Evidence for the emergence of β-trefoils by 'Peptide Budding' from an IgG-like β-sandwich.
As sequence and structure comparison algorithms gain sensitivity, the intrinsic interconnectedness of the protein universe has become increasingly apparent. Despite this general trend, β-trefoils have emerged as an uncommon counterexample: They are an isolated protein lineage for which few, if any, sequence or structure associations to other lineages have been identified. If β-trefoils are, in fact, remote islands in sequence-structure space, it implies that the oligomerizing peptide that founded the β-trefoil lineage itself arose de novo. To better understand β-trefoil evolution, and to probe the limits of fragment sharing across the protein universe, we identified both 'β-trefoil bridging themes' (evolutionarily-related sequence segments) and 'β-trefoil-like motifs' (structure motifs with a hallmark feature of the β-trefoil architecture) in multiple, ostensibly unrelated, protein lineages. The success of the present approach stems, in part, from considering β-trefoil sequence segments or structure motifs rather than the β-trefoil architecture as a whole, as has been done previously. The newly uncovered inter-lineage connections presented here suggest a novel hypothesis about the origins of the β-trefoil fold itself-namely, that it is a derived fold formed by 'budding' from an Immunoglobulin-like β-sandwich protein. These results demonstrate how the evolution of a folded domain from a peptide need not be a signature of antiquity and underpin an emerging truth: few protein lineages escape nature's sewing table.


An economic and antitrust analysis of the distribution of medical products.
The techniques used to distribute medical products are designed to maximize the manufacturers' profits by charging a relatively low price to hospitals and a relatively high price to other purchasers, such as doctors and nursing homes. This pricing scheme raises complex antitrust problems, including vertical price fixing between the manufacturer and its distributors, price discrimination by the manufacturer, and agreements between the manufacturer and the hospitals restricting the hospitals' ability to resell. This Article examines these antitrust issues.


Brachytherapy for in-stent restenosis in general interventional practice: a single institution's experience using four radiation devices.
The effectiveness of brachytherapy for the treatment of in-stent restenosis (ISR) has been established in a number of large randomized controlled trials. Efficacy of this therapy in general population is less well established. We report our experience of 207 patients, 236 coronary lesions, treated with brachytherapy between November 2000 and November 2002. All commercially available brachytherapy devices, as well as one investigational device, were utilized. This cohort was followed over 9 months and clinical outcomes were obtained with subsequent analysis of patient and lesion-specific characteristics. Average treatment age was 62.5 years; 73% were male and the most frequent presentation was unstable angina (74%). All patients had successful delivery of radiation, with no in-hospital deaths. Novoste BetaCath device was used for 163 (65%) lesions, Cordis Checkmate for 56 (24%) lesions, Interventional Therapies device in 13 (8%) lesions, and Guidant Galileo in 4 lesions (3%). At a mean follow-up of 9.1 months, 78.7% were free of major adverse cardiac event (MACE). Twenty-one patients required repeat PTCA (10.1%), 19 had CABG (9.2%), 3 had MI (1.4%), and there was 1 death (0.5%). Unadjusted MACE rates for each device were 21% for Novoste, 28% for Checkmate, 8% for Interventional Therapies, and 50% for Galileo. Lesion length, minimal lumen diameter, renal failure, diabetes, and smoking did not predict treatment failure; only age was inversely correlated with MACE (P=.002). When applied across a spectrum of patients, lesions, and devices, brachytherapy retains its effectiveness with outcomes similar to those reported in randomized clinical trials.


Effects of perchlorate and exogenous T4 on growth, development and tail resorption of Rana chensinensis.
Endocrine disruptors have been demonstrated to exert adverse effects on growth and development of amphibians by disrupting hormone levels. Tail resorption, which is one of the most remarkable events during amphibian metamorphosis, is closely associated with thyroid hormones levels. However, limited research has been conducted on the effects of endocrine disruptors on tail resorption in amphibians. This study explored the effects of NaClO4 and T4 on the growth, development and tail resorption during the metamorphosis of Rana Chensinensis. The results demonstrated that exposure to NaClO4 led to an increase in body size and a delay in metamorphosis of R. Chensinensis tadpoles. Histological analysis revealed that both NaClO4 and exogenous T4 exposure resulted in thyroid gland injury, and NaClO4 treatment delayed the degradation of notochord and muscles, thereby delaying tail resorption. Moreover, transcriptome sequencing results showed that apoptosis-related genes (APAF1, BAX and CASP6) and cell component degradation-related genes (MMP9 and MMP13) were highly expressed in the T4 exposure group, and the expression of oxidative stress-related genes (SOD and CAT) was higher in the NaClO4 exposure group. Taken together, both NaClO4 and exogenous T4 affect tail resorption in R. Chensinensis, thereby affecting their adaptation to terrestrial life. The present study will not only provide a reference for future experimental research on the effects of other endocrine disruptors on the growth, development and tail resorption of amphibians but will also provide insights into environmental protection and ecological risk assessment.


Clinical implications of basic research in hepatocellular carcinoma.
A 58-year old Caucasian female has compensated hepatitis C related cirrhosis. Her surveillance ultrasound showed hypodense liver nodules and subsequent triple phase CT scan showed five tumor nodules with diameters ranging from 3-5cms involving both hepatic lobes. The nodules showed characteristic radiologic findings on the CT scan and she was diagnosed with hepatocellular carcinoma (HCC) based on non-invasive criteria. There was also associated right portal vein tumor thrombosis. Her functional capacity at diagnosis was slightly limited, but she was capable of performing all activities of daily living and self-care. Her laboratory tests at diagnosis were as follows: sodium 129mmol/L, potassium 3.6mmol/L, blood urea nitrogen 22mg/dL, creatinine 1.0mg/dL, albumin 2.9g/dl, bilirubin 1.8mg/dl, alanine aminotransferase 87U/L, aspartate aminotransferase 68U/L, alkaline phosphatase 139U/L, white blood cell 3.5x10(9)/L, hemoglobin 10.4, platelet count 73x10(9)/L, international normalized ratio 1.9 and alpha-fetoprotein 5200ng/ml. An upper endoscopy was negative for esophageal or gastric varices. Based on the tumor burden, presence of macrovascular invasion, ECOG performance status of 1 and Child-Pugh class A she was classified to have BCLC stage C HCC. She was started on sorafenib therapy at 400mg oral twice daily but unfortunately this had to be discontinued since she experienced severe diarrhea and skin rash. She now returns for follow-up and requests information on the available therapeutic options. This particular case scenario is not uncommon and does raise several clinically relevant questions: This review provides a comprehensive overview of the current state of HCC management and also examines the clinical implications of recent basic research in HCC.


Protective and antioxidant effects of Rhizophora mangle L. against NSAID-induced gastric ulcers.
The bark of Rhizophora mangle, the red mangrove, has been used traditionally in folk medicine of Caribbean countries due to its antiseptic, astringent, haemostatic and antifungal properties. Aqueous extracts are rich in tannins and have been proven experimentally to possess antibacterial, wound healing and antiulcerogenic effects. This work was designed to determine the gastroprotective effect of Rhizophora mangle in a model of diclofenac-induced ulcers in rats and to study the mechanisms involved, using the proton pump inhibitor omeprazole as a comparison. The lyophilized extract was given by oral gavage (125 and 62.5mg/kg) three times at 12h intervals before administering diclofenac 100mg/kg. Pretreatment with the extract resulted in a significant decrease of the ulcerated area (P<0.01). Rhizophora mangle induced a recovery of PGE(2) levels, which had been depleted by diclofenac. No anti-inflammatory effect was observed ex vivo or in vitro. The highest dose of the extract provoked a marked increase in glutathione peroxidase and superoxide dismutase activity, which was comparable to omeprazole. Furthermore, lipid peroxidation levels were inhibited in a dose-dependent manner. These results suggest that the gastroprotective effect of Rhizophora mangle in this experimental model appears through an antioxidant and prostaglandin-dependent way.


Bioprospecting acid- and arsenic-tolerant plant growth-promoting rhizobacteria for mitigation of arsenic toxicity in acidic agricultural soils.
Widespread use of chemical fertilizers and falling productivity in traditional agricultural practices has led to the biodiversity hotspot of North-Eastern region of India to face imminent threat to soil nutrients and biodiversity. The present work aimed to isolate rhizobacteria from Oryza sativa L. to evaluate their plant growth-promoting traits like indole, ammonia, siderophore production, and phosphate solubilization followed by in vitro plant growth promotion and anti-fungal assessment against Curvularia oryzae. Moreover, presence of heavy metals such as arsenic in chemical fertilizers and in groundwater contributes to arsenic contamination of agricultural soil. Taking this into consideration for the present study, the background metal content of the bulk soil, roots and grains of rice was measured. Arsenic tolerance of the rhizobacterial isolates was assessed using different concentrations of arsenite- and arsenate-supplemented media. 16S rRNA gene sequencing and phylogenetic tree analysis identified the isolates as Bacillus paramycoides, B. albus, B. altitudinis, B. koreensis, B. megaterium, B. wiedmannii, B. paramycoides, Chryseobacterium gleum, Stenotrophomonas maltophilia and Pseudomonas shirazica. Considering the acidic nature of the paddy growing soil, the growth kinetics of the isolates were monitored in acid and arsenic-supplemented conditions for 48 h of growth. Few isolates showed potent anti-fungal activity against the late blight phytopathogen, Curvularia oryzae MTCC 2605, apart from being potential growth promoters. The findings open vistas for the mass production of the characterized PGP rhizobacteria for their application in rehabilitation of the degrading arsenic contaminated paddy fields.


