Solitary Metastasis to the Breast From Thigh Myxoid Liposarcoma.
Metastasis to the breast from non-mammary malignancies are rare and suggestive of advanced disease. Accurate and prompt diagnosis of breast metastasis can provide important prognostic information and guide treatment planning. Interestingly, in contrast to primary breast malignancies, non-mammary metastatic breast lesions often have benign-appearing imaging characteristics. Knowing a patient's clinical history and having prior breast imaging studies for comparison is important for making accurate assessments and appropriate recommendations. Imaging-guided biopsy is often indicated for definitive tissue diagnosis. We report a rare case of solitary metastasis to the breast from thigh myxoid liposarcoma.


Ancient skeletons as silent witnesses of lead exposures in the past.
Lead is stored in calcified tissues, and the lead levels in human remains will therefore reflect in vivo exposures in the past, provided that postmortem contamination can be ruled out or successfully removed. Reliable chemical testimonies from archeological finds indicate that prepollution exposures to lead were of the order of 1% of current-day exposures in industrialized countries. Examination of these silent witnesses of past times has also shown that lead exposures during recent historical periods were much higher than today. Studies in this area provide a framework for evaluation of lead exposures. The results would suggest that an ideal control group should not be exposed to lead levels any higher than the low, prepollution levels.


Approach to the Synthesis of 2,3-Disubstituted-3H-quinazolin-4-ones Mediated by Ph3P-I2.
Readily available N-substituted amides or their requisite carboxylic acids or acid chlorides have been used to construct 2,3-disubstituted-3H-quinazolin-4-ones in a one-pot procedure. Key transformation in this convergent approach involves Ph3P-I2-mediated formation of amidine upon condensation of an amide or the intermediate amide with methyl anthranilate. Cyclization of the amidine-tethered anthranilate then affords 2,3-disubstituted-3H-quinazolin-4-ones in good to excellent yields under mild conditions.


DOPA decarboxylase gene is associated with nicotine dependence.
Cigarette smoking is a prevalent and harmful behavior. Although the heritability of nicotine dependence (ND) is well documented and many candidate genetic regions have been identified, few of them were confirmed. This may be, in part, due to analytic methods that sacrifice power. Using a recently developed, more powerful method for testing association between a genetic marker and an ordinal trait, we analyzed data from 1879 smokers and nonsmokers from 600 nuclear families of African- or European-American (AA or EA) ancestry. This method increases power principally by accounting for differences in severity between affected subjects. To demonstrate the more powerful method, we re-analyzed an existing dataset, which confirmed the association of the DOPA decarboxylase (DDC) gene on chromosome 7p11 with measures of nicotine dependence. Although none of the eight single nucleotide polymorphisms (SNPs) studied were found to be significantly associated with nicotine dependence (unadjusted p-value > 0.01), we identified haplotypes from those SNPs that were significantly associated with nicotine dependence in both AA and EA samples. The associated haplotypes differed in the AA and EA samples. The strongest association (p-value = 0.003) was identified between the 'heaviness of smoking index' and haplotype C-A-T-G in SNPs rs921451-rs3735273-rs1451371-rs2060762. However, this association was not found significant in a previous report (p-value = 0.19) that used the same sample, underscoring the importance of using the statistical methods that use more of the available phenotypic information, and thereby better reflect the distribution of the phenotypes.


The mutagenic and antimutagenic activity of Sutherlandia frutescens extracts and marker compounds.
Sutherlandia frutescens (L.) R. Br is endemic to Southern Africa where it has been traditionally used for cancer and diabetes. In recent times it has been marketed for its reputed (but not proven) anticancer, antidiabetic and anti-HIV properties. Little is known about the mutagenic and antimutagenic potential of extracts and common marker compounds of Sutherlandia frutescens. Therefore this study aimed to investigate the putative efficacy and possible long-term adverse effects of using this herb. Ethylacetate (EA) and 50% Methanol (MeOH) extracts were screened for mutagenic and antimutagenic activity using the Ames assay utilising TA97a, TA98, TA100 and TA102 in the presence and absence of metabolic activation. Four compounds, L-arginine, L-canavanine, GABA and D-pinitol known to occur in sutherlandia were also included. The total polyphenolic content of the both extracts was determined using the Folin-Ciocalteau method and FRAP and ABTS were used to determine the anti-oxidant potential of the extracts. The extracts and the standards did not show any cytotoxicity except in TA97a. The EA extract exhibited antimutagenicity against all the bacterial strains at all concentrations tested. The MeOH extract showed both pro-mutagenic and antimutagenic activities with 2-acetamidofluorene and aflatoxin B1 in the presence of metabolic activation of TA98 and TA100, respectively. All compounds, except L-canavanine exhibited antimutagenic activity against all strains. L-canavanine, on the other hand showed co-mutagenicity with 9-aminoacridine on TA97a, at all test concentrations. The extracts and pure compounds exhibited their antimutagenic activity in a dose response manner. L-arginine and GABA showed an some antimutagenic response. EA extract had three times the total phenolic content (12.56 μg GE / mg) observed in the MeOH extract. There was correlation between total phenolic content, antioxidant potential and antimutagenicity. Both extracts exhibited a protective effect, with the EA extract exhibiting greater potency. L-canavanine acted as a co-mutagen in a dose response manner without metabolic activation. It is suggested that the EA extract be priotized for future development work as it showed a better risk profile and activity.


Aging increases flexibility of postural reactive responses based on constraints imposed by a manual task.
This study compared the effect of stability constraints imposed by a manual task on the adaptation of postural responses between 16 healthy elderly (mean age = 71.56 years, SD = 7.38) and 16 healthy young (mean age = 22.94 years, SD = 4.82) individuals. Postural stability was perturbed through unexpected release of a load attached to the participant's trunk while performing two versions of a voluntary task: holding a tray with a cylinder placed with its flat side down (low constraint) or with its rolling round side down (high constraint). Low and high constraint tasks were performed in alternate blocks of trials. Results showed that young participants adapted muscular activation and kinematics of postural responses in association with previous experience with the first block of manual task constraint, whereas the elderly modulated postural responses based on the current manual constraint. This study provides evidence for flexibility of postural strategies in the elderly to deal with constraints imposed by a manual task.


Orbital Ectopic Lymphoid Follicles with Germinal Centers in Aquaporin-4-IgG-Positive Neuromyelitis Optica Spectrum Disorders.
Neuromyelitis optica spectrum disorders (NMOSDs) are important autoimmune central nervous system (CNS) astrocytopathy causing acute myelitis, optic neuritis (ON), and encephalitis associated with significant morbidities and mortality. It is important to diagnose NMOSDs early as they are treatable. The majority of NMOSDs patients are seropositive for aquaporin-4 IgG (AQP4-IgG) autoantibodies, which target CNS aquaporin-4 (AQP4) expressed abundantly in astrocytic foot processes. We report the novel observation of orbital masses containing ectopic lymphoid follicles with germinal centres (GC) in two patients with AQP4-IgG-positive NMOSD. Both patients had severe extensive myelitis with symptomatic or asymptomatic ON, with the ectopic lymphoid structures detected on initial presentation. Histolopathological studies confirmed that the orbital masses contained reactive lymphoid follicles with GC containing B cells and plasma cells. Our observations support that AQP4-IgG positive NMOSDs patients have underlying AQP4 autoimmunity and suggest that ON (symptomatic or asymptomatic) may trigger formation of orbital ectopic GC contributing to development of high-affinity AQP4-specific memory B cells and plasma cells, which produce highly pathogenic AQP4-IgG.


Glycyl-glutamine (beta-endorphin(30-31)) inhibits morphine-induced dopamine efflux in the nucleus accumbens.
Glycyl-glutamine (Gly-Gln) is an endogenous dipeptide that is synthesized from beta-endorphin post-translationally. Previously, we showed that Gly-Gln prevents acquisition of morphine-conditioned place preference, a behavioral test of morphine reward, but does not interfere with morphine analgesia. In this study, we tested the hypothesis that Gly-Gln inhibits morphine reward by blocking morphine-induced dopamine efflux in the nucleus accumbens (NAc). Extracellular dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were sampled by microdialysis and analyzed by high-performance liquid chromatography with electrochemical detection. Guide cannulas were implanted in the right NAc and left lateral ventricle of male Sprague-Dawley rats stereotaxically. Approximately 24 h later, a microdialysis probe was inserted into the NAc and perfused at 1 microl/min. Gly-Gln (1, 3, 30, or 100 nmol/5 microl) or saline was administered intracerebroventricularly, morphine (2.5 mg/kg) was injected intraperitoneally (i.p.) 2 min later, and extracellular dopamine and DOPAC were sampled at 20-min intervals. Morphine administration increased extracellular dopamine concentrations by approximately 600% within 40 min. Gly-Gln pretreatment inhibited the rise in extracellular dopamine in a dose-related manner; the lowest significantly inhibitory dose was 1 nmol. Gly-Gln also inhibited the morphine-induced rise in extracellular DOPAC concentrations but did not affect extracellular dopamine or DOPAC in control animals. Gly-Gln (100 nmol/5 microl) prevented morphine-induced dopamine efflux in rats treated with morphine chronically (10 mg/kg, i.p. twice daily for 6 days), although it did not affect DOPAC concentrations significantly. These data support the hypothesis that Gly-Gln abolishes the rewarding effect of morphine by inhibiting the ability of morphine to stimulate dopamine release in the NAc.


Isolated Renal Mucormycosis in Immunocompetent Hosts: Clinical Spectrum and Management Approach.
Isolated renal mucormycosis in immunocompetent hosts is a rare entity. We present the largest case series of isolated renal mucormycosis in immunocompetent hosts. Retrospective data of isolated renal mucormycosis from March 2012 to June 2017 was reviewed. Fifteen patients of isolated renal mucormycosis were identified. Contrast-enhanced computed tomography scan showed enlarged globular kidneys with decreased or patchy enhancement, perinephric stranding and thickened Gerota's fascia in all patients. Ten patients with unilateral involvement underwent nephrectomy and two of four patients with bilateral renal mucormycosis underwent bilateral nephrectomy. Two patients were managed with intravenous antifungal therapy alone. Overall, the mortality rate in our series was 40% (6/15). Isolated renal mucormycosis in healthy immunocompetent hosts is an emerging new entity. Prompt diagnosis based on the characteristic clinical and radiological picture and starting high-dose antifungal therapy at least 24 hours before surgical debridement offer the best chance of survival in these patients.


