endpoint is conversion to active treatment. The secondary endpoints include symptoms, distant metastases and mortality. All patients will be followed for 10-15 years. Inclusion started in October 2011. In March 2013, 148 patients were included at 13 Swedish urological centres. It is hoped that the results of SAMS will contribute to fewer patients with indolent, low-risk prostate cancer receiving unnecessary treatment and more patients on active surveillance who need treatment receiving it when the disease is still curable. The less intensive investigational follow-up in the SAMS-FU trial would reduce the healthcare resources allocated to this large group of patients if it replaced the present standard schedule.


Postoperative Surgical Site Infection among Patients with Caesarean Delivery in the Department of Obstetrics and Gynaecology in a Tertiary Care Centre: A Descriptive Cross-sectional Study.
Surgical site infections are the commonest nosocomial infections following surgeries. They not only increase the morbidity and mortality following surgeries but also have a great impact both psychologically and financially. The aim of this study was to find out the prevalence of postoperative surgical site infection among patients with caesarean delivery in the Department of Obstetrics and Gynaecology in a tertiary care centre. This descriptive cross-sectional study was conducted in the Department of Obstetrics and Gynaecology of a tertiary care centre after taking ethical approval from the Institutional Review Committee (Reference number: 495(6-11)E2 077/078). Data from 1 July 2021 to 1 July 2022 were collected between 1 September 2022 to 30 November 2022 from the hospital records. All the pregnant women undergoing caesarean delivery during the study period were included. Convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated. Out of 1326 patients who underwent caesarean delivery, surgical site infection was seen in 38 (2.86%) (1.96-3.76, 95% Confidence Interval). Among 38 women, anaemia was seen in 11 (28.94%), diabetes mellitus in 6 (15.79%) and hypertension in 5 (13.16%). The prevalence of surgical site infection following caesarean delivery was found to be lower than other studies done in similar settings. hypertension; prevalence; surgical site infection.


Dynamic changes in DNA methylation during thermal control establishment affect CREB binding to the brain-derived neurotrophic factor promoter.
Thermal control establishment develops during a critical period by alterations in cellular properties in the frontal hypothalamus. These alterations may be modulated by the epigenetic code that determines the repertoire of transcribed proteins. Here we demonstrate transient changes in the expression of brain-derived neurotrophic factor (Bdnf) during both thermal conditioning and re-exposure of conditioned chicks to heat stress, relative to their age-matched naive counterparts. These changes coincide with changes in CpG methylation pattern in the avian Bdnf promoter region. Reduction in methylation during heat conditioning was observed at a cAMP response element-binding (CREB) site which coincided with both elevation in phospho-CREB levels and its binding to the Bdnf promoter. At the same time, an increase in methylation was observed at two other CpG sites, accompanied by elevation of the DNA methyltransferase 3a (DNMT3a) expression. DNMT3a was also found to bind to the two elevated methyl CpG sites, but not to the CREB binding site. These data suggest that complex and dynamic changes in DNA methylation are involved in the regulation of Bdnf expression during thermotolerance acquisition.


Diagnosis of functional kidney failure of cirrhosis with Doppler sonography: prognostic value of resistive index.
Time-velocity wave-form analysis of Doppler signals from small intrarenal arteries allows estimation of intrarenal arteriolar vascular resistance. Among the various indexes proposed, the resistive index is the most widely used for this estimation. To investigate whether the resistive index is useful in the diagnosis of functional kidney failure and prediction of survival in cirrhotic patients with ascites, we measured resistive index, kidney and liver function and plasma levels of renin, aldosterone and antidiuretic hormone in 10 healthy subjects, 12 patients with compensated cirrhosis and 32 patients with cirrhosis and ascites (17 with kidney failure). A total of 28 clinical and laboratory variables were analyzed for prognostic value. Resistive index was significantly increased in patients with kidney failure (0.74 +/- 0.01) compared with those in the other three groups (0.64 +/- 0.01, 0.64 +/- 0.02 and 0.67 +/- 0.01) and correlated significantly with glomerular filtration rate, arterial pressure, plasma renin activity and free water clearance in the cirrhotic patients. The sensitivity and specificity of the resistive index in detecting kidney failure in patients with ascites were 71% and 80%, respectively. Nine variables were correlated with survival in the univariate analysis, including resistive index, age, hepatomegaly, blood urea nitrogen, serum creatinine, plasma sodium concentration, glomerular filtration rate, plasma renin activity and plasma concentration of antidiuretic hormone. Multivariate analysis disclosed only three independent predictors of survival: plasma renin activity, plasma concentration of antidiuretic hormone and serum sodium concentration. In conclusion, resistive index is a sensitive method to assess intrarenal hemodynamics in patients with cirrhosis and ascites. It also has predictive value for survival in these patients.