Effects of exercise intensity and duration on fat metabolism in trained and untrained older males.
Advancing age is associated with changes in fat and carbohydrate (CHO) metabolism, which is considered a risk factor for cardiovascular disease and diabetes. The effects of exercise intensity and duration on fat and CHO metabolism in elderly male subjects were investigated in the present study. Seven trained (63.7+/-4.7 years) and six untrained (63.5+/-4.5 years) healthy males performed three 30 min trials on a cycle ergometer at 50, 60 and 70% VO2max and two other trials at 60 and 70% VO2max in which the total energy expenditure was equal to that for 30 min at 50% VO2max Respiratory measures were undertaken throughout the exercise and blood samples taken before and immediately after each trial. Statistical analyses revealed a significant effect of exercise intensity on fat oxidation when the exercise durations were equated as well as when the energy expenditure was held constant for the three trials, though no training effect was noted. Total carbohydrate oxidation increased significantly with exercise intensity (P<0.05) and with training. Significantly higher levels of non-esterified free fatty acid (NEFA) and glycerol were observed for trained compared with untrained though not for B-hydroxybutyrate (3-OH) or insulin. No differences in NEFA, glycerol, 3-OH were evident for increases in exercise intensity. Carbohydrate and fat oxidation are significantly affected by exercise intensity in elderly males, although only CHO oxidation is influenced by training. Furthermore, training-induced increases in the availability of NEFA and glycerol are not associated with an increase in fat oxidation, rather an increase in CHO oxidation.


Enrichment of Na+-Ca2+ exchange in cardiac sarcolemmal vesicles by alkaline extraction.
Exposure of canine cardiac sarcolemmal vesicles to alkaline media (greater than or equal to pH 12) results in the extraction of 33% of the protein. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis shows that specific proteins are being solubilized. Most of the phospholipid and sialic acid remains with the pellet after centrifugation. Electron microscopy reveals that alkaline treatment does not cause gross morphological damage to the vesicles, although freeze-fracture demonstrates some aggregation of intramembrane particles. The data indicate that high pH probably removes peripheral proteins and leaves the integral proteins in place. We find complete recovery of Na+-Ca2+ exchange activity in alkaline-extracted membranes after solubilization and reconstitution. These vesicles contain only 50% of the protein of vesicles reconstituted from control sarcolemma. Thus, the specific activity of Na+-Ca2+ exchange is doubled. Alkaline extraction is a useful and reproducible procedure for enrichment of the Na+-Ca2+ exchange protein. (Na+ + K+)-ATPase is completely inactivated by exposure to pH 12 medium though immunodetection shows that the (Na+ + K+)-ATPase proteins are not extracted. We detect both alpha and alpha + forms of (Na+ + K+)-ATPase and deduce that the Na+ pump proteins do not comprise a major fraction of sarcolemmal protein.


Ventricular pacing burden in patients with left bundle branch block after transcatheter aortic valve replacement therapy.
Electrophysiological testing has been proposed in the latest European Society of Cardiology (ESC) guidelines for cardiac pacing to identify left bundle branch block (LBBB) patients with infrahisian conduction delay (IHCD) after transcatheter aortic valve replacement (TAVR). While in general IHCD is defined by a His-ventricular (HV) interval of >55 ms, a cut-off of ≥70 ms to trigger pacemaker (PM) implantation has been proposed in the latest ESC guidelines. The ventricular pacing (VP) burden during follow-up in such patients is largely unknown. As such, we aimed to assess the VP burden during follow-up of patients receiving PM therapy for LBBB after TAVR based on an HV interval > 55 ms and ≥70 ms. All patients with new-onset or pre-existing LBBB after undergoing TAVR at a tertiary referral center underwent EP testing the day after TAVR. In patients with a prolonged HV interval (>55 ms), PM implantation was performed by a trained electrophysiologist in a standardized fashion. All devices were programmed to avoid unnecessary VP by specific algorithms (e.g., AAI-DDD). 701 patients underwent TAVR at the University Hospital of Basel. One hundred seventy-seven patients presented with new-onset or pre-existing LBBB the day following TAVR and underwent EP testing. An HV interval > 55 ms was found in 58 patients (33%) and an HV interval ≥ 70 ms in 21 patients (12%). 51 patients (mean age 84 ± 6.2 years, 45% women) agreed to receive a PM, out of which 20 (39%) patients had an HV Interval over 70 ms. Atrial fibrillation was present in 53% of the patients. A dual chamber PM was implanted in 39 (77%), and a single chamber PC in 12 (23%) patients, respectively. Median follow-up was 21 months. The median VP burden overall was 3%. The median VP burden was not significantly different between patients with an HV ≥ 70 ms (6.5 [0.8-52]) and those with an HV between 55 and 69 ms (2 [0-17], p = .23). 31% of patients demonstrated a VP burden < 1%, 27% 1%-5% and 41% > 5%. The median HV intervals in patients with VP burdens < 1%, 1%-5% and >5% were 66 (IQR 62-70) ms, 66 (IQR 63-74) ms and 68 (IQR 60-72) ms, respectively, p = .52. When only assessing patients with an HV interval 55-69 ms, 36% demonstrated a VP burden of <1%, 29% of 1%-5% and 35% of >5%. In patients with an HV Interval ≥ 70 ms, 25% demonstrated a VP burden < 1%, 25% of 1%-5% and 50% of >5% %, p = .64 (Figure). In patients with LBBB after TAVR and IHCD defined by an HV interval > 55 ms, VP burden is relevant in a non-negligible amount of patients during follow-up. Further studies are warranted to define the optimal cut-off value for the HV interval or to develop risk models incorporating HV measurements and other risk factors to trigger PM implantation in patients with LBBB after TAVR.


Influence of synthetic parameters on the size, structure, and stability of dodecanethiol-stabilized silver nanoparticles.
Metal nanoparticles (NP) are very attractive because of their size- and shape-dependent properties. A widely used preparation of ligand-stabilized metal NP is the two-phase liquid-liquid method using dodecanethiol (DT) as ligand. This work presents various procedures to synthesize dodecanethiol-capped silver NPs, all of them based on a two-phase liquid-liquid method. Small alterations in the synthetic parameters lead to dramatic modifications in the nanoparticles' average size, size distribution width, stability, and structure, as well as in their ability to self-assemble.


Cholera prevention, control strategies, challenges and World Health Organization initiatives in the Eastern Mediterranean Region: A narrative review.
The resurgence of cholera is presenting unusual challenges in the Eastern Mediterranean Region (EMR), where it is considered endemic in nine-member states. The risk of a cholera outbreak spreading to non-endemic countries remains high. We discuss the regional trends of cholera, regional burden, and challenges with a focus on World Health Organization (WHO) initiatives in the region that could be useful in preventing and controlling the disease in similar contexts. Despite significant progress in the control of cholera worldwide, the disease continues to be a major public health problem across the region, where it constitutes both an emerging and re-emerging threat. Recurring cholera outbreaks are an indication of deprived water and sanitation conditions as well as weak health systems, contributing to the transmission and spread of the cholera infection. We note that despite the challenges in eliminating cholera in the region, effective implementation of the proposed WHO EMR Strategic framework, among other measures, could sustain the region's cholera prevention, preparedness, and response needs.


Adenosquamous-cell carcinoma of the ovary: report of a case with positive peritoneal fluid cytology.
Cytologic examination of peritoneal fluid showed only malignant squamous cells, without revealing adenocarcinomatous cell components, in a patient who had an endometrioid adenosquamous-cell carcinoma of the ovary. Histologic examination of the ovary demonstrated diffuse squamous-cell carcinoma with rare foci of endometrioid and abortive malignant glands, as well as isolated mucin-positive cells. The cytologic differential diagnosis of malignant squamous cells in peritoneal fluid and the pathogenesis of squamous-cell carcinoma of the ovary are discussed.


Sertraline inhibits the transport of PAT1 substrates in vivo and in vitro.
Intestinal nutrient transporters may mediate the uptake of drugs. The aim of this study was to investigate whether sertraline interacts with the intestinal proton-coupled amino acid transporter 1 PAT1 (SLC36A1). In vitro investigations of interactions between sertraline and human (h)PAT1, hSGLT1 (sodium-glucose linked transporter 1) and hPepT1 (proton-coupled di-/tri-peptide transporter 1) were conducted in Caco-2 cells using radiolabelled substrates. In vivo pharmacokinetic investigations were conducted in male Sprague-Dawley rats using gaboxadol (10 mg·kg(-1), p.o.) as a PAT1 substrate and sertraline (0-30.6 mg·kg(-1)). Gaboxadol was quantified by hydrophilic interaction chromatography followed by MS/MS detection. Sertraline inhibited hPAT1-mediated L-[(3)H]-Pro uptake in Caco-2 cells. This interaction between sertraline and PAT1 appeared to be non-competitive. The uptake of the hSGLT1 substrate [(14)C]-α-methyl-D-glycopyranoside and the hPepT1 substrate [(14)C]-Gly-Sar in Caco-2 cells was also decreased in the presence of 0.3 mM sertraline. In rats, the administration of sertraline (0.1-10 mM, corresponding to 0.3-30.6 mg·kg(-1), p.o.) significantly reduced the maximal gaboxadol plasma concentration and AUC after its administration p.o. Sertraline is an apparent non-competitive inhibitor of hPAT1-mediated transport in vitro. This inhibitory effect of sertraline is not specific to hPAT1 as substrate transport via hPepT1 and hSGLT1 was also reduced in the presence of sertraline. In vivo, sertraline reduced the amount of gaboxadol absorbed, suggesting that the inhibitory effect of sertraline on PAT1 occurs both in vitro and in vivo. Hence, sertraline could alter the bioavailability of drugs absorbed via PAT1.