The aggregate nature of human mesenchymal stromal cells in native bone marrow.
The clinical application of mesenchymal stromal cells (MSC) faces several obstacles, such as the lack of a standard method for direct isolation as well as a low frequency and concern about the safety of their in vitro expansion. Although the density-gradient separation technique is used as the first step in most methods of MSC isolation to enrich mononuclear cells, the efficiency of this method has not so far been examined. This study was designed to address this issue. Human bone marrow (BM) samples were laid over Ficoll-Paque, and after centrifugation the upper and lower fractions were cultured separately. Surface markers, differentiation potential and the number of emerged cells were determined. The isolated cells from both the upper and lower fractions were characteristic of MSC. Although it is commonly believed that MSC are single suspending mononuclear cells and so are enriched in the upper fraction of Ficoll-Paque after density-gradient separation, our data showed that considerable numbers of these cells were accumulated in the lower fraction. Further data indicated that MSC were actually present as cell aggregates in BM and they could be enriched effectively by a simple filtration method. The aggregate nature of MSC in BM is in agreement with the concept that they are one of the main elements of the hematopoietic stem cell niche. In addition, the simple filtration method proposed here to isolate cell aggregates may provide opportunities for instant stem cell therapy without the need for extensive in vitro expansion.


Biofilm formation by the emerging fungal pathogen Trichosporon asahii: development, architecture, and antifungal resistance.
Trichosporon asahii is the most common cause of fatal disseminated trichosporonosis, frequently associated with indwelling medical devices. Despite the use of antifungal drugs to treat trichosporonosis, infection is often persistent and is associated with high mortality. This drove our interest in evaluating the capability of T. asahii to form a biofilm on biomaterial-representative polystyrene surfaces through the development and optimization of a reproducible T. asahii-associated biofilm model. Time course analyses of viable counts and a formazan salt reduction assay, as well as microscopy studies, revealed that biofilm formation by T. asahii occurred in an organized fashion through four distinct developmental phases: initial adherence of yeast cells (0 to 2 h), germination and microcolony formation (2 to 4 h), filamentation (4 to 6 h), and proliferation and maturation (24 to 72 h). Scanning electron microscopy and confocal scanning laser microscopy revealed that mature T. asahii biofilms (72-h) displayed a complex, heterogeneous three-dimensional structure, consisting of a dense network of metabolically active yeast cells and hyphal elements completely embedded within exopolymeric material. Antifungal susceptibility testing demonstrated a remarkable rise in the MICs of sessile T. asahii cells against clinically used amphotericin B, caspofungin, voriconazole, and fluconazole compared to their planktonic counterparts. In particular, T. asahii biofilms were up to 16,000 times more resistant to voriconazole, the most active agent against planktonic cells (MIC, 0.06 microg/ml). Our results suggest that the ability of T. asahii to form a biofilm may be a major factor in determining persistence of the infection in spite of in vitro susceptibility of clinical isolates.


Electronic and interfacial behavior of gemini metallosurfactants with copper(II)/pseudohalide cascade cores.
In this paper we discuss the newly synthesized binuclear species [Cu2(L(PY18))2(μ1,1-N3)2(N3)2] (1) and [Cu2(L(PY18))2(μ1,3-SCN)2(NCS)2] (2), as obtained from the monometallic precursor [Cu(L(PY18))Br2]. These gemini metallosurfactants incorporate metal/anion cascade cores and are investigated by experimental and theoretical methods. Diagnostic IR stretches support the presence of μ1,1-bridged (end-on, 2075 cm(-1)) azide groups in 1 and μ1,3-bridged (end-to-end, 2117 cm(-1)) thiocyanate groups in 2. Anion-to-copper LMCT electronic processes at 390 and 440 nm for 1 and at 415 nm for 2 reinforce the nature of the metal/anion cascade cores. Both species are redox-active, magnetically uncoupled due to poor orbital overlap, and robust in the presence of strongly coordinating solvents. At the air-water interface, 1 and 2 yield Langmuir films with high collapse pressures of ca. 60 mN m(-1). Domain formation is considerably less extensive than that observed for the related monometallic precursor and the average molecular areas are in good agreement with their modeled molecular size. The resulting Langmuir-Blodgett films are isolated on silica substrates and investigated using IR-reflectance/absorbance spectroscopy.


Booster dose vaccination for preventing hepatitis B.
Antibodies against hepatitis B surface antigen (HBsAg) wane over time following hepatitis B immunisation; hence, it is unclear whether people vaccinated in three-dose or four-dose schedules of the hepatitis B vaccine are still immune when the hepatitis B surface antibody (anti-HBs) level in their body is undetectable, or lower than the level usually considered protective. This question may potentially be answered indirectly by measuring the anamnestic immune response to a booster dose of vaccine. The term 'booster' (or revaccination) refers to an additional dose of hepatitis B vaccine (HBV) given some time post-primary vaccination to induce immune memory and improve protection against hepatitis B virus (HBV) infection. To assess the benefits and harms of booster dose hepatitis B vaccination, more than five years after the primary vaccination, for preventing HBV infection in healthy individuals previously vaccinated with the hepatitis B vaccine, and with hepatitis B surface antibody (anti-HBs) levels below 10 mIU/mL. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, conference databases, and reference lists of articles to January 2016. We also contacted authors of articles. In addition, we searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials (May 2016). Randomised clinical trials addressing anamnestic immune response to a booster dose of hepatitis B vaccine, more than five years after the primary vaccination, in apparently healthy participants, vaccinated in a three-dose or four-dose schedule of the hepatitis B vaccine during the primary vaccination, without receiving an additional dose or immunoglobulin. Both review authors decided if the identified studies met the inclusion criteria or not. Primary outcomes included the proportion of participants with anamnestic immune response in non-protected participants and signs of HBV infection. Secondary outcomes were the proportion of participants that developed local and systemic adverse events following a booster dose injection. We planned to report the weighted proportion with 95% confidence intervals (CIs). There were no eligible randomised clinical trials fulfilling the inclusion criteria of this review. We were unable to include any randomised clinical trials on the topic; only randomised clinical trials will be able to provide an answer as to whether a booster dose vaccination is able to protect against hepatitis B infection.


Extracorporeal life support prior to left ventricular assist device implantation leads to improvement of the patients INTERMACS levels and outcome.
The objective of this study was to evaluate the outcome of left ventricular assist device (LVAD) implantation after initial extracorporeal life support (ECLS) in patients with cardiogenic shock and the incidence of post implantation right ventricular failure. All patients on ECLS therapy for cardiogenic shock prior to LVAD implantation (n = 15) between October 2011 and January 2014 were analyzed. Baseline patient characteristics, as well as detailed pre-operative treatment and postoperative outcome data were collected retrospectively. At time of admission to our unit all patients were classified INTERMACS II or higher (12 [80%] INTERMACS I). Improvement to INTERMACS III temporary cardiac support (TCS) at time of LVAD implantation was successful in 14 patients (93.3%). End-organ function recovered during ECLS support. No patient needed ongoing ECLS or additional right ventricular support after LVAD implantation. Both in-hospital and 30-day mortality was 6.7% (n = 1). The median duration of LVAD support was 687.9 ± 374.5 days. At the end of the study (follow-up 810.7 +/- 338.9 days), 13 (86.7%) patients were alive. The majority of patients (10 [66.7%]) remained on LVAD support. Transplantation could be performed in 1 (6.7%) patient, 2 (13.3%) patients could be successfully weaned. LVAD implantation in ECLS patients leads to improvement of INTERMACS level to INTERMACS III TCS status. Excellent mid-term survival comparable to true INTERMACS III-IV patients could be shown. ECLS prior to LVAD as a bridge-to-bridge therapy may help to lower mortality in primarily unstable patients.


Surface tension measurement of normal human blood samples by pendant drop method.
The surface tension of blood plays an important role not only in the birth and decompression sickness but also in other functionality of the organism. It also provides capillary action during blood flow process. In this article, a simple and low-cost device is designed and fabricated for measuring the surface tension of blood by pendant drop method. In this device, a droplet of blood is formed in a closed chamber on tip of an 18-gauge blunt needle and it is photographed by a camera in very humid conditions (RH = 99%) to minimise the evaporation. A wetted wick is provided at the bottom of the chamber for maintaining constant relative humidity in chamber. Surface tension of blood is inferred using drop shape factor method and image analysis technique at various experimental conditions. This device is validated and calibrated with surface tension measurements of water and silicone oil. Its measurements are in good agreement against data reported in literature. Post-validation, surface tensions of blood samples with and without anticoagulant of healthy persons at various temperatures (range from 20 to 40 °C) was measured. It was found that the surface tension of normal blood samples strongly correlates with blood temperature. The surface tension of female blood was remarkably different from same of male blood. However, the effect of age (21-60 year) on the surface tension was negligible for all practical purposes. Increased percentage of anticoagulant in blood increases its surface tension. This research specifies a baseline for surface tension of normal blood samples at various conditions which in turn provides new insights to pathologists in identifying various disease conditions.


Rational design of novel antimicrobials: blocking purine salvage in a parasitic protozoan.
All parasitic protozoa obtain purine nucleotides solely by salvaging purine bases and/or nucleosides from their host. This observation suggests that inhibiting purine salvage may be a good way of killing these organisms. To explore this idea, we attempted to block the purine salvage pathway of the parasitic protozoan Tritrichomonas foetus. T. foetus is a good organism to study because its purine salvage depends primarily on a single enzyme, hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase), and could provide a good model for rational drug design through specific enzyme inhibition. Guided by the crystal structure of T. foetus HGXPRTase, we used structure-based drug design to identify several non-purine compounds that inhibited this enzyme without any detectable effect on human HGPRTase. One of these compounds, 4-[N-(3, 4-dichlorophenyl)carbamoyl]phthalic anhydride (referred to as TF1), was selected for further characterization. TF1 was shown to be a competitive inhibitor of T. foetus HGXPRTase with respect to both guanine (in the forward reaction; Ki = 13 microM) and GMP (in the reverse reaction; Ki = 10 microM), but showed no effect on the homologous human enzyme at concentrations of up to 1 mM. TF1 inhibited the in vitro growth of T. foetus with an EC50 of approximately 40 microM. This inhibitory effect was associated with a decrease in the incorporation of exogenous guanine into nucleic acids, and could be reversed by supplementing the growth medium with excess exogenous hypoxanthine or guanine. Thus, rationally targeting an essential enzyme in a parasitic organism has yielded specific enzyme inhibitors capable of suppressing that parasite's growth.


Annihilation of point defects on a line.
We discuss the evolution of the distribution function of distances between point defects of opposite signs distributed on a line of finite length interacting via a potential attractive at short distances and repulsive at large distances. The standard deviation of the distribution grows quickly at short times, attains maximum, and decreases logarithmicaly at longer times. The distance between the defects increases monotonically and at equilibrium is about two times larger than the distance at which the repulsive force attains maximum. The distance dependent viscosity does not change qualitatively these conclusions, but only increases the time scale of evolution by one order of magnitude.


Overlapping phenomena of bipolar disorder and epilepsy--a common pharmacological pathway.
Studies and data on prevalence, recognition and clinical features of bipolar disorder (BD) in epilepsy remain limited. Still, there is a growing evidence of BD and epilepsy being frequent co-morbid conditions with some features suggesting shared pathophysiological mechanisms that include the episodic course of both conditions, the possible kindling mechanism and the efficacy of some antiepileptic drugs (AEDs) in BD. The aim of this paper is to review concepts of overlapping phenomena of bipolar disorder and epilepsy. A literature review of the theoretical bases of the relationship between BD and epilepsy is presented. The comorbidity of epilepsy and mood disorders was a subject of interest of many studies for decades. Bipolar disorder and epilepsy have a number of clinical, biochemical and pathophysiological features in common. Bipolar disorder in epilepsy, excluding the ictal or periictal symptoms, can be categorized using standardized measures. Standardized psychiatric interview procedures based on DSM criteria like SCID-I or MINI provide comprehensive way to diagnose mood disorders in patients with epilepsy.


Characterization of Italian honeys (Marche Region) on the basis of their mineral content and some typical quality parameters.
The characterization of three types of Marche (Italy) honeys (Acacia, Multifloral, Honeydew) was carried out on the basis of the their quality parameters (pH, sugar content, humidity) and mineral content (Na, K, Ca, Mg, Cu, Fe, and Mn). Pattern recognition methods such as principal components analysis (PCA) and linear discriminant analysis (LDA) were performed in order to classify honey samples whose botanical origins were different, and identify the most discriminant parameters. Lastly, using ANOVA and correlations for all parameters, significant differences between diverse types of honey were examined. Most of the samples' water content showed good maturity (98%) whilst pH values were in the range 3.50 - 4.21 confirming the good quality of the honeys analysed. Potassium was quantitatively the most relevant mineral (mean = 643 ppm), accounting for 79% of the total mineral content. The Ca, Na and Mg contents account for 14, 3 and 3% of the total mineral content respectively, while other minerals (Cu, Mn, Fe) were present at very low levels. PCA explained 75% or more of the variance with the first two PC variables. The variables with higher discrimination power according to the multivariate statistical procedure were Mg and pH. On the other hand, all samples of acacia and honeydew, and more than 90% of samples of multifloral type have been correctly classified using the LDA. ANOVA shows significant differences between diverse floral origins for all variables except sugar, moisture and Fe. In general, the analytical results obtained for the Marche honeys indicate the products' high quality. The determination of physicochemical parameters and mineral content in combination with modern statistical techniques can be a useful tool for honey classification.


Extracellular Influences: Molecular Subclasses and the Microenvironment in Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancer and carries the worst prognosis of all common cancers. Five-year survival rates have not surpassed 6% for some decades and this lack of improvement in outcome urges a better understanding of the PDAC-specific features which contribute to this poor result. One of the most defining features of PDAC known to contribute to its progression is the abundance of non-tumor cells and material collectively known as the stroma. It is now well recognized that the different non-cancer cell types, signalling molecules, and mechanical properties within a tumor can have both tumor-promoting as well as -inhibitory effects. However, the net effect of this intratumour heterogeneity is not well understood. Heterogeneity in the stromal makeup between patients is even less well established. Such intertumour heterogeneity is likely to be affected by the relative contributions of individual stromal constituents, but how these contributions exactly relate to existing classifications that demarcate intertumour heterogeneity in PDAC is not fully known. In this review, we give an overview of the available evidence by delineating the elements of the PDAC stroma and their contribution to tumour growth. We do so by interpreting the heterogeneity at the gene expression level in PDAC, and how stromal elements contribute to, or interconnect, with this.


Expression and prognosis analysis of GINS subunits in human breast cancer.
GINS subunits, a protein complex composed of GINS1, GINS2, GINS3 and GINS4 in the human genome and the expression level of each GINS subunits plays an important role in different human cancers. As one of the most common malignancies after lung cancer in the world, precise biomarkers for early diagnosis and treatment in breast cancer are important. The purpose of our study was to elucidate the expression and prognostic value of GINS subunits in breast cancer.The purpose of present study was to explore the expression level of GINS subunits in breast cancer patients.In the present study, we investigated the gene alteration, gene expression and potential prognostic value of GINS subunits by using the Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, cBioPortal, and bc-GenExMiner databases. Then, the GeneMANIA database was used to show the genes that associated with GINS subunits. Furthermore, gene ontology pathway analysis was conducted by using the Metascape database. Finally, immune infiltration analysis in GINS subunits were evaluated using the Tumor Immune Estimation Resource (TIMER) database.Our analyses demonstrated that the expression levels of different GINS subunits were different between breast cancer and normal breast tissues. The expression levels of GINS1, GINS2, and GINS4 were significantly higher in breast cancer tissues than in normal tissues. Survival analysis revealed that increased the expression levels of GINS subunits were associated with poor prognoses in all patients with breast cancer. Gene ontology pathway enrichment analysis of the GINS subunits suggested that GINS subunits involved in pathways including the cell cycle checkpoint, DNA replication and other meaningful signaling pathways.We systemically analyzed the expression, prognostic, clinicopathologic values, and potential functional networks of GINS subunits in breast cancer. Our findings showed that individual GINS subunits could be new potential prognostic biomarkers for breast cancer. However, further verification studies are still needed to prove the clinical value of GINS subunits in breast cancer patients.


[Sedation with intravenous midazolam during upper gastrointestinal endoscopy--changes in hemodynamics, oxygen saturation and memory].
Cardiorespiratory adverse effects are often observed in patients undergoing upper gastrointestinal endoscopy with sedation. In this study, we examined hemodynamics, oxygen saturation and memory during upper gastrointestinal endoscopy under sedation with intravenous midazolam. Eight healthy outpatients without any obvious complications received intravenous midazolam 5 mg for sedation for upper gastrointestinal endoscopy. Blood pressure, heart rate and percutaneous arterial oxygen saturation (SpO2) were measured before, during and after endoscopy. After the arousal by intravenous flumazenil, we inquired the patients about the level of memory during the endoscopy. Blood pressure decreased significantly two minutes after midazolam administration, but increased significantly after the insertion of an endoscope which was not different from the control value. Heart rate increased significantly one and three minutes after the insertion of the endoscope. SpO2 decreased significantly after midazolam administration and stayed at around 95%. No patients remembered the procedure. Sedation with intravenous midazolam during upper gastrointestinal endoscopy is useful to control the cardiovascular responses, and to obtain amnesia. However, a decrease in SpO2 should be watched carefully.


Influenza H3 hemagglutinin vaccine with scrambled immunodominant epitopes elicits antibodies directed toward immunosubdominant head epitopes.
Vaccination is the most effective countermeasure to reduce the severity of influenza. Current seasonal influenza vaccines mainly elicit humoral immunity targeting hemagglutinin (HA). In particular, the amino acid residues around the receptor-binding site in the HA head domain are predominantly targeted by humoral immunity as "immunodominant" epitopes. However, mutations readily accumulate in the head domain due to high plasticity, resulting in antigenic drift and vaccine mismatch, particularly with influenza A (H3N2) viruses. A vaccine strategy that targets more conserved immunosubdominant epitopes is required to attain a universal vaccine. Here, we designed an H3 HA vaccine antigen with various amino acids at immunodominant epitopes of the HA head domain, termed scrambled HA (scrHA). In ferrets, scrHA vaccination induced lower serum neutralizing antibody levels against homologous virus compared with wild-type (WT) HA vaccination; however, similar levels of moderately neutralizing titers against antigenically distinct H3N2 viruses were observed. Ferrets vaccinated with scrHA twice and then challenged with homologous or heterologous virus showed the same level of reduced virus shedding in nasal swabs as WT HA-vaccinated animals but reduced body temperature increase, whereas WT HA-vaccinated ferrets exhibited body temperature increases similar to those of mock-vaccinated animals. scrHA elicited antibodies against HA immunodominant and -subdominant epitopes at lower and higher levels, respectively, than WT HA vaccination, whereas antistalk antibodies were induced at the same level for both groups, suggesting scrHA-induced redirection from immunodominant to immunosubdominant head epitopes. scrHA vaccination thus induced broader coverage than WT HA vaccination by diluting out the immunodominancy of HA head epitopes. IMPORTANCE Current influenza vaccines mainly elicit antibodies that target the immunodominant head domain, where strain-specific mutations rapidly accumulate, resulting in frequent antigenic drift and vaccine mismatch. Targeting conserved immunosubdominant epitopes is essential to attain a universal vaccine. Our findings with the scrHA developed in this study suggest that designing vaccine antigens that "dilute out" the immunodominancy of the head epitopes may be an effective strategy to induce conserved immunosubdominant epitope-based immune responses.