L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab.
EGFR-specific tyrosine kinase inhibitors (TKIs), especially osimertinib, have changed lung cancer therapy, but secondary mutations confer drug resistance. Because other EGFR mutations promote dimerization-independent active conformations but L858R strictly depends on receptor dimerization, we herein evaluate the therapeutic potential of dimerization-inhibitory monoclonal antibodies (mAbs), including cetuximab. This mAb reduces viability of cells expressing L858R-EGFR and blocks the FOXM1-aurora survival pathway, but other mutants show no responses. Unlike TKI-treated patient-derived xenografts, which relapse post osimertinib treatment, cetuximab completely prevents relapses of L858R+ tumors. We report that osimertinib's inferiority associates with induction of mutagenic reactive oxygen species, whereas cetuximab's superiority is due to downregulation of adaptive survival pathways (e.g., HER2) and avoidance of mutation-prone mechanisms that engage AXL, RAD18, and the proliferating cell nuclear antigen. These results identify L858R as a predictive biomarker, which may pave the way for relapse-free mAb monotherapy relevant to a large fraction of patients with lung cancer.


Indentation response of human patella with elastic modulus correlation to localized fractal dimension and bone mineral density.
The goal of this study was to determine material properties for the anterior cortex and subcortical regions of human patellae and relate those properties to mineral density and fractal dimension of the bone. Ten human patellae were obtained from eight fresh frozen human cadavers and subjected to anteriorly-directed spherical indentation-relaxation experiments using two different sized indenters to two different indentation depths. Response data were fit to a three-mode viscoelastic model obtained through elastic-viscoelastic correspondence of the Hertzian contact relation for spherical indentation. A location-specific effective bone density measurement that more heavily weighted bone material close to the indentation site (by von Mises stress distribution) was determined from micro-computed tomography (38µm resolution) data captured for each specimen. The same imagery data were used to compute location specific fractal dimension estimates for each indentation site. Individual and averaged patella material models verified the hypothesis that when the larger indenter and greater indentation depth is used to engage the surface and deeper (trabecular) bone, the bone exhibits a more compliant response than when only the surface (cortical) bone was engaged (instantaneous elastic modulus was 325MPa vs. 207MPa, p<0.05). Effective bone mineral density was shown to be a significant predictor of the elastic modulus for both small and large indentation types (p<0.05) despite relatively low correlations. Exponential regressions of fractal dimension on elastic modulus showed significant relationships with high correlation for both the small (R(2)=0.93) and large (R(2)=0.97) indentations.


Integrating data from asymmetric multi-models can identify drought-resistant groundnut genotypes for drought hot-spot locations.
Water/drought stress experiments are frequently conducted under imposed stress or rainout shelters, while natural drought hot-spot investigations are rare. The "drought hot spot" in Anantapur, Andhra Pradesh, India, is appropriate for drought stress evaluation due to its hot, arid environment, limited rainfall, with over 50% rainfall variability. According to reports, 30 out of 200 groundnut cultivars in India are supposed to possess drought-tolerant characteristics. However, these cultivars are yet to be evaluated in areas that are prone to drought. This study tested these drought-tolerant genotypes in naturally drought-prone areas of Anantapur under rainfed conditions from Kharif 2017 to 2019. Pod yield and rainfall-use-efficiency (RUE) were measured for these genotypes. Genotype and genotype*environment interactions affected pod yield and RUE (GEI). The AMMI model exhibits significant season-to-season variability within the same area with environmental vectors > 90° angles. GGE biplot suggested the 2018 wet season for drought-resistant cultivar identification. Kadiri5 and GPBD5 were the most drought-tolerant cultivars for cultivation in Anantapur and adjacent regions. These types could also be used to generate drought-tolerant groundnut variants for drought-prone regions.


Patenting strategies, the authentication US fiscal methodology, discovery and development of imidazole-containing peptide compounds with free-radical scavenging and transglycating properties acting as targeted drug regulators and homeostatic agents with diverse therapeutic activities for pharmacy of diabetes and metabolic diseases.
Diabetes mellitus is the seventh-leading cause of death in the US and diabetic complications are interlaced with specific diverse microvascular and macrovascular pathologies resulting from hyperglycemia. The society should expand prowess and patenting of biotechnology to cure disease and complications. The work summarizes biological activities of patented carnosine mimetics resistant in formulations to enzymatic hydrolysis with human carnosinases that are acting as a universal form of antioxidant, deglycating and transglycating agents that inhibit sugar-mediated protein crosslinking, chelate or inactivate a number of transition metal ions (including ferrous and copper ions), possess lipid peroxidase type of activity and protection of antioxidant enzymes from inactivation. L-Carnosine released systemically from N-acetylcarnosine lubricant eye drops or from skeletal muscle during exercise is transported into hypothalamic tuberomammillary nucleus-histamine neurons and hydrolyzed. The resulting L-histidine is subsequently converted into histamine acting as metabolic fuel feeding for the hypothalamic histaminergic system. This mechanism is responsible for the effects of L-carnosine on autonomic neurotransmission and physiological function of pancreas, stimulating in vivo regeneration of insulin-producing β cells. Therapeutic benefits for imidazole-containing antioxidants (nutraceutical non-hydrolyzed carnosine, carcinine, D-carnosine, ophthalmic prodrug N-acetylcarnosine, leucyl-histidylhydrazide and patented formulations thereof) are an essential part of diabetes treatment.


MetaboShiny: interactive analysis and metabolite annotation of mass spectrometry-based metabolomics data.
Direct infusion untargeted mass spectrometry-based metabolomics allows for rapid insight into a sample's metabolic activity. However, analysis is often complicated by the large array of detected m/z values and the difficulty to prioritize important m/z and simultaneously annotate their putative identities. To address this challenge, we developed MetaboShiny, a novel R/RShiny-based metabolomics package featuring data analysis, database- and formula-prediction-based annotation and visualization. To demonstrate this, we reproduce and further explore a MetaboLights metabolomics bioinformatics study on lung cancer patient urine samples. MetaboShiny enables rapid and rigorous analysis and interpretation of direct infusion untargeted mass spectrometry-based metabolomics data.


Organ histopathological changes and its function damage in mice following long-term exposure to lanthanides chloride.
Due to increasing applications of lanthanides (Ln) in industry and daily life, numerous studies confirmed that Ln exposure may result in organ damages in mice and rats, while very few studies focused on several organs damages simultaneously. In order to compare the toxicity of Ln on organs, mice were exposed to LaCl(3), CeCl(3), and NdCl(3) of a dose of 20 mg/kg body weight for consecutive 60 days, respectively, then histopathological changes of liver, kidney, and heart, and their function were investigated. The results showed that long-term exposure to Ln caused cell necrosis and basophilia of liver, ambiguity of renal tubule architecture, congestion of blood vessel and capillary of kidney, and heart hemorrhage. The histopathological changes of liver, kidney, and heart in mice caused by Ce(3+) was most severe; the effect by Nd(3+) was slighter than Ce(3+) but more severe than La(3+). The assay of serum biochemical parameters suggested that Ln exposure severely impaired the functions of liver, kidney, and myocardium in mice. These findings suggested that long-term exposure to Ln resulted in histopathological changes of liver, kidney, and heart, and their function damages. Therefore, we thought that long-term application of the products containing Ln on human should be cautious.


Roles and expectations for mental health professionals in law enforcement agencies.
To assess consumer needs for and attitudes toward mental health services within law enforcement agencies, a questionnaire composed of a comprehensive list of mental health services potentially available to police departments was administered to populations of police officers and mental health workers. Respondents rated the services according to perceived utility of the service for law enforcement needs. Generally, police officers seemed receptive to several kinds of mental health service, although they were less enthusiastic about the value of the services than professionals. The implication of these data for the community mental health worker are discussed in terms of establishing and maintaining effective, mutually satisfying relationships with law enforcement agencies.


Successful Treatment of Pediatric Posttraumatic Tibiofibular Synostosis by Resection and Peroneal Artery Perforator Adipofascial Flap: A Case Report.
Pediatric posttraumatic tibiofibular synostosis (PPTFS) is a rare postfracture complication that often leads to growth abnormalities. There are very few reports demonstrating the long-term efficacy of surgical treatment. An 11-year-old boy with PPTFS displayed progressive prominence of the fibular head and shortening of the lateral malleolus subsequent to a fracture suffered at the age of 5 years. He was treated by synostosis resection and a peroneal artery perforator adipofascial flap. Eight years postoperatively, the synostosis had not recurred, and his earlier growth abnormalities were nearly normal. Peroneal artery perforator adipofascial flap is effective for pregrowth spurt PPTFS.