Properties and distribution of single voltage-gated calcium channels in adult hippocampal neurons.
1. The properties of single voltage-gated calcium channels were investigated in acutely exposed CA3 and CA1 pyramidal neurons and granule cells of area dentata in the adult guinea pig hippocampal formation. 2. Guinea pig hippocampal slices were prepared in a conventional manner, then treated with proteolytic enzymes and gently shaken to expose the somata of the three cell types studied. Standard patch-clamp techniques were used to record current flow through calcium channels in cell-attached membrane patches with isotonic barium as the charge carrier. 3. Single-channel current amplitudes were measured at different membrane potentials. Single-channel current-voltage plots were constructed and single-channel slope conductances were found to fall into three classes. These were (approximately) 8, 14, and 25 pS, and were observed in all three cell types. 4. The three groups of channels differed from each other in voltage dependence of activation: from a holding potential of -80, the small-conductance channel began to activate at about -40 to -30 mV, the medium-conductance channel at about -20 mV, and the large-conductance channel at approximately 0 mV. 5. Ensemble averages of single-channel currents during voltage steps revealed differences in voltage-dependent inactivation. The small-conductance channel inactivated completely within approximately 50 ms during steps from -80 to -10 mV or more positive. Steps to less positive potentials resulted in less inactivation. The medium-conductance channel displayed variable inactivation during steps from -80 to 0 mV. Inactivation of this channel during a 160-ms step ranged from virtually zero to approximately 100%. The large-conductance channel displayed no significant inactivation during steps as long as 400 ms. 6. The large-conductance channel was strikingly affected by the dihydropyridine agonist Bay K8644 (0.5-2.0 microM), resulting in a high probability of channel opening, prolonged openings, and an apparent increase in the number of channels available for activation. The medium and small-conductance channels were not noticeably affected by the drug. 7. The large-conductance channel could be induced to open at very negative membrane potentials by holding the patch for several seconds at 20 or 30 mV and stepping to -30 or -40 mV. This process was enhanced by Bay K8644, resulting in prolonged openings at potentials as negative as -100 mV.(ABSTRACT TRUNCATED AT 400 WORDS)


Methods development for epidemiologic investigations of the health effects of prolonged ozone exposure. Part I: Variability of pulmonary function measures.
The acute and subacute effects of ambient concentrations of ozone on lung function have been studied extensively in a variety of settings. Such studies generally have focused on measures of function that reflect either lung volumes or flows that are influenced by the physiology of large and small airways (e.g., forced expiratory volume in one second [FEV1). Data from animal studies suggest that the effects of prolonged exposure to elevated ambient concentrations of ozone result in abnormalities in the centriacinar region of the lung; and dosimetry models for humans predict that long-term exposure to ozone could impact the same areas of the human lung. However, alterations in structure at this level of the lung are not well reflected by measuring FEV1 until substantial structural changes have occurred. Measures of the lung function that reflect the functional mechanics of airways smaller than 2 mm in diameter are considered to be more relevant. At least one epidemiologic study has provided evidence that small-airway functions may be relevant to effects of prolonged exposure to environments with high concentrations of oxidants. A considerable body of physiologic data has established that flow rates measured during the terminal portion of a maximum expiratory flow-volume (MEFV) curve are largely governed by airways smaller than 2 mm in diameter A similar interpretation has been given to changes in the slope of phase III (delta N2) of the single-breath nitrogen washout (SBNW) curve. Despite the attractiveness of these measures in relation to airway physiology, some data suggest that measurements of flow via the terminal portions of MEFV and SBNW curves have much greater within-subject variability than forced vital capacity (FVC and FEV1. The present study was undertaken as part of a larger feasibility study to develop methods to study the effects of prolonged exposure to elevated ambient ozone levels on lung function in adolescents. A convenience sample of 239 freshmen (ages 16-20 years) entering the University of California, Berkeley were recruited to participate in this protocol. All were lifelong residents of the San Francisco Bay Area or the Los Angeles Basin. Subjects were studied on two occasions five to seven days apart. At each test session, subjects performed up to eight forced expiratory maneuvers to produce three acceptable and reproducible MEFV curves by modified American Thoracic Society criteria. Tests of SBNW were then performed on the basis of detailed criteria for validity and reproducibility. Eight attempts to generate three curves were allowed. The delta N2 was obtained by a least-squares regression of nitrogen concentrations between the 750-mL and 1750-mL volume points. Instantaneous flow at 75% of expired volume (FEF75%), average flow between the 25% and 75% volume points (FEF25%-75%), and delta N2 were the principal outcomes. Variance components were estimated with a nested random effects model with adjustments for important covariates. The average within-subject coefficients of variation (+/-SD of distribution of means) for male subjects were: FEV1 1.2 (+/-0.8); FEF25%-75% 3.2 (+/-2.3); FEF75% 5.8 (+/-5.0); and delta N2 17.9 (+/-12.3); for female subjects they were: FEV1 1.4 (+/-0.9); FEF25%-75% 3.0 (+/-2.2); FEF75% 6.2 (+/-5.2); and delta N2 19.9 (+/-17.0). The variance attributed to test session was less than 1% for all measures. The percentages of variance due to within-subject variation for each measure (adjusted for sex, area of residence, ethnicity, and height) were: FVC 3.6%; FEV1 3.0%; FEF25%-75% 5.2%; FEF75% 8.9%; and delta N2 23.9%. Of all subjects tested, 234 (97.9%) could provide at least two acceptable MEFV curves, but only 218 (91.2%) could provide at least two acceptable SBNW curves. The results were unchanged by recent history of acute, respiratory illness.(ABSTRACT TRUNCATED)


Fetal growth in maternal anaemia.
The effect of maternal iron deficiency anemia on fetal growth was studied in 54 anaemic (haemoglobin < 11.0 g/dl) mothers. Twenty-two mothers served as controls (haemoglobin > or = 11.0 g/dl). All the women had singleton live births at term gestation. The maternal iron status was assessed by serum ferritin estimation. The birth weight, head circumference, chest circumference, mid-arm circumference, and crown heel length were significantly low in infants born to women with moderate (haemoglobin 6.1 +/- 8.5 g/dl) and severe anaemia (haemoglobin < or = 6.0 g/dl), in comparison to infants born to non-anaemic women. Similarly, birth weight, mid-arm circumference, and crown-heel length were significantly low in infants of women with depleted iron stores (serum ferritin < 10 micrograms/l) than in infants of women with serum ferritin levels of 20 micrograms/l or more. All indices of fetal growth showed linear relationships with maternal haemoglobin, as well as with serum ferritin. The growth retarding effect of maternal anaemia was more on fetal birth weight and mid-arm circumference than on other anthropometric indices of the newborn.


Mitigation of pennyroyal oil hepatotoxicity in the mouse.
Pennyroyal oil ingestion has been associated with severe hepatotoxicity and death. The primary constituent, R-(+)-pulegone, is metabolized via hepatic cytochrome P450 to toxic intermediates. The purpose of this study was to assess the ability of the specific cytochrome P450 inhibitors disulfiram and cimetidine to mitigate hepatotoxicity in mice exposed to toxic levels of R-(+)-pulegone. 20-g female BALB/c mice were pretreated with either 150 mg/kg of cimetidine intraperitoneal (IP), 100 mg/kg of disulfiram IP, or both. After one hour, mice were administered 300 mg/kg of pulegone IP and were killed 24 hours later. Data were analyzed using ANOVA. Post-hoc t-tests used Bonferroni correction. There was a tendency for lower serum glutamate pyruvate transaminase in the disulfiram and cimetidine groups compared with the R-(+)-pulegone group. The differences were significant for both the cimetidine and the combined disulfram and cimetidine groups compared with the R-(+)-pulegone group. Pretreatment with the combination of disulfiram and cimetidine most effectively mitigated R-(+)-pulegone-induced hepatotoxicity. Within the limitations of a pretreatment animal model, the combination of cimetidine and disulfiram significantly mitigates the effects of pennyroyal toxicity and does so more effectively than either agent alone. These data suggest that R-(+)-pulegone metabolism through CYP1A2 appears to be more important in the development of a hepatotoxic metabolite than does metabolism via CYP2E1.


Stable and specific expression of 4-coumarate:coenzyme A ligase gene (4CL1) driven by the xylem-specific Pto4CL1 promoter in the transgenic tobacco.
The ability of 4-coumarate:coenzyme A ligase promoter from Populus tomentosa (Pto4CL1p) to drive expression of the GUS reporter gene and 4-coumarate:coenzyme A ligase gene in tobacco has been studied using transgenic plants produced by Agrobacterium-mediated transformation. Intense GUS histochemical staining was detected in the xylem of stem in transgenic tobacco plants carrying the 1140 bp Pto4CL1p promoter. To further investigate the regulation function of the tissue-specific expression promoter, Pto4CL1p, a binary vector containing Pto4CL1p promoter fused with 4CL1 gene was transferred into tobacco. The activity of the 4CL1 enzyme doubled in the stems of transgenic tobacco but did not increase in the leaves. The content of lignin was increased 25% in the stem but there was no increase in the leaves of transgenic tobacco.


Interplay of sequence, conformation, and binding at the Peptide-titania interface as mediated by water.
The initial stages of the adsorption of a hexapeptide at the aqueous titania interface are modeled using atomistic molecular dynamics simulations. This hexapeptide has been identified by experiment [Sano, K. I.; Shiba, K. J. Am. Chem. Soc. 2003, 125, 14234] to bind to Ti particles. We explore the current hypothesis presented by these authors that binding at this peptide-titania interface is the result of electrostatic interactions and find that contact with the surface appears to take place via a pair of oppositely charged groups in the peptide. Our data indicate that the peptide may initially recognize the water layers at the interface, not the titania surface itself, via these charged groups. We also report results of simulations for hexapeptide sequences with selected single-point mutations for alanine and compare these behaviors with those suggested from observed binding affinities from existing alanine scan experiments. Our results indicate that factors in addition to electrostatics also contribute, with the structural rigidity conferred by proline suggested to play a significant role. Finally, our findings suggest that intrapeptide interaction may provide mechanisms for surface detachment that could be detrimental to binding at the interface.


Photocatalytic activity for hydrogen evolution of electrospun TiO2 nanofibers.
We report herein a simple procedure for the fabrication of TiO2 nanofibers by the combination of electrospinning and sol-gel techniques by using poly(vinylpyrrolidone) (PVP), titanium(IV) butoxide, and acetylacetone in methanol as a spinning solution. TiO2 nanofibers (260-355 nm in diameter), with a bundle of nanofibrils (20-25 nm in diameters) aligned in the fiber direction, or particle-linked structures were obtained from the calcination of as-spun TiO2/PVP composite fibers at temperatures ranging from 300 to 700 degrees C. These nanofibers were utilized as photocatalysts for hydrogen evolution. The nanofiber photocatalyst calcined at 450 degrees C showed the highest activity among the TiO2 nanofibers tested such as ones prepared by the hydrothermal method and anatase nanoparticles (Ishihara ST-01). These results indicate that one-dimensional electrospun nanofibers with highly aligned bundled nanofibrils are beneficial for enhancement of the crystallinity, large surface area, and higher photocatalytic activity.


Preparation of DNA-adsorbed TiO2 particles with high performance for purification of chemical pollutants.
Photocatalysis using semiconductors such as titanium dioxide (TiO2) has been studied and applied to the treatment of wastewater and purification of air, because of its ability to decompose organic contaminants. However, there are still problems associated with the practical application of photocatalytic reactions, one of which is that contact between the reactants and catalysts is absolutely required, because the reaction occurs atthe surface of the catalysts. This restrictsthe purification of pollutants on a large scale. In this study, we developed novel DNA-adsorbed TiO2 particles (DNA-TiO2) to solve the problem. Because DNA has an unique double-stranded structure and interacts with several chemicals, DNA-TiO2 can accumulate chemicals on the surface of TiO2. DNA intercalators (Methylene Blue and ethidium bromide), small amounts of which exist in large-volume solutions, were instantaneously trapped in DNA-TiO2 and degraded under ultraviolet (UV) light rapidly, compared to nonadsorbed TiO2. The efficiency of removal and photocatalytic degradation was dependent on the amount of DNA adsorbed on the surface of TiO2 and was independent of the size of DNA. Even if the pH (2-10) and temperature (approximately 56 degrees C) of the solution were changed, DNA remained stable on TiO2, and the ability to remove intercalators was also maintained. DNA-TiO2 could accumulate other pigments such as Acridine Orange, Orange II, Neutral Red, Brilliant Green, and Crystal Violet. These results suggested that DNA-TiO2 is beneficial for the removal and degradation of chemicals having affinity for DNA and dispersing in a large field.


Congenital hypothyroidism: diagnosis, treatment, and prognosis.
Congenital hypothyroidism is a common but preventable cause of mental retardation. The incidence of congenital hypothyroidism in the newborn population is about 1:3500 to 1:4000. Infants with Down's syndrome are at a special risk. Fort et al. reported an incidence of persistent primary congenital hypothyroidism in infants with Down's syndrome of 1:141 or 28 times higher than the general newborn population. Premature infants have varying degrees of immaturity of hypothalamic-pituitary-thyroid system and are at a special risk for a variety of thyroid disorders. These patients need adequate understanding and interpretation of their laboratory values before institution of replacement hormonal therapy. Screening programs are available in 48 states and have led to prompt diagnosis and recognition of most cases that would otherwise be missed. Prevention of mental retardation depends on early and adequate treatment. This requires close cooperation between the program and the physicians involved in the care of the infant. Many state screening programs maintain a list of experts who are available for consultation, if necessary.


Thyroid disease.
Hyperthyroidism and hypothyroidism are common disorders in the elderly and may remain unrecognised until a patient presents with an apparently unrelated problem. The finding of an elevated level of thyroid stimulating hormone (TSH) with a normal serum thyroxine (T4) level represents "subclinical hypothyroidism", which does not necessarily require treatment. Iodine can precipitate hyperthyroidism in patients with autonomous thyroid tissue and the iodine-rich antiarrhythmic agent, amiodarone, may cause either hyperthyroidism or hypothyroidism. The metabolism and clearance of numerous therapeutic agents is altered when thyroid status is abnormal, so that dose adjustment may be necessary. In cardiac failure secondary to hyperthyroidism, great care must be taken in prescribing beta-blockers and diuretics; dosage of digitalis preparations may need to be increased. Thyroid replacement therapy can aggravate myocardial ischaemia and it may be appropriate to consider coronary artery bypass grafting before hypothyroidism is fully corrected. Antithyroid drugs, surgery and radioactive iodine all have a place in the treatment of hyperthyroidism in the elderly, depending on factors such as disease severity and the characteristics of the goitre. T4 may be given together with an antithyroid drug in a "block-replace" regimen.


Conditions for imaging emulsions in the environmental scanning electron microscope.
Environmental scanning electron microscopy (ESEM) is a technique capable of imaging volatile and/or insulating samples in their natural state, without prior specimen preparation. It is thus a powerful potential tool for the study of the structure and dynamics of emulsions and other complex liquid systems, at a resolution greater than that obtainable by conventional optical microscopy. We present images of a variety of liquid systems containing micron-scale and smaller features. The morphology of these systems may be clearly discerned. The contrast observed between the liquid phases was consistent with the model proposed by Stokes et al. (1998). The limits of resolution were determined by sample motion and by beam damage effects; under optimum conditions, resolution of a few tens of nanometers was obtained. This compares favourably with conventional and confocal optical microscopy. In some samples, thin films (solid or liquid) could be observed at the liquid/gas interface. Some of these films were so thin that they did not completely obscure the underlying structure of the bulk sample.


Clinical management and outcomes of patients with Hermansky-Pudlak syndrome pulmonary fibrosis evaluated for lung transplantation.
Pulmonary fibrosis is a progressive, fatal manifestation of Hermansky-Pudlak syndrome (HPS). Some patients with advanced HPS pulmonary fibrosis undergo lung transplantation despite their disease-associated bleeding tendency; others die while awaiting donor organs. The objective of this study is to determine the clinical management and outcomes of a cohort with advanced HPS pulmonary fibrosis who were evaluated for lung transplantation. Six patients with HPS-1 pulmonary fibrosis were evaluated at the National Institutes of Health Clinical Center and one of two regional lung transplant centers. Their median age was 41.5 years pre-transplant. Three of six patients died without receiving a lung transplant. One of these was referred with end-stage pulmonary fibrosis and died before a donor organ became available, and donor organs were not identified for two other patients sensitized from prior blood product transfusions. Three of six patients received bilateral lung transplants; they did not have a history of excessive bleeding. One patient received peri-operative desmopressin, one was transfused with intra-operative platelets, and one received extracorporeal membrane oxygenation and intra-operative prothrombin complex concentrate, platelet transfusion, and desmopressin. One transplant recipient experienced acute rejection that responded to pulsed steroids. No evidence of chronic lung allograft dysfunction or recurrence of HPS pulmonary fibrosis was detected up to 6 years post-transplant in these three lung transplant recipients. In conclusion, lung transplantation and extracorporeal membrane oxygenation are viable options for patients with HPS pulmonary fibrosis. Alloimmunization in HPS patients is an important and potentially preventable barrier to lung transplantation; interventions to limit alloimmunization should be implemented in HPS patients at risk of pulmonary fibrosis to optimize their candidacy for future lung transplants.


Estimation of 10-Year Risk of Coronary Heart Disease in Nepalese Patients with Type 2 Diabetes: Framingham Versus United Kingdom Prospective Diabetes Study.
Predicting future coronary heart disease (CHD) risk with the help of a validated risk prediction function helps clinicians identify diabetic patients at high risk and provide them with appropriate preventive medicine. The aim of this study is to estimate and compare 10-year CHD risks of Nepalese diabetic patients using two most common risk prediction functions: The Framingham risk equation and United Kingdom Prospective Diabetes Study (UKPDS) risk engine that are yet to be validated for Nepalese population. We conducted a hospital-based, cross-sectional study on 524 patients with type 2 diabetes. Baseline and biochemical variables of individual patients were recorded and CHD risks were estimated by the Framingham and UKPDS risk prediction functions. Estimated risks were categorized as low, medium, and high. The estimated CHD risks were compared using kappa statistics, Pearson's bivariate correlation, Bland-Altman plots, and multiple regression analysis. The mean 10-year CHD risks estimated by the Framingham and UKPDS risk functions were 17.7 ± 12.1 and 16.8 ± 15 (bias: 0.88, P > 0.05), respectively, and were always higher in males and older age groups (P < 0.001). The two risk functions showed moderate convergent validity in predicting CHD risks, but differed in stratifying them and explaining the patients' risk profile. The Framingham equation predicted higher risk for patients usually below 70 years and showed better association with their current risk profile than the UKPDS risk engine. Based on the predicted risk, Nepalese diabetic patients, particularly those associated with increased numbers of risk factors, bear higher risk of future CHDs. Since this study is a cross-sectional one and uses externally validated risk functions, Nepalese clinicians should use them with caution, and preferably in combination with other guidelines, while making important medical decisions in preventive therapy of CHD.


Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study.
Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans. In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity (P<0.0001), a 34% increase in HDL cholesterol (P<0.0001), and a 7% decrease in LDL cholesterol (P=0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL2, HDL3, and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests. We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects (P=0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.


Simultaneous Reduction and Functionalization of Graphene Oxide by 4-Hydrazinobenzenesulfonic Acid for Polymer Nanocomposites.
Graphene oxide (GO) was functionalized and reduced simultaneously by a new reductant, 4-hydrazinobenzenesulfonic acid (HBS), with a one-step and environmentally friendly process. The hydrophilic sulfonic acid group in HBS was grafted onto the surface of GO through a covalent bond. The successful preparation of HBS reduced GO (HBS-rGO) was testified by scanning electron microscope (SEM), X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared spectra (FTIR), X-ray photoelectron spectroscopic (XPS) and thermogravimetric analysis (TGA). The interlayer space of HBS-rGO was increased to 1.478 nm from 0.751 nm for GO, resulting in a subdued Van der Waals' force between layers and less possibility to form aggregations. The aqueous dispersibility of graphene was improved to 13.49 mg/mL from 0.58 mg/mL after the functionalization. The viscosity of the epoxy resin based HBS-rGO composite could be regulated by an adjustment of the content of HBS-rGO. This study provides a new and applicable approach for the preparation of hydrophilic functionalized graphene, and makes it possible for the application of graphene in some functional polymer nanocomposites, such as specialty water-based coatings.


Japan Society of Hepatology guidelines for sarcopenia in liver disease (1st edition): Recommendation from the working group for creation of sarcopenia assessment criteria.
Sarcopenia is defined by muscle loss and muscle dysfunction. Sarcopenia is classified into primary and secondary types, based on the cause. Primary sarcopenia is mainly aging-related sarcopenia, whereas secondary sarcopenia is the reduced muscle mass and strength that accompanies an underlying disease. Given the essential role of the liver in metabolism, secondary sarcopenia due to nutritional disorders or other factors can frequently occur in liver disease. In 2015, the Japan Society of Hepatology (JSH) decided to establish its own assessment criteria for sarcopenia in liver disease because the number of liver disease patients with sarcopenia is expected to increase and there is cumulative evidence to indicate sarcopenic patients have poor clinical outcomes. A working group to create assessment criteria for sarcopenia has thus been established by the JSH. In this article, we summarize the current knowledge with regard to sarcopenia and present the assessment criteria for sarcopenia in liver disease proposed by the JSH (1st edition). To the best of our knowledge, this is globally the first proposed assessment criteria for sarcopenia specializing in liver disease.