Protein kinases C-gamma and -delta are involved in insulin-like growth factor I-induced migration of colonic epithelial cells.
The mechanisms by which epithelial cells migrate during the repair of damaged colonic mucosa are poorly understood. This study investigated the insulin-like growth factor I (IGF-I) signaling pathway leading to HT29-D4 human colonic epithelial cell line migration. IGF-stimulated cell migration was determined using a wound model in the presence or absence of kinase inhibitors. Activation of protein kinase C (PKC) was determined by immunodetection. IGF-I and insulin induce cell migration without affecting cell proliferation through their cognate receptors. Des(1-3)-IGF-I, a truncated analogue of IGF-I, was more potent than IGF-I, suggesting that IGF-binding proteins secreted in the medium modulated IGF-I-induced cell migration. Inhibition of phosphatidylinositol 3-kinase, PKC, and mitogen-activated protein kinases eliminated cell restitution. Long-term exposure of cells to phorbol myristate acetate caused the depletion of PKC-delta and -gamma and prevented also IGF-I-induced cell motility. IGF-I also induced activation of PKC-delta and -gamma only. IGF-I stimulates colonic restitution through the activation of multiple signaling pathways including activation of phosphatidylinositol 3-kinase, PKC-delta and -gamma, and mitogen-activated protein kinases.


Quality of Life Impacts of Bright Light Treatment, Fluoxetine, and the Combination in Patients with Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial.
Bright light therapy is increasingly recommended (alone or in combination with antidepressant medication) to treat symptoms of nonseasonal major depressive disorder (MDD). However, little is known about its impacts on quality of life (QoL), a holistic, patient-valued outcome. This study utilizes secondary outcome data from an 8-week randomized, controlled, double blind trial comparing light monotherapy (n = 32), fluoxetine monotherapy (n = 30), and the combination of these (n = 27) to placebo (n = 30). QoL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). Treatment-related differences in QoL improvements were assessed using a repeated measures analysis of variance. The influence of potential predictors of QoL (demographic variables and change in depressive symptoms) were investigated via hierarchical linear regression. Q-LES-Q-SF scores significantly improved across all treatment conditions; however, no significant differences were observed between treatment arms. QoL remained poor relative to community norms by the end of the trial period: Across conditions, 70.6% of participants had significantly impaired QoL at the 8-week assessment. Reduction in depressive scores was a significant predictor of improved QoL, with the final model accounting for 54% of variance in QoL change scores. The findings of this study emphasize that improvement in QoL and reduction in depressive symptoms in MDD, while related, cannot be taken to be synonymous. Adjunctive therapies may be required to address unmet QoL needs in patients with MDD receiving antidepressant or light therapies. Further research is required to explore additional predictors of QoL in order to better refine treatments for MDD.


Prognostic models and risk scores: can we accurately predict postoperative nausea and vomiting in children after craniotomy?
Postoperative nausea and vomiting (PONV) is a problem for many children after craniotomy. Prognostic models and risk scores help identify who is at risk for an adverse event such as PONV to help guide clinical care. The purpose of this article is to assess whether an existing prognostic model or risk score can predict PONV in children after craniotomy. The concepts of transportability, calibration, and discrimination are presented to identify what is required to have a valid tool for clinical use. Although previous work may inform clinical practice and guide future research, existing prognostic models and risk scores do not appear to be options for predicting PONV in children undergoing craniotomy. However, until risk factors are further delineated, followed by the development and validation of prognostic models and risk scores that include children after craniotomy, clinical judgment in the context of current research may serve as a guide for clinical care in this population.


Cost of reproduction: parental survival and production of recruits in the Willow Tit Parus montanus.
Brood sizes of the Willow Tit were altered experimentally by subtracting or adding two nestlings in 1986 and 1987 in the vicinity of Oulu, northern Finland. The manipulated broods were within the normal range observed in natural conditions. Unaltered broods were used as controls. Data from natural broods from 1978-1985 were available for comparison. When the nestlings were 13 days old they were ringed and weighed and their tarsus, wing, and tail lengths were measured. On the same day the parents were caught, weighed, and measured. In 1986 there were no differences in nestling mortality between the reduced, control, or enlarged broods; i.e. parents were able to fledge the two extra young. In 1987 starvation was most pronounced in the enlarged broods. This resulted in the number of fledglings being practically the same in each manipulation category. Especially the body weight, but also the other indices of body size, decreased as a function of the brood size category, suggesting that there may be quality differences between the young reared in different experimental groups. In 1986 there was a non-significant trend towards lower body weight of the parents attending reduced, control, or enlarged broods, in that order. In 1987 the differences were much smaller. These results were not due to size differences between the groups, so possibly the increased reproductive effort of raising extra young was responsible for the trend observed in 1986. There were no significant differences in parental survival associated with the manipulation category, although the trend in the females was consistent with the hypothesis of reproductive cost. It is possible that environmental conditions in 1986 were so favourable that the tits were not unduly stressed even when attending two extra young. Correlative data from 1978-1985 did not support the cost hypothesis either. A non-significant trend towards reduced post-fledging survival and recruitment of the young was observed with increased brood size. The average fitness value of parents, incorporating parental survival and number of recruits, showed that the success of the adults raising enlarged broods may be lower than that of others. It seems that the reproductive cost, if it exists, decreases individual fitness value by reducing the chances of recruiting descendants into the next generation. The reproductive stress may be insufficient to reduce the subsequent survival of parents. More data are however needed to confirm these results.


Insights into the protective effects of influenza vaccination: More hospitalizations but lower follow-up mortality during the 2014/15 influenza season in a Swiss cohort.
Observational studies of influenza vaccination are criticized as flawed due to unmeasured confounding. The goal of this cohort study was to explore the value and role of secondary claims data to inform the effectiveness of influenza vaccination, while systematically trying to reduce potential bias. We iteratively reviewed the components of the PICO approach to refine study design. We analyzed Swiss mandatory health insurance claims of adult patients with chronic diseases, for whom influenza vaccination was recommended in 2014. Analyzed outcomes were all-cause mortality, hospitalization with a respiratory infection or its potential complication, and all-cause mortality after such hospitalization, adjusting for clinical and health care use variables. Cox and multi-state models were applied for time-to-event analysis. Of 343,505 included persons, 22.4% were vaccinated. Vaccinated patients were on average older, had more morbidities, higher health care expenditures, and had been more frequently hospitalized. In non-adjusted models, vaccination was associated with increased risk of events. Adding covariates decreased the hazard ratio (HR) both for mortality and hospitalizations. In the full model, the HR [95% confidence interval] for mortality during season was 0.82 [0.77-0.88], and closer to null effect after season. In contrast, HR for hospitalizations was increased during season to 1.28 [1.15-1.42], with estimates closer to null effect after season. HR in multi-state models were similar to those in the single-outcome models, with HR of mortality after hospitalization negative both during and after season. In patients with chronic diseases, influenza vaccination was associated with more frequent specific hospitalizations, but decreased risk of mortality overall and after such hospitalization. Our approach of iteratively considering PICO elements helped to consider various sources of bias in the study sequentially. The selection of appropriate, specific outcomes makes the link between intervention and outcome more plausible and can reduce the impact of confounding.


tRNA turnaround.
Two recently published papers (Takano et al., 2005 and Shaheen and Hopper, 2005) demonstrate that in S. cerevisiae, cytoplasmic tRNAs can be transported into the nucleus. This retrograde movement may expose mature tRNAs to nuclear proofreading or it may regulate tRNA availability in response to amino acid availability.


Zeolitic Imidazolate Framework‑8 (ZIF-8) modified titanium alloy for controlled release of drugs for osteoporosis.
The aim of this work was to prepare a biocompatible implant material that enables the release of drug for osteoporosis-risedronate. To achieve this goal, a titanium implant coated with a biocompatible Zeolitic Imidazolate Framework 8 (ZIF-8) layer was prepared that promotes osseointegration at the bone-implant interface. The modifications of the titanium alloy as well as sorption and desorption processes were confirmed using a variety of methods: SEM, EDS XPS, and FT-IR imaging (to determine surface modification, drug distribution, and risedronate sorption), and UV-Vis spectroscopy (to determine drug sorption and release profile). Both the ZIF-8 layer and the drug are evenly distributed on the surface of the titanium alloy. The obtained ZIF-8 layer did not contain impurities and zinc ions were strongly bounded by ZIF-8 layer. The ZIF-8 layer was stable during drug sorption. The drug was released in small doses for 16 h, which may help patients recover immediately after surgery. This is the first case of using ZIF-8 on the surface of the titanium alloy as carrier that releases the drug under the influence of body fluids directly at the site of the disease. It is an ideal material for implants designed for people suffering from osteoporosis.


Down regulation of B cells by immunization with a fusion protein of a self CD20 peptide and a foreign IgG.Fc fragment.
In vivo studies of mice were performed to investigate whether auto-reactive antibodies specific for self CD20 antigen on B cells could be induced by immunizing with a CD20 peptide linked to a foreign, human IgG.Fc fragment through a T cell immunologically inert linker peptide and how such an auto-reactivity, if generated, would affect the levels of B cells. The dimeric Fc fusion protein containing the extracellular 44-amino acid portion of CD20, and the CH2-CH3 domains of human gamma 1 immunoglobulin were prepared. After several subcutaneous immunizations with this CD20-Fc protein, mice produced anti-CD20 antibodies that can bind to native CD20 on normal B cells and B-lymphoma cells. In mice immunized with the CD20-Fc protein, the fraction of B cells in total peripheral blood lymphocytes decreased to about 40%, significantly lower than that of mice immunized with human IgG. In addition, antibody response towards an irrelevant bystander antigen, chicken ovalbumin, was weakened compared with that of mice immunized with human IgG. These results show that auto-reactive antibodies specific for CD20 can be induced by immunizing with an autologous CD20 peptide fused with a foreign IgG.Fc and that the auto-antibodies can partially reduce the levels of B cells and their response to other antigens.