Human osteogenic protein-1 induces osteogenic differentiation of adipose-derived stem cells harvested from mice.
Osteogenic protein-1 (OP-1) has been shown to stimulate undifferentiated cells to produce mineralized tissue. Adipose tissue is a rich source of undifferentiated cells for tissue engineering purposes. The purpose of this study was to investigate the effect of OP-1 on osteogenic differentiation of adipose-derived stem cells and the production of bony tissue in vitro. Adipose-derived stem cells (ADSCs) were isolated from inguinal fat pads of adult mice. Following cell expansion the cells were plated in 8-well chambered slides. The cells received one of four treatments: Group 1 cells were maintained in control medium, Group 2 cells were cultured in a common osteogenic medium, Group 3 cells were cultured in osteogenic medium supplemented with 250ng/mL of OP-1, and Group 4 cells were cultured with 250ng/mL of OP-1 added to control medium. Osteogenic differentiation of ADSCs was determined by estimating the number and size of mineralized nodules, and the amount of extracellular osteopontin secreted into cell culture medium. Mineralized nodule production was assessed at day 21 with von Kossa staining. Extracellular osteopontin release was measured after 8 and 21 days by enzyme-linked immunosorbant assay (ELISA). ANOVA/Tukey tests were used to identify differences among the four treatment groups for mineralized nodule production and osteopontin release (p<or=0.05). Deposition of calcified nodules and osteopontin secretion was significantly greater for cell cultures incubated with OP-1 (p<or=0.05). At day 21, no significant differences in osteopontin secretion were noted among groups incubated with osteogenic nutrients and/or OP-1 (p>0.05), which were significantly higher than the group incubated in cell growth medium only (p<or=0.05). No significant differences in osteopontin secretion were noted between 8 and 21 days for any group (p>0.05). Linear regression analysis demonstrated a linear relationship was present between the presence of calcified nodules and the amount of osteopontin released (p<or=0.05). OP-1 is a powerful inducer of osteogenic differentiation of adult adipose-derived stem cells.


Placement of free gingival grafts on denuded alveolar bone. Part I: clinical evaluations.
Fourteen patients were examined and determined to lack an adequate zone of attached gingiva in the mandibular incisor region. Each patient was treated on the left side of the mandible by placement of a free gingival graft on denuded bone and 12 of the 14 patients received a free gingival graft on retained periosteum in the right mandibular anterior region. Two patients were treated on the right side by either bone denudation or periosteal bed preparation without graft placement to permit histological evaluation of wound healing under these circumstances. Grafts were retained for time intervals from 1 week to 24 weeks. All patients were evaluated clinically for graft "take", graft healing, graft shrinkage, and graft mobility.


Diagnosis of prion diseases.
Prion diseases are usually diagnosed clinically and confirmed by post-mortem histopathological examination of brain tissue. The only reliable molecular marker for prion diseases is PrP(Sc), the pathological conformer of the prion protein that accumulates in the central nervous system and, to a lesser extent, in lymphoreticular tissues. For BSE, several commercial diagnostic kits based on the post-mortem immunochemical detection of PrP(Sc) in brain tissue are now available. These rapid screening tests have been used in active surveillance of BSE and have greatly improved the detection of infected cattle before their entry into the human food chain. At present, no diagnostic test exists for the detection of prion diseases in live animals or humans. New diagnostic techniques aimed at increasing sensitivity and specificity of PrP(Sc) detection in body fluids and at identifying novel surrogate markers are under development. In this report, we review the classical diagnostic methods as well as present and future tools for the diagnosis of prion diseases.


PATTERNS OF FRUIT-SET: WHAT CONTROLS FRUIT-FLOWER RATIOS IN PLANTS?
Fruit-set values for 447 species of plants were examined for variations due to compatibility, breeding system, life form, latitude, type of fruit, and type of pollination. The results indicate significant differences between self-compatible and self-incompatible species in terms of 1) average fruit-set and 2) the effect of the independent variables. Breeding system, life form, and latitude were found to be the only significant independent variables for self-incompatible species, while fruit type and latitude were found to be significant for self-compatible plants. Although latitude was a significant variable for self-compatible and self-incompatible species, it was correlated with other variables and may actually have no direct effect on fruit-flower ratios in plants. Hypotheses explaining the effect of the significant independent variables on fruit-flower ratios were then examined and, when possible, predictions were tested. The results indicate that the selective-abortion and bet-hedging hypotheses may be important factors contributing to the low fruit-set in self-incompatible plants, while the male-function hypothesis may explain the lower fruit-flower ratios in hermaphrodites.


Improvement of vertigo symptoms after 2 months of Vertigoheel treatment: a case series in patients with bilateral vestibulopathy and functional dizziness.
Dizziness is a common leading symptom in bilateral vestibulopathy (BVP) and functional dizziness (FD), with significant negative effects on functional ability and quality of life. Vertigoheel is a widely used non-prescription drug for the treatment of vertigo. In order to generate systematic data for Vertigoheel in BVP and FD, we conducted a non-interventional study assessing vertigo symptoms. This study was conducted as an open-label, prospective, monocentric, non-interventional case series (ClinicalTrials.gov identifier NCT05897853). Patients with BVP and FD received Vertigoheel according to market approval for an observational period of 2 months. Change from baseline after 2 months was assessed for the following endpoints: Dizziness Handicap Inventory (DHI) as the primary endpoint, quality of life (QoL) by EQ-5D-5L, and body sway by static posturography. Patients with FD were additionally assessed for depression and anxiety by PHQ-9 and GAD-7 questionnaires. Patients with BVP were assessed for vestibular function by video head impulse testing and caloric testing. Adverse events and other safety-related observations were evaluated. Of 41 patients with FD and 13 with BVP, two with FD and none with BVP dropped out before the follow-up visit. Both patient groups showed significantly improved disability caused by dizziness after 2 months: In BVP, the DHI decreased on average by 13.2 points from 45.4 to 32.2 (p < 0.001). In FD, the DHI decreased on average by 12.0 points from 46.5 to 34.5 (p < 0.001). In patients with FD, significant improvements were also observed for the secondary endpoints QoL, anxiety, and depression. No significant change was observed for posturography readouts. In patients with BVP, there were no statistically significant improvements for the secondary endpoints QoL, posturography, or vestibular function within the observation period. The study found no evidence of a safety risk. The study provides evidence for Vertigoheel's clinical safety and limited evidence - because of the non-interventional design - for its effectiveness in BVP and FD that are considered disease entities with high medical need for new treatment options. The results may serve as the basis for randomized placebo-controlled trials.


Anticancer drugs induce mdr1 gene expression in recurrent ovarian cancer.
Ovarian cancer is currently the most lethal gynecologic malignancy in Europe and the US. Platin analogues and paclitaxel demonstrate high remission rates, but unfortunately the efficacy of cytostatic agents is limited by the development of multidrug resistance (mdr). Clinical paclitaxel resistance is often associated with mdr1 overexpression. In a recent study, we introduced a highly specific quantitative real-time reverse transcriptase polymerase chain reaction for the quantification of mdr1 transcripts. In the present study, we demonstrate that primary tumor cells from patients with recurrent ovarian cancer overexpress mdr1. To evaluate mdr1 expression, we collected tumor cells from 77 ovarian cancer patients (13 chemotherapy-naive ovarian cancer, 64 recurrent ovarian cancer). Cancer cells were aspirated from 49 solid specimens (63%) and 28 ascitic fluids (37%). Subsequently, cancer cells were exposed in 221 short-term cultures either to blank medium (control) or to a single anticancer drug, cisplatin, doxorubicin or paclitaxel. The drug concentrations applied referred to clinical relevant doses. mdr1 mRNA expression was significantly higher in specimens from recurrent ovarian cancer incubated in paclitaxel than in specimens from chemotherapy-naive ovarian cancer. No significant differences were detectable between the mean value of mdr1 mRNA expression in tumor specimens from recurrent ovarian cancer incubated in cisplatin or doxorubicin. Differences within the untreated patients group were also not statistically significant. The result of this study confirms clinical observations, as well as in-vitro studies based on tumor cell lines, that paclitaxel resistance is correlated with mdr1 overexpression.


A Green Route to Conjugated Polyelectrolyte Interlayers for High-Performance Solar Cells.
Synthesis of fluorene-based conjugated polyelectrolytes was achieved via Suzuki polycondensation in water and completely open to air. The polyelectrolytes were conveniently purified by dialysis and analysis of the materials showed properties expected for fluorene-based conjugated polyelectrolytes. The materials were then employed in solar cell devices as an interlayer in conjunction with ZnO. The double interlayer led to enhanced power conversion efficiency of 10.75 % and 15.1 % for polymer and perovskite solar cells, respectively.