Geometric and potential driving formation and evolution of biomolecular surfaces.
This paper presents new geometrical flow equations for the theoretical modeling of biomolecular surfaces in the context of multiscale implicit solvent models. To account for the local variations near the biomolecular surfaces due to interactions between solvent molecules, and between solvent and solute molecules, we propose potential driven geometric flows, which balance the intrinsic geometric forces that would occur for a surface separating two homogeneous materials with the potential forces induced by the atomic interactions. Stochastic geometric flows are introduced to account for the random fluctuation and dissipation in density and pressure near the solvent-solute interface. Physical properties, such as free energy minimization (area decreasing) and incompressibility (volume preserving), are realized by some of our geometric flow equations. The proposed approach for geometric and potential forces driving the formation and evolution of biological surfaces is illustrated by extensive numerical experiments and compared with established minimal molecular surfaces and molecular surfaces. Local modification of biomolecular surfaces is demonstrated with potential driven geometric flows. High order geometric flows are also considered and tested in the present work for surface generation. Biomolecular surfaces generated by these approaches are typically free of geometric singularities. As the speed of surface generation is crucial to implicit solvent model based molecular dynamics, four numerical algorithms, a semi-implicit scheme, a Crank-Nicolson scheme, and two alternating direction implicit (ADI) schemes, are constructed and tested. Being either stable or conditionally stable but admitting a large critical time step size, these schemes overcome the stability constraint of the earlier forward Euler scheme. Aided with the Thomas algorithm, one of the ADI schemes is found to be very efficient as it balances the speed and accuracy.


Age-related enhancement in visuomotor learning by a dual-task.
Many daily activities require performance of multiple tasks integrating cognitive and motor processes. While the fact that both processes go through deterioration and changes with aging has been generally accepted, not much is known about how aging interacts with stages of motor skill acquisition under a cognitively demanding situation. To address this question, we combined a visuomotor adaptation task with a secondary cognitive task. We made two primary findings beyond the expected age-related performance deterioration. First, while young adults showed classical dual-task cost in the early motor learning phase dominated by explicit processes, older adults instead strikingly displayed enhanced performance in the later stage, dominated by implicit processes. For older adults, the secondary task may have facilitated a shift to their relatively intact implicit learning processes that reduced reliance on their already-deficient explicit processes during visuomotor adaptation. Second, we demonstrated that consistently performing the secondary task in learning and re-learning phases can operate as an internal task-context and facilitate visuomotor memory retrieval later regardless of age groups. Therefore, our study demonstrated age-related similarities and differences in integrating concurrent cognitive load with motor skill acquisition which, may in turn, contributes to the understanding of a shift in balance across multiple systems.


[Immune lymphocyte inhibition of activation of DNA synthesis in mixed cultures of normal lymphocytes in vitro].
Substitution of normal lymphocytes by immune ones as responding cells in the "one-way" mixed lymphocyte culture (MLC) results in inhibition of the DNA synthesis. This phenomenon is reproduced irrespective of the mouse strains used, immunization method (in vivo or in vitro) and various MLC techniques (macro- or microcultures, the presence of mercaptoethanol in the medium, control variants). Unlike the cytotoxic effect of immune lymphocytes showing a sharp peak on the 8th day after in vivo immunization, inhibition of the DNA synthesis activation in MLC occurred as the second day, and persisted for several weeks after immunization; this inhibition was reproduced on addition of a small fraction (5 to 10%) of immune lymphocytes to normal ones.


Pulmonary edema in severe preeclampsia-eclampsia: analysis of thirty-seven consecutive cases.
During approximately a 9-year period, 37 severe preeclamptic-eclamptic patients had pulmonary edema for an incidence of 2.9%. The incidence was significantly higher in older patients (p less than 0.0001) and in multigravid patients (p less than 0.05). Eleven (30%) had antepartum edema with 10 (90%) of the 11 having preexisting chronic hypertension. Twenty-six (70%) had postpartum edema with an average onset of 71 hours post partum. The majority of these patients had excessive colloid and crystalloid infusions for various medical, surgical, and obstetric complications. There were four maternal deaths and morbidity was significant. Eighteen patients had disseminated intravascular coagulopathy, 17 had sepsis, 12 had abruptio placentae, 10 had acute renal failure, six had hypertensive crisis, five had cardiopulmonary arrest, two had rupture of the liver, and two had ischemic cerebral damage. The overall perinatal mortality was 530/1000 and neonatal morbidity was significant. Pulmonary edema is infrequent in severe preeclampsia-eclampsia without associated medical, surgical and obstetric complications. The occurrence of pulmonary edema in such patients is associated with high maternal and perinatal mortality and morbidity.


Impact of polyunsaturated fatty acid degradation on survival and acidification activity of freeze-dried Weissella paramesenteroides LC11 during storage.
The impact of polyunsaturated fatty acid (PUFA) degradation on the survival and acidification activity of freeze-dried Weissella paramesenteroides LC11 was investigated over 90-days storage at 4 degrees C or 20 degrees C in vacuum-sealed aluminium foil or glass tubes with two water activities (a(w)=0.11 or 0.23). Colony counts, acidification activity (% lactic acid/g), linoleic/palmitic (18:2/16:0) or linolenic/palmitic (18:3/16:0) ratio by gas chromatography and 18:2 or 18:3 oxylipins by reversed phase-high performance liquid chromatography were determined. The viable cells, acidification activity and 18:2/16:0 or 18:3/16:0 ratio decreased as the storage time increased. The survival, acidification activity and 18:2/16:0 or 18:3/16:0 ratio were greatest for the freeze-dried strain held in vacuum-sealed aluminium foil at 4 degrees C. The 18:2/16:0 or 18:3/16:0 ratio decrease was correlated with the accumulation of 18:2 or 18:3 oxylipins during storage in glass tubes. Hydroperoxy PUFAs, hydroxy PUFAs, divinyl ether PUFAs and oxo PUFAs were the main oxylipins identified. A large decrease in the 18:2/16:0 or 18:3/16:0 ratio and a rapid accumulation of oxylipins during storage might be enough to cause high cell death and loss of metabolic activity. These results provide further experimental support for the hypothesis that lipid oxidation and survival or activity of freeze-dried bacteria might be related.


Hirschsprung-associated enterocolitis develops independently of NOD2 variants.
BACKGROUD/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) represents a cause for significant pre- and postoperative morbidity and mortality in Hirschsprung disease (HD). Although multiple studies on HAEC have been performed and several mechanisms have been presumed, the pathogenesis of this condition remains unclear. As changes in colonic mucosal defense are key factors suggested in both Crohn's disease (CD) and HAEC pathogenesis, the aim of the current study was to investigate genetic alterations in the most important susceptibility gene for Crohn's enterocolitis (NOD2) to see whether carriers of polymorphisms within the NOD2 gene are predisposed to the development of HAEC. Genotyping for the NOD2 variants in exon 4 (p.Arg702Trp [rs2066844]), exon 8 (p.Gly908Arg [rs2066845]), and exon 11 (p.1007fs [rs2066847]) was performed in 52 white children with HD (41 boys, 11 girls), 152 healthy controls, and 152 children with CD (onset of disease <17 years; mean, 11.8 years). Seventeen patients with HD (32.7%) were carriers of a RET germline mutation, 35 children (67.3%) had short segment disease, and 17 (32.7%) had long segment disease. Ten children (19.2%) with HD were heterozygous carriers of at least one NOD2 variant vs 17 (11.2%) in the healthy control group and 69 (45.4%) in the CD cohort. Hirschsprung-associated enterocolitis was observed in 7 children (13.5%), with 4 having short segment HD and 3 with long segment HD; but none of them were carriers of NOD2 variants. Our study shows that NOD2 variants described to be causatively associated with CD do not predispose to the development of HAEC. As data on the molecular basis of HAEC are limited, the distinct mechanisms involved in the pathogenesis of this complication remain unclear.


Serum resistin levels in patients with rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis.
The purpose of this meta-analysis was to investigate whether serum resistin level was associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) by comparing serum resistin levels between RA or SLE patients and normal controls. PubMed and EMBASE databases (up to May 13, 2014) were used to search all related articles. The weighted mean differences (WMDs) with 95 % confidence interval (CI) were calculated using random-effect model analysis. The Cochrane Q test and I(2) statistic were used to test heterogeneity. To assess publication bias, the Egger's test and visual observation of a funnel plot were used. The Newcastle-Ottawa scale was used to assess the study quality. The STATA statistical software (version 11.0) was applied to deal with statistical data. A total of eight studies of RA including 620 patients and 460 healthy controls, and six studies of SLE including 559 patients and 430 healthy controls were finally included in the meta-analysis. The results revealed that the serum resistin levels in RA were significantly higher than those in normal controls (WMD = 0.767 ng/ml, 95 % CI = 0.114-1.419, P = 0.021), but there was no significant difference between SLE patients and normal controls (WMD = 2.771 ng/ml, 95 % CI = -0.521-6.063, P = 0.099). Publication bias was undetected. In conclusion, this meta-analysis indicate that serum resistin level was significantly elevated in RA patients.


Expression and mutation of p53 gene in the lung of mice intratracheal injected with crystalline silica.
The genotoxic effect of crystalline silica (Qt) in the lung was studied to clarify that silicosis conferred a significant increase in risk subsequent lung cancer. C57BL/6N mice received a single tracheal injection of Qt at dose of 2 mg/mouse. Lung p53mRNA was suppressed significantly, but no change of p21mRNA 15 months after treatment. Mutation of p53 gene was not identified at 15 months in the Qt group. Silicotic lesions were observed in the lungs of Qt group, but silicosis with pulmonary neoplasia was no detected. These results indicated that genetic changes in the silicotic lung might lead to facilitation of carcinogenesis.


Multispectroscopic methods reveal different modes of interaction of anti cancer drug mitoxantrone with Poly(dG-dC).Poly(dG-dC) and Poly(dA-dT).Poly(dA-dT).
The interaction of mitoxantrone with alternating Poly(dG-dC).Poly(dG-dC) and Poly(dA-dT).Poly(dA-dT) duplex has been studied by absorption, fluorescence and Circular Dichroism (CD) spectroscopy at Drug to Phosphate base pair ratios D/P=20.0-0.04. Binding to GC polymer occurs in two distinct modes: partial stacking characterized by red shifts of 18-23nm at D/P=0.2-0.8 and external binding at D/P=1.0-20.0 whereas that to AT polymer occurs externally in the entire range of D/P. The binding constant and number of binding sites is 3.7×10(5)M(-1), 0.3 and 1.3× 10(4)M(-1), 1.5 in GC and AT polymers, respectively at low D/P ratios. CD binding isotherms show breakpoints at D/P=0.1, 0.5 and 0.25, 0.5 in GC and AT polymers, respectively. The intrinsic CD bands indicate that the distortions in GC polymer are significantly higher than that in AT polymer. Docking studies show partial insertion of mitoxantrone rings between to GC base pairs in alternating GC polymer. Side chains of mitoxantrone interact specifically with base pairs and DNA backbone. The studies are relevant to the understanding of suppression or inhibition of DNA cleavage on formation of ternary complex with topoisomerase-II enzyme and hence the anti cancer action.


Combined continuous monitoring of systemic and cerebral oxygen metabolism after cardiac arrest.
Cerebral oxygenation was assessed in 8 patients in cardiac arrest during the 24 h after resuscitation, by continuous fiber-optic monitoring of jugular bulb venous oxygen saturation (SjO2), in conjunction with continuous monitoring of mixed venous oxygen saturation (SvO2). Three patients survived and 5 died. SjO2 and SvO2 patterns were compared between surviving and non-surviving patients with regard to their prognostic and therapeutic implications. The mean SjO2 of the survivors (67%) was significantly lower than that of the non-survivors (80%) (P < 0.001), whereas the corresponding SvO2 value was higher in the survivor group (74%) than in the non-survivor group (64%) (P < 0.001). Three of the non-survivors died of brain death within 5 days after resuscitation, and then the others died of respiratory or cardiovascular failure without recovering from deep coma. The high SjO2 of the non-survivors suggests that an inability of damaged neurons to use oxygen may be an indicator of poor neurological outcome in resuscitated patients after cardiac arrest. When SjO2 was < 45%, Sv-O2 was extremely low, reflecting cardiovascular failure after resuscitation. SjO2 may thus serve to warn of deterioration in cardiopulmonary function and serve as a predictor of outcome in cardiac arrest survivors.


How to document and report orthopedic complications in clinical studies? A proposal for standardization.
The documentation of complications is critical for the evaluation of therapeutic interventions in orthopedics. However, there is a lack of accepted methodological standardization and definitions. We propose a concept to support the consensus development of a standardized management and classification of complications in clinical research. Complication events are examined regarding their clinical presentation, their timing of occurrence as well as their potential causal interrelationship for any given patient. Their clinical presentation is distinguished by their likely triggers, their therapeutic management, and their outcome. Complications are events (including relevant deviations from their expected healing process) that are harmful to patients and can be described as local to the treated injury/disease or systemic (when they affect the rest of the body). The treatment of a complication, e.g. by way of an unplanned surgical intervention, and its outcome should be carefully documented. Complication review boards with independent clinicians should be established to validate complication records. In this proposal, a number of complication examples are presented to illustrate the concept and demonstrate its practical use. This management and classification system has already proven valuable in the documentation and analysis of complication data from a number of published clinical studies. Because of this new standardized assessment process, it facilitates the communication of complications between clinicians and researchers, and helps to develop clear definitions for specific orthopedic complications.


A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation.
To mediate the degradation of biomacromolecules, lysosomes must traffic towards cargo-carrying vesicles for subsequent membrane fusion or fission. Mutations of the lysosomal Ca(2+) channel TRPML1 cause lysosomal storage disease (LSD) characterized by disordered lysosomal membrane trafficking in cells. Here we show that TRPML1 activity is required to promote Ca(2+)-dependent centripetal movement of lysosomes towards the perinuclear region (where autophagosomes accumulate) following autophagy induction. ALG-2, an EF-hand-containing protein, serves as a lysosomal Ca(2+) sensor that associates physically with the minus-end-directed dynactin-dynein motor, while PtdIns(3,5)P(2), a lysosome-localized phosphoinositide, acts upstream of TRPML1. Furthermore, the PtdIns(3,5)P(2)-TRPML1-ALG-2-dynein signalling is necessary for lysosome tubulation and reformation. In contrast, the TRPML1 pathway is not required for the perinuclear accumulation of lysosomes observed in many LSDs, which is instead likely to be caused by secondary cholesterol accumulation that constitutively activates Rab7-RILP-dependent retrograde transport. Ca(2+) release from lysosomes thus provides an on-demand mechanism regulating lysosome motility, positioning and tubulation.


Influenza viruses and cross-reactivity in healthy adults: humoral and cellular immunity induced by seasonal 2007/2008 influenza vaccination against vaccine antigens and 2009 A(H1N1) pandemic influenza virus.
We analyzed humoral and cellular immune responses against vaccine antigens and the new A(H1N1) virus in healthy adults before and after immunization with the 2007/2008 commercially available trivalent subunit MF59-adjuvanted influenza vaccine during the Fall 2007, prior to the emergence of the new virus. Antibody titers were significantly boosted only against the three vaccine antigens. Seasonal vaccination boosted pre-existing cellular responses upon stimulation of peripheral blood mononuclear cells not only with the homologous three vaccine antigens, but also with the heterologous new 2009 A(H1N1) and with a highly conserved peptide present in the stalk region of hemagglutinin (HA). These results show that cross-reactive cell responses against the new virus were present before the circulation of the virus and were boosted by seasonal vaccination. The cross-reactivity of cellular responses might, at least in part, explain the low pathogenicity of the new pandemic virus. The finding of cellular immunity, that can be increased by seasonal vaccination, against the conserved HA peptide, underline the potential use, in human vaccines, of conserved peptides of the stalk region of HA characterized by broad immunogenicity in experimental systems.


Characterization of RBPome in Oxidative Stress Conditions.
Cellular redox signaling is triggered by accumulation of various reactive oxygen species (ROS) that integrate with other signaling cascades to enable plants to ultimately respond to (a)biotic stresses. The identification of key regulators underlying redox signaling networks is therefore of high priority. This chapter describes an improved mRNA interactome capture method that allows to systematically detect oxidative stress responsive regulators in the post-transcriptional gene regulation (PTGR) pathway. The protocol includes PSB-D suspension cell culture preparation, setup of oxidative stress conditions, short-term exposure to UV irradiation, cell lysis, pull-down and purification of crosslinked messenger ribonucleoproteins, their mass spectrometric analyses, and identification of proteome by statistical analyses. As result, a comprehensive inventory of the functional oxidative stress responsive RBPome (OxRBPome) is generated, which paves the way toward new insights into PTGR processes in redox signaling.


Stochastic coherence in an oscillatory gene circuit model.
We show that noise-induced oscillations in a gene circuit model display stochastic coherence, that is, a maximum in the regularity of the oscillations as a function of noise amplitude. The effect is manifest as a system-size effect in a purely stochastic molecular reaction description of the circuit dynamics. We compare the molecular reaction model behavior with that predicted by a rate equation version of the same system. In addition, we show that commonly used reduced models that ignore fast operator reactions do not capture the full stochastic behavior of the gene circuit. Stochastic coherence occurs under conditions that may be physiologically relevant.


Impact of Insurance Status on Radiation Treatment Modality Selection Among Potential Candidates for Prostate, Breast, or Gynecologic Brachytherapy.
The Patient Protection and Affordable Care Act looks to expand both private and Medicaid insurance. To evaluate how these changes may affect the field of radiation oncology, we evaluated the association of insurance status with the use of brachytherapy in cancers for which this treatment technique is used. A total of 190,467 patients met the inclusion criteria, of whom 95,292 (50.0%) had breast cancer, 61,096 (32.1%) had prostate cancer, 28,194 (14.8%) had endometrial cancer, and 5885 (3.1%) had cervical cancer. A multivariate logistic regression model was used to determine the association between insurance status and receipt of brachytherapy among patients treated definitively for prostate and cervical cancer or postoperatively for breast and endometrial cancer. The rates of non-Medicaid insurance were 49.9% (cervical), 85.3% (endometrial), 87.4% (breast), and 90.9% (prostate) (P<.001). In a logistic regression, patients who received radiation therapy were less likely to receive brachytherapy if they had Medicaid coverage (odds ratio [OR] 0.57, 95% confidence interval [CI] 0.53-0.61, P<.001) or did not have insurance coverage (OR 0.50, 95% CI 0.45-0.56, P<.001) compared with those with non-Medicaid insurance. On subset analysis, patients with Medicaid coverage or without insurance coverage were significantly less likely to receive brachytherapy than were those with non-Medicaid insurance for all 4 sites, except for patients with endometrial cancer. Despite being a cost-effective treatment modality, brachytherapy is less often used in the definitive or postoperative management of cancer in patients with Medicaid coverage or without insurance. Upcoming health policy changes resulting in the expansion of private insurance and Medicaid will likely increase access to and demand for brachytherapy.


Nutritional Management in Adult Patients With Dysphagia: Position Paper From Japanese Working Group on Integrated Nutrition for Dysphagic People.
This position paper prepared by the Japanese Working Group on Integrated Nutrition for Dysphagic People (JWIND) aims to summarize the need for nutritional management in adult patients with dysphagia, the issues that nutrition professionals should address, and the promising approaches as well as to propose a vision for the future of nutritional care for adult patients with dysphagia. JWIND is a joint certification system recognized by the Japan Dietetic Association and the Japanese Society of Dysphagia Rehabilitation; its members are mostly experts known as "Certified Specialist of Registered Dietitian for Dysphagia Rehabilitation." Malnutrition and dysphagia are associated with each other. Therefore, malnutrition detection and intervention are essential for patients with dysphagia. However, evidence on the usefulness nutritional assessment and intervention to ensure appropriate nutritional care remains insufficient. Here, we present current knowledge of the relationship between primary diseases causing dysphagia and malnutrition, the indicators used for nutritional assessment, and nutritional interventions such as texture-modified diet (TMD) quality improvement, oral nutritional supplementation, and comprehensive intervention. We also discuss the current status and issues in nutritional care for adult patients with dysphagia. Furthermore, we have proposed measures that nutrition professionals should consider based on 3 perspectives: nutritional assessment, TMD, and nutritional intervention. Individualized and specialized nutritional management by registered dietitians (RDs) through appropriate assessment of the nutritional status of adult patients with dysphagia is needed. To maintain and improve swallowing function and nutritional status, RDs should intervene from the state of risk or early dysphagia onset, providing individualized care per their expertise as part of a multidisciplinary team. However, systematic clinical practice and research regarding the association of nutrition with dysphagia are currently insufficient. Therefore, further clinical practice and evidence building, including the verification of the efficacy on nutritional support through intervention research, are needed.


Chemotherapy and irradiation interaction.
The combination of chemotherapeutic drugs with radiation therapy has perhaps been one of the most promising strategies for current cancer radiotherapy practice, and has a strong biologic rationale. Concurrent chemoradiotherapy has been shown to improve survival and locoregional control of various cancers compared with radiotherapy alone. This article reviews the biologic rationale and principles fundamental to the use of chemoradiotherapy, and discusses mechanistic interactions between drugs and radiation, the knowledge of which is essential in developing optimal treatment strategies. Chemotherapeutic agents, particularly those shown to augment the radiation response of tumors, will be reviewed, and novel compounds and some of the exciting emerging strategies for chemoradiotherapy will be presented.


Homo-Tandem Polymer Solar Cells with VOC >1.8 V for Efficient PV-Driven Water Splitting.
Efficient homo-tandem and triple-junction polymer solar cells are constructed by stacking identical subcells composed of the wide-bandgap polymer PBDTTPD, achieving power conversion efficiencies >8% paralleled by open-circuit voltages >1.8 V. The high-voltage homo-tandem is used to demonstrate PV-driven electrochemical water splitting with an estimated solar-to-hydrogen conversion efficiency of ≈6%.


Human T-cell leukemia virus type I and adult T-cell leukemia.
Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia (ATL) in about 5% of carriers after a long latent period. After its infection, HTLV-I promotes the clonal proliferation of HTLV-I infected cells in vivo by actions of encoded viral proteins, including Tax. However, leukemic cells frequently lack the expression of Tax by the genetic and epigenetic changes of HTLV-I provirus, suggesting that Tax is not always necessary after transformation. Alternatively, ATL cells without Tax protein could escape from the host immune system since Tax is the major target of cytotoxic lymphocytes. During the latent period, alterations of host genome accumulate, finally leading to onset of ATL.


Studies in REST. II. An overview of REST technology.
This paper briefly summarizes current knowledge about Reduced Environmental Stimulation Therapy (REST). Major effects consistently produced by REST include (a) superlearning, (b) optimal physiological and psychological functioning, and (c) diminished denial and defensiveness. Persons showing greatest impairment or psychological disturbance prior to REST typically show the greatest "improvement" or change toward optimal levels of functioning afterward. REST facilitates natural homeostatic processes. Despite three decades of overwhelmingly positive research findings, REST technology has thus far received little understanding or acceptance. Common misconceptions about REST (formerly known as "sensory deprivation") are critically assessed and shown to be unfounded.


Mild hypercapnia with hyperventilation attenuates recovery from anesthesia in elderly patients.
Mild hypercapnia with hyperventilation has been reported to significantly decrease recovery time from inhaled anesthesia in young and middle-aged patients. However, its efficacy has not yet been clarified in elderly patients, although delayed emergence can deteriorate their quality of recovery. We enrolled 30 elderly patients (≥65 years) and 30 middle-aged patients (45-64 years) who were scheduled for ophthalmic surgery and allocated them to the control or the device group. Anesthesia was maintained with 1.5% sevoflurane. Mild hypercapnic hyperventilation was induced by the ANEclear anesthesia recovery device. The primary outcome was the time from vaporizer shut-off to initial response (eye or mouth opening, nodding, or grasping hand) in elderly patients. The secondary outcomes were the time to extubation and leaving the operating room (OR), the time to reach 50% of the difference between BIS at extubation and vaporizer shut-off (BIS ET50), and interaction between the recovery measures and patient age. The ANEclear significantly reduced the time to initial response, extubation, leaving the OR, and BIS ET50 in both age groups: their means and 95% CI of the ratio of two means (Mean(ANEclear)/Mean(control)) were 0.576 (0.500, 0.660), 0.595 (0.523, 0.673), 0.713 (0.622, 0.812), and 0.547 (0.444, 0.663), respectively, in the elderly group, and 0.717 (0.591, 0.849), 0.723 (0.609, 0.842), 0.855 (0.736, 0.982), and 0.631 (0.463, 0.813), respectively, in the middle-aged group. The recovery measures were shortened equally in both age groups: P values for the interaction were 0.060679, 0.062534, 0.069215, and 0.420061, respectively. Recovery time was significantly decreased by the ANEclear in the elderly group. This reduction was comparable to the time for middle-aged patients.


Integration of Epstein-Barr virus DNA.
The application to herpesviruses of different standard methods fo measuring tumour-virus integration is discussed. The evidence for the presence of integrated virus DNA in EBV-transformed cells is summarized.


Prodromal Parkinson's disease as defined per MDS research criteria in the general elderly community.
Recently, the International Parkinson and Movement Disorder Society has defined research criteria for prodromal Parkinson's disease (PD), but to date their predictive value has not yet been tested in population-based cohorts. We retrospectively applied these criteria to the longitudinal Bruneck Study cohort aged 55-94 years using recorded data on all included risk and prodromal markers that are quick and easily assessable. After excluding participants with idiopathic PD or secondary parkinsonism, prevalence of probable prodromal PD in the remaining 539 participants was 2.2% (95% confidence interval, 1.2%-3.9%). Of 488 participants followed up over 5 years, 11 developed incident PD. Sensitivity of "probable prodromal PD" status for incident PD was 54.6% (95% confidence interval, 28.0%-78.8%), specificity was 99.2% (97.8%-99.8%), positive predictive value was 60.0% (31.2%-83.3%), and negative predictive value was 99.0% (97.5%-99.6%). Our findings suggest that the new research criteria for prodromal PD are a promising tool to identify cases of incident PD over 5 years, arguing for their usefulness in defining target populations for disease-prevention trials. © 2016 International Parkinson and Movement Disorder Society.


Myocardial perfusion imaging with cardiac computed tomography: state of the art.
Cardiac computed tomography (CCT) has become an important tool for the anatomic assessment of patients with suspected coronary disease. Its diagnostic accuracy for detecting the presence of underlying coronary artery disease and ability to risk stratify patients are well documented. However, the role of CCT for the physiologic assessment of myocardial perfusion during resting and stress conditions is only now emerging. With the addition of myocardial perfusion imaging to coronary imaging, CCT has the potential to assess both coronary anatomy and its functional significance with a single non-invasive test. In this review, we discuss the current state of CCT myocardial perfusion imaging for the detection of myocardial ischemia and myocardial infarction and examine its complementary role to CCT coronary imaging.


Repeat expansion in C9ORF72 is not a major cause of amyotrophic lateral sclerosis among Iranian patients.
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in populations of European descent. It was recently found that a hexanucleotide repeat expansion in C9ORF72 is its most common cause in these populations. The contribution of C9ORF72 to ALS is notably lower in the Far East, but its role in other populations is unknown. Results of C9ORF72 screening in 78 unrelated Iranian ALS patients are reported here. The repeat expansion was observed in only 1 (5.9%) of the familial and 1 (1.6%) of the sporadic cases. These figures are to be compared, respectively, with 30% and 6.9% among patients of European ethnicity. Screenings of C9ORF72 in other Middle East countries will reveal whether the low contribution of C9ORF72 to ALS is a feature of the entire region. During the screenings, it was noted that in a single family, 3 individuals affected with ALS, Parkinson's disease, or frontotemporal dementia all carried the repeat expansion. The finding suggests the mutation does rarely contribute to the etiology of Parkinson's disease.


Alcohol consumption, sex, and use of psychotropic substances among male Hong Kong-mainland China cross-border substance users.
The study investigated the prevalence and associated factors for co-occurrence of psychotropic substance use, alcohol consumption and sexual activities among substance users. Totally, 1167 Hong Kong Chinese males aged 18-30 having used substances in mainland China in the last year were identified. Of them, 72.5% and 42.7% respectively reported having consumed alcohol and engaged in sexual activities in conjunction with the last episode of substance use. Among those using substances exclusively in mainland China, multivariate analyses showed that having friends who frequently used substances in China (OR=3.18) and being accompanied by friends in the last episode of substance use (OR=2.31) were associated with alcohol consumption; older age (OR=2.01), higher education level (OR=2.31), alcohol consumption (OR=2.72), belief that substance use increased sexual potency (OR=2.81) and use of multiple types of psychotropic substances in China (OR=2.94) were significantly associated with having sex in conjunction with the last episode of using psychotropic substances. Cross-border psychoactive substance use often co-occurs with alcohol and sex. High levels of risk are involved. Different types of preventive programs need to be integrated.


Vero cells expressing porcine circovirus type 2-capsid protein and their diagnostic application.
Porcine circovirus type 2 (PCV2) is the causative agent of postweaning multisystemic wasting syndrome (PMWS) in swine. Although the incidences of PCV2-related diseases are ubiquitous throughout the world, the serological tools are rather limited, mainly because the virus does not induce any cytopathic effects in cells. The purpose of this study was to develop a rapid, sensitive and easy quantitative immunofluorescence assay (QIFA) using the recombinant PCV2 nucleocapsid protein (NCP) for the detection of PCV2-specific antibodies in pig sera. The recombinant PCV2 NCP was expressed in Vero cells by a lentivirus system. The performance of QIFA using these Vero cells as a diagnostic antigen was compared with currently available C-ELISA and I-ELISA; the relative sensitivity turned out to range from 92.5% up to 99.3%. The relative specificity was 93.3% when compared to C-ELISA as the gold standard. The serological experiment also indicated the inverse relationship between QIFA and the viral load in serum, semen, feces samples from 7 PCV2-positive boars. In addition, the PCV2 sequence detected from bone marrow cells shows 99% of sequence identity with PCV2 genome, confirming the infectivity of PCV2.


Suicide and death ideation in older adults obtaining aging services.
To assess the frequency and correlates of death and suicide ideation in older adults accessing aging services. Cross-sectional. Data for this study were collected via in-home interviews. Aging Services Network (ASN) care management clients aged 60 years and older (N = 377) were recruited for this study. The PHQ-9 and the Paykel Suicide Scale were used to assess death and suicide ideation. Correlates of death and suicide ideation were also examined. Fourteen percent of subjects endorsed current death or suicide ideation, 27.9% of subjects endorsed death ideation in the past year, and 9.3% of subjects endorsed suicide ideation in the last year. Current death and suicide ideation were associated with greater depressive symptoms. As compared with individuals without ideation, individuals with death ideation demonstrated higher levels of depressive symptoms, more medical conditions, and lower social support. Individuals with suicide ideation demonstrated higher depressive and anxiety symptoms and less perceived social support. Finally, as compared with individuals with death ideation, individuals with suicide ideation demonstrated higher depressive and anxiety symptoms and more alcohol misuse. Death and suicide ideation are common among ASN clients. There were both differences and similarities between correlates of death and suicide ideation. ASN providers are uniquely situated to address many of the correlates of suicide ideation identified in this study; in order to effectively manage suicide ideation in an ASN setting, however, links to primary and mental health care providers are necessary.


Predictive and Prognostic Role of Pre-Therapy and Interim 68Ga-DOTATOC PET/CT Parameters in Metastatic Advanced Neuroendocrine Tumor Patients Treated with PRRT.
Peptide receptor radionuclide therapy (PRRT) is an effective therapeutic option in patients with metastatic neuroendocrine tumor (NET). However, PRRT fails in about 15-30% of cases. Identification of biomarkers predicting the response to PRRT is essential for treatment tailoring. We aimed to evaluate the predictive and prognostic role of semiquantitative and volumetric parameters obtained from the 68Ga-DOTATOC PET/CT before therapy (bPET) and after two cycles of PRRT (iPET). A total of 46 patients were included in this retrospective analysis. The primary tumor was 78% gastroenteropancreatic (GEP), 13% broncho-pulmonary and 9% of unknown origin. 35 patients (76.1%) with stable disease or partial response after PRRT were classified as responders and 11 (23.9%) as non-responders. Logistic regression analysis identified that baseline total volume (bTV) was associated with therapy outcome (OR 1.17; 95%CI 1.02-1.32; p = 0.02). No significant association with PRRT response was observed for other variables. High bTV was confirmed as the only variable independently associated with OS (HR 12.76, 95%CI 1.53-107, p = 0.01). In conclusion, high bTV is a negative predictor for PRRT response and is associated with worse OS rates. Early iPET during PRRT apparently does not provide information useful to change the management of NET patients.


Local compression patterns beneath pneumatic tourniquets applied to arms and thighs of human cadavera.
Distributions of tissue fluid pressure were examined beneath a standard pneumatic tourniquet in six upper extremities and six lower extremities of fresh human cadavera, disarticulated at the shoulder and hip, respectively. A standard 8-cm-wide tourniquet cuff was applied at mid-humerus or mid-femur position. Tissue fluid pressures were measured by 100-cm-long slit catheters inserted parallel to the bone at four tissue depths: subcutaneous, subfascial, mid-muscle, and adjacent to bone. All arms and thighs were studied at the following cuff pressures: 100, 150, 200, 250, 300, 400, and 500 mm Hg. Tissue fluid pressure was always maximal in subcutaneous tissue at mid-cuff. Transmission of cuff pressures to deeper tissues was significantly less (p less than 0.01) in the thighs with a girth of 40-52 cm than in the arms with a girth of 22-33 cm. At the four tissue depths studied, tissue fluid pressures fell steeply in a longitudinal direction near the cuff edge to levels near zero at points 1-2 cm outside each cuff edge. Our results suggest that wider cuffs are required on thighs than on arms to provide a bloodless field during limb surgery and to minimize underlying tissue injury associated with high cuff pressures. Our recommendation for wider tourniquet cuffs than those presently used during orthopaedic surgery is contrary to recent prevailing knowledge.


Combined estimation of tetanus and diphtheria antitoxin in human sera by the in vitro Toxin-Binding Inhibition (ToBI) test.
The use of the principle of inhibition of toxin binding to an antitoxin coated immunoassay plate as described in a previous paper for tetanus antitoxin titration, was adapted for the estimation of diphtheria antitoxin in human sera. With a few modifications, a Toxin-Binding Inhibition (ToBI) test was developed which could be used for a combined estimation of both tetanus and diphtheria antitoxin levels. The application of streptavidin-biotinylated peroxidase complex when using small serum samples (less than 50 microliters) is discussed. Antitoxin titres (both diphtheria and tetanus) of 0.002 IU ml-1 were detectable by the ToBI test, this being far below the level considered to be protective in man. Sera from 140 adults with different vaccination histories were titrated for both tetanus and diphtheria antitoxin. Good correlations were found between the estimates obtained by the ToBI test and those obtained by the toxin-neutralization (TN) test in mice (tetanus antitoxin) and those obtained in the in vitro neutralization test in VERO cells (diphtheria antitoxin). It is concluded that the ToBI test is a simple and reliable alternative to the functional models currently in use for the estimation of diphtheria and tetanus antitoxin levels. In addition, the ToBI test eliminates the need for laboratory-animal or cell-culture facilities and can be performed with small quantities of serum as required in field trials.


Tamoxifen Treatment and the Reduced Risk of Hyperlipidemia in Asian Patients With Breast Cancer: A Population-Based Cohort Study.
The association between tamoxifen (TMX) treatment and the risk of developing hyperlipidemia remains unclear. The records of 41,726 patients with breast cancer (28,266 received TMX and 13,460 did not) were obtained from the Taiwan National Health Insurance Research Database for the period from January 2000 to December 2008. Three-fold women without breast cancer were the control group (N = 125, 178). The main end point was developing hyperlipidemia during the follow-up. During a mean follow-up of 9 years, the patients with breast cancer demonstrated a rate of developing hyperlipidemia that was 6% less (adjusted hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.90-0.97) than that of the control participants without breast cancer. Stratification by age group indicated that only women aged ≥ 55 years who were diagnosed with breast cancer exhibited a significantly reduced risk of hyperlipidemia compared with the control group. With the use of 2 types of adjusted models, we observed that the TMX