Host DNA damage response factors localize to merkel cell polyomavirus DNA replication sites to support efficient viral DNA replication.
Accumulating evidence indicates a role for Merkel cell polyomavirus (MCPyV) in the development of Merkel cell carcinoma (MCC), making MCPyV the first polyomavirus to be clearly associated with human cancer. With the high prevalence of MCPyV infection and the increasing amount of MCC diagnosis, there is a need to better understand the virus and its oncogenic potential. In this study, we examined the relationship between the host DNA damage response (DDR) and MCPyV replication. We found that components of the ATM- and ATR-mediated DDR pathways accumulate in MCPyV large T antigen (LT)-positive nuclear foci in cells infected with native MCPyV virions. To further study MCPyV replication, we employed our previously established system, in which recombinant MCPyV episomal DNA is autonomously replicated in cultured cells. Similar to native MCPyV infection, where both MCPyV origin and LT are present, the host DDR machinery colocalized with LT in distinct nuclear foci. Immunofluorescence in situ hybridization and bromodeoxyuridine (BrdU) incorporation analysis showed that these DDR proteins and MCPyV LT in fact colocalized at the actively replicating MCPyV replication complexes, which were absent when a replication-defective LT mutant or an MCPyV-origin mutant was introduced in place of wild-type LT or wild-type viral origin. Inhibition of DDR kinases using chemical inhibitors and ATR/ATM small interfering RNA (siRNA) knockdown reduced MCPyV DNA replication without significantly affecting LT expression or the host cell cycle. This study demonstrates that these host DDR factors are important for MCPyV DNA replication, providing new insight into the host machinery involved in the MCPyV life cycle. MCPyV is the first polyomavirus to be clearly associated with human cancer. However, the MCPyV life cycle and its oncogenic mechanism remain poorly understood. In this report, we show that, in cells infected with native MCPyV virions, components of the ATM- and ATR-mediated DDR pathways accumulate in MCPyV LT-positive nuclear foci. Such a phenotype was recapitulated using our previously established system for visualizing MCPyV replication complexes in cells. By combining immunofluorescent staining, fluorescence in situ hybridization, and BrdU incorporation analysis, we demonstrate that DDR proteins are important for maintaining robust MCPyV DNA replication. This study not only provides the first look into the microscopic details of DDR factor/LT replication complexes at the MCPyV origin but also provides a platform for further studying the mechanistic role of host DDR factors in the MCPyV life cycle and virus-associated oncogenesis.


Cyclotides as drug design scaffolds.
Cyclotides are ultra-stable peptides derived from plants. They are around 30 amino acids in size and are characterized by their head-to-tail cyclic backbone and cystine knot. Their exceptional stability and tolerance to sequence substitutions has led to their use as frameworks in drug design. This article describes recent developments in this field, particularly developments over the last two years relating to the grafting of bioactive peptide sequences into the cyclic cystine knot framework of cyclotides to stabilize the sequences. Grafted cyclotides have now been developed that interact with protein or enzyme targets, both extracellular and intracellular, as well as with cell surface receptors and membranes.


Chronic exposure to kappa-opioids enhances the susceptibility of immortalized neurons (F-11kappa 7) to apoptosis-inducing drugs by a mechanism that may involve ceramide.
Chronic exposure of embryonic brain to opioids leads to microcephaly and developmental abnormalities. An immortalized mouse neuroblastoma x dorsal root ganglion hybrid cell line stably transfected to overexpress kappa-opioid receptors (F-11kappa7) showed complete loss of kappa-receptor binding to [3H]U69,593 after exposure to the kappa-agonist U69,593 for 24 h. U69,593 had no measurable effect on cell viability as determined by either cell viability or DNA fragmentation assays. However, when cell death (apoptosis) was induced by either staurosporine or the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002, cells pretreated with U69,593 for 24 h showed increased apoptosis compared with untreated cells. Thus, staurosporine (50 nM), wortmannin (4 microM), and LY294002 (30 microM) treatment for 24 h induced a 50% loss of cell viability and DNA fragmentation in 24 h. U69,593 pretreatment produced the same killing at lower concentrations, namely, 20 nM staurosporine, 2 microM wortmannin, and 14 microM LY294002, respectively. The effects of U69,593 were time-, dose-, and naloxone-reversible, suggesting that they are receptor-mediated. However, coaddition of U69,593 at the same time as staurosporine, wortmannin, or LY294002 did not enhance apoptosis. All three drugs that induced apoptosis were found to increase the level of ceramide, and pretreatment with U69,593 further increased the rate of formation of ceramide, a lipid that induces apoptosis in cells. We propose that chronic exposure to kappa-receptor agonists promotes increased vulnerability of neurons to apoptosis.


Self DNA from lymphocytes that have undergone activation-induced cell death enhances murine B cell proliferation and antibody production.
Systemic lupus erythematosus (SLE) is characterized by prominent autoinflammatory tissue damage associated with impaired removal of dying cells and DNA. Self DNA-containing immune complexes are able to activate both innate and adaptive immune responses and play an important role in the maintenance and exacerbation of autoimmunity in SLE. In this study, we used DNA from lymphocytes that have undergone activation-induced cell death (ALD-DNA) and analyzed its role on the activation and differentiation of B cells from normal BALB/c mice as well as lupus-prone MRL+/+ and MRL/lpr mice. We found that ALD-DNA directly increased the expression of costimulatory molecules and the survival of naïve B cells in vitro. Although ALD-DNA alone had little effect on the proliferation of naïve B cells, it enhanced LPS-activated B cell proliferation in vitro and in vivo. In addition, ALD-DNA increased plasma cell numbers and IgG production in LPS-stimulated cultures of naïve B cells, in part via enhancing IL-6 production. Importantly, B cells from lupus mice were hyperresponsive to ALD-DNA and/or LPS relative to normal control B cells in terminal plasma cell differentiation, as evidenced by increases in CD138+ cell numbers, IgM production, and mRNA levels of B lymphocyte-induced maturation protein-1 (Blimp-1) and the X-box binding protein 1 (XBP1). Furthermore, ALD-DNA enhanced CD40-activated naïve B cell proliferation. Collectively, these data indicate that self DNA can serve as a DAMP (damage-associated molecular pattern) that cooperates with signals from both innate and adaptive immunity to promote polyclonal B cell activation, a common characteristic of autoimmune diseases.


Oligosaccharide structures mediating agglutination of sheep erythrocytes by Staphylococcus saprophyticus.
Agglutination of sheep erythrocytes by Staphylococcus saprophyticus was used as a model system for adherence studies. Glycolipids were isolated from sheep erythrocyte membranes, and oligosaccharides were prepared by trifluoroacetolysis. The oligosaccharides were characterized by sugar analyses, methylation analyses, gas-liquid chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy. We showed that oligosaccharides containing terminal beta-D-galactose-p-(1-4)-beta-D-2-acetamido-2-deoxyglucose-p-(1- were good inhibitors of the hemagglutination of sheep erythrocytes by S. saprophyticus.


Atlas-based relaxometry and subsegment analysis of the substantia nigra pars compacta using quantitative MRI: a healthy volunteer study.
Parkinson's disease is a neurodegenerative disorder caused by neuronal cell loss in the substantia nigra pars compacta (SNpc). We aimed to perform atlas-based relaxometry using an anatomical SNpc atlas and obtain baseline values of SNpc regions in healthy volunteers. Neuromelanin (NM)-sensitive imaging of the midbrain and whole-brain 3D T1 weighted images of 27 healthy volunteers (20 males; aged 36.3 ± 11.5 years) were obtained. An anatomical SNpc atlas was created using NM-sensitive images in standard space, and divided into medial (MG), dorsal (DG), and ventrolateral (VG) groups. Proton density (PD), T1, and T2 values in these regions were obtained using quantitative MRI. The relationships between PD, T1, and T2 values in each SNpc region and age were evaluated. The VG PD value was significantly higher than the MG and DG values. MG, DG, and VG T1 values were significantly different, whereas the T2 value of the MG was significantly lower than the DG and VG values. Moreover, a significant negative correlation between PD and T1 values of the MG and age was observed. The PD, T1, and T2 values of the SNpc regions measured in standard space using an anatomical atlas can be used as baseline values. PD and T1 values of the SNpc regions may be associated with NM concentrations. An anatomical SNpc atlas was created using NM-sensitive MRI and can be used for the quantitative evaluation of subsegments of the SNpc in standard space.


Mistakes that heterosexual people make when trying to appear non-prejudiced: the view from LGB people.
In two studies, lesbians, gay men and bisexuals were queried concerning mistakes that well-meaning heterosexual people have made when interacting with them. In qualitative, open-ended research, we determined that the most common mistakes concerned heterosexuals' pointing out that they know someone who is gay, emphasizing their lack of prejudice, and relying on stereotypes about gays. Following up with a quantitative, close-ended questionnaire, we determined that the mistakes respondents experienced most often involved heterosexuals (a) relying on stereotypes and (b) ignoring gay issues; the most annoying mistakes were heterosexuals (a) using subtle prejudicial language and (b) not owning up to their discomfort with gay issues. We used two theoretical perspectives, shared reality theory and the contact hypothesis, to analyze the quantitative responses. Implications for intergroup relationships between heterosexual people and gay people are discussed.


Implications of axillary sentinel lymph node biopsy in immediate autologous breast reconstruction.
For patients with invasive breast cancer, if the results of an axillary sentinel node biopsy are determined to be positive after permanent pathologic examination, the current recommendation is to perform a complete axillary node dissection. Subsequent axillary surgery may compromise the blood supply to an immediate autologous breast reconstruction. The purpose of this study was to determine which clinicopathologic factors in clinically node-negative breast cancer patients may be associated with an increased risk of positive axillary nodes. Identification of these factors will allow surgeons to modify their approach to immediate autologous breast reconstruction in these high-risk patients. The relationship between presenting clinicopathologic characteristics and the incidence of axillary metastases was analyzed by chi-square test and multivariate analysis in 167 patients with invasive breast cancer and a clinically negative axilla who underwent modified radical mastectomy with an immediate free transverse rectus abdominis musculocutaneous (TRAM) flap reconstruction. Axillary nodal metastases were found in 35 percent of clinically node-negative breast cancer patients. Multivariate analysis showed that patient age of 50 years or younger (p = 0.019), T2 tumor stage or greater (p = 0.031), and presence of lymphovascular invasion on the initial biopsy specimen (p < 0.001) were independent predictors of axillary metastases in clinically node-negative patients. Based on these results, the authors propose an algorithm for decision making in clinically node-negative breast cancer patients who desire autologous breast reconstruction and sentinel lymph node biopsy. Options for immediate autologous breast reconstruction in patients undergoing mastectomy and axillary sentinel lymph node biopsy that may minimize the risk of vascular damage on reoperation include the use of the internal mammary artery and vein as recipient vessels for a free TRAM flap or a pedicled TRAM flap. If an axillary-based blood supply is used, the authors are considering the use of cadaveric dermis to isolate the pedicle of the flap away from the remaining axillary contents. New developments in breast cancer diagnosis and treatment necessitate a team approach, with increased communication between the breast surgeon and the plastic surgeon in planning surgery for these patients.


[The proteolytic etiopathogenesis of pulmonary emphysema].
Laennec and later workers attributed the aetiopathogenesis of emphysema to mechanical causes. This view has been superseded by the current proteolytic theory. It is now believed that the destruction of the pulmonary parenchyma in emphysema occurs when the homeostatic equilibrium between cellular proteases (polymorphonucleates and macrophages) and serum antiproteases (primarily alpha-1-antitrypsin) which protects the respiratory ways, is disturbed. This imbalance not only produces idiopathic emphysema due to alpha-1-antitrypsin but also post-bronchitic forms due to increased protease release.


Selective IAP inhibition results in sensitization of unstimulated but not CD40-stimulated chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis.
Despite recent advances in therapy, chronic lymphocytic leukaemia (CLL) remains incurable and new treatment strategies are therefore urgently required. Inhibitor of apoptosis proteins (IAPs) are over-expressed in CLL, suggesting both a role in disease pathogenesis and the potential for therapeutic targeting. To explore these questions, we evaluated the effects on primary CLL cells of AZD5582, a novel potent and selective inhibitor of IAPs. AZD5582 at nanomolar concentrations induced extensive degradation of cIAP-1 and cIAP-2, but minimally of X chromosome-linked IAP (XIAP). However, these effects of AZD5582 produced little or no direct cytotoxicity, nor did they sensitize CLL cells to p53-dependent killing by fludarabine or p53-independent killing by dexamethasone. In contrast, AZD5582 significantly enhanced apoptosis induced by the death receptor (DR) agonist tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Importantly, killing by TRAIL plus AZD5582 was independent of adverse prognostic features including TP53 deletion which is strongly associated with chemoresistance in CLL. Coculture experiments involving transfected mouse fibroblasts expressing human CD40L (CD154) to mimic the effect of T cells at sites of tissue involvement showed that CD40 stimulation almost completely prevented the killing of CLL cells by TRAIL plus AZD5582 despite up-regulating TRAIL receptors 1 and 2. In conclusion, our findings confirm the rate-limiting, upstream involvement of IAPs in the extrinsic but not intrinsic apoptotic pathway of CLL cells and suggest that drug combinations that simultaneously activate DRs and inhibit IAPs may have therapeutic potential in patients with CLL who have failed T-cell-depleting chemotherapy.


Deep Learning-based Artificial Intelligence Improves Accuracy of Error-prone Lung Nodules.
Introduction: Early detection of lung cancer is one way to improve outcomes. Improving the detection of nodules on chest CT scans is important. Previous artificial intelligence (AI) modules show rapid advantages, which improves the performance of detecting lung nodules in some datasets. However, they have a high false-positive (FP) rate. Its effectiveness in clinical practice has not yet been fully proven. We aimed to use AI assistance in CT scans to decrease FP. Materials and methods: CT images of 60 patients were obtained. Five senior doctors who were blinded to these cases participated in this study for the detection of lung nodules. Two doctors performed manual detection and labeling of lung nodules without AI assistance. Another three doctors used AI assistance to detect and label lung nodules before manual interpretation. The AI program is based on a deep learning framework. Results: In total, 266 nodules were identified. For doctors without AI assistance, the FP was 0.617-0.650/scan and the sensitivity was 59.2-67.0%. For doctors with AI assistance, the FP was 0.067 to 0.2/scan and the sensitivity was 59.2-77.3% This AI-assisted program significantly reduced FP. The error-prone characteristics of lung nodules were central locations, ground-glass appearances, and small sizes. The AI-assisted program improved the detection of error-prone nodules. Conclusions: Detection of lung nodules is important for lung cancer treatment. When facing a large number of CT scans, error-prone nodules are a great challenge for doctors. The AI-assisted program improved the performance of detecting lung nodules, especially for error-prone nodules.


"Thucydides syndrome" reconsidered: new thoughts on the "Plague of Athens".
A recently published theory (N Engl J Med 1985;313:1027-30) argues that the famous Athenian epidemic of 430 B.C. was caused by a combination of influenza and toxin-producing staphylococci (the "Thucydides syndrome"). Although it is accepted by some medical authorities, and ostensibly supported by identification of modern cases, the theory's plausibility has not been carefully examined. The authors used an epidemiologic approach supplemented by historical and clinical observations to examine the likelihood that a "Thucydides syndrome" could have caused the Athenian epidemic. Arguing against the influenza theory are epidemiologic and clinical features of the disease, mathematical models of the spread of influenza, and empirical observations of epidemic influenza in premodern populations of known size and crowding. The authors conclude that neither influenza nor a "Thucydides syndrome" could have produced the Athenian epidemic. Epidemiologic features suggest either a zoonotic or vectorborne disease, a disease associated with an environmental source, or a respiratory infection with unusual alternative mechanisms of spread.


Case report: From anxiety disorders to psychosis, a continuum in transitional age youth?
To date, among individuals meeting ultra-high risk criteria for psychosis, the relationship between the presence of anxiety disorders and the risk of psychotic transition raises several unanswered questions. This case report describes the clinical progression of a 17-year-old male initially presenting anxious symptoms meeting the DSM-V criteria for panic disorder. The patient also reported social withdraw, mild depressive symptoms, insomnia and fatigue. Over a 6 month period, a gradual onset of subthreshold psychotic symptoms suggested a prodromal phase of a psychotic disorder. A detailed assessment of UHR criteria for psychosis was performed. The overall level of social and occupational functioning was assessed by the SOFAS, which showed a 35% drop over a 12 months period. The CAARMS, has also been administered. The patient met the diagnostic criteria for UHR, APS group. The care plan included psychiatric follow-up, pharmacologic treatment, individual psychological follow-up and individual and familial psychoeducation. Over a 6 months period, the patient did not experienced a first psychotic episode and presented a partial improvement of psychotic symptoms. The DSM-V categorical approach does not seem to adapt well to early clinical presentations in transitional age youth. A transdiagnostic and dimensional approach allows to better identify at-risk patients of psychiatric disorders and implement early intervention strategies.


[Hospitalized children's parents' anxiety in critical care units].
Child hospitalization is a potentially stressful process that affects both patients and family members. Describe the anxiety that the parents of admitted children at a Intensive Care Units, Pediatric (PICU) and/or Neonatal (NICU) during the first week of hospitalization. Observational study descriptive, transversal conducted at the Gregorio Marañón Hospital, in PICU and NICU. The inclusion criteria were: patients who didn't exceed the week admitted but they were at hospital more than one day, patients whose therapeutic effort wasn't limited and spanish-speaker parents. The sample size was 60 parents. We designed a questionnaire to measure sociodemographic variables and others related with the social support. The resulting variable, anxiety like State Anxiety (SA) and Trait Anxiety (TA) were determined by the STAI inventory. All the parents showed anxiety the average females SA was 44.59 (+/- 8.02) while the average of men was 44.32 (+/- 6.69). The results show a TA average of 34.73 (+/- 4.09) in woman and 34.95 (+/- 4.93) in men. 83% of the parents of the sample participated in their child caring, having this variable relationship with level of SA (p<0.05). Moreover 98% of parents understood the information given and were satisfied with it. All the parents presented anxiety, both SA and TA. They felt informed and supported by nurse. All these actions are directed towards an integral attention taking into account the family as the unit.


Genetic variation and posttranslational modification of bovine κ-casein: effects on caseino-macropeptide release during renneting.
Chymosin-induced cleavage of κ-casein (κ-CN) occurs during the first enzymatic phase in milk coagulation during cheese manufacturing, where the hydrophilic C-terminal peptide of κ-CN, named caseino-macropeptide (CMP), is released into the whey. The CMP peptide is known for its rather heterogeneous composition with respect to both genetic variation and multiple posttranslational modifications, including phosphorylation and O-linked glycosylation. An approach of liquid chromatography coupled with mass spectrometry was used to investigate (1) the overall protein profile and (2) the release of various forms of CMP after addition of chymosin to individual cow milk samples from 2 breeds, Danish Jersey (DJ) and Danish Holstein-Friesian (DH). The cows were selected to represent distinct homo- and heterozygous types of the κ-CN genetic variants A, B, and E (i.e., genotypes AA, BB, AB, EE, and AE). Initially, investigation of the protein profile showed milk with κ-CN BB exhibited the highest relative content of κ-CN, whereas AE milk exhibited the lowest, and after 40min of renneting >90% of intact κ-CN was hydrolyzed by chymosin in milk representing all κ-CN genotype. By in-depth analysis of the CMP chromatographic profile, multiple CMP isoforms with 1 to 3 O-linked glycans (1-3 G) and 1 to 3 phosphate groups (1-3 P) were identified, as well as nonmodified CMP isoforms. The number of identified CMP isoforms varied to some extent between breeds (21CMP isoforms identified in DJ, 26CMP isoforms in DH) and between κ-CN genetic variants (CMP variant A being the most heterogeneous compared with CMP B and E), as well as between individual samples within each breed. The predominant forms of glycans attached to CMP were found to be the acidic tetrasaccharide {N-acetyl-neuraminic acid α(2-3)galactose β(1-3)[N-acetyl-neuraminic acid α(2-6)]N-acetyl galactose} or trisaccharides {N-acetyl-neuraminic acid α(2-3)galactose β(1-3)N-acetyl galactose and galactose β(1-3)[N-acetyl-neuraminic acid (α2-6)]N-acetyl galactose}. The CMP release was calculated to follow first-order kinetics and was determined by the measurement of CMP content during renneting. The highest rate of release for all CMP isoforms occurred from 0 to 2min after chymosin addition. Concurring results from both breeds showed that CMP variant A with 1-2 P had the highest reaction rate of CMP release, followed by CMP B 1-2 P and then by CMP E 1-2 P (only in DH). All the identified glycosylated CMP isoforms had lower reaction rates of release compared with that of nonglycosylated CMP, thus glycan modifications seemed to negatively influence the reaction rate of chymosin-induced hydrolysis of κ-CN.


Enhanced exchange-coupling effect in Nd-Fe-B/Fe-B nanocomposite magnet.
Soft phase magnetic Fe-B nanoparticles were prepared by coprecipitation and the hard phase magnetic Nd-Fe-B nanoparticles were obtained from mechanical ball mill of the bulk Nd-Fe-B with a shaker mill. Also mechanical ball mill technique was applied to the mixture of Nd-Fe-B and Fe-B nanoparticles to build up an exchange-coupled nanocomposite magnet. It was loaded in electronic furnace and annealed under a flow of hydrogen at 953 K for 30 min. The exchange coupled interaction of isotropic magnets was characterized by smooth hysteresis loop with a high value of remanence (Mr/Ms > 0.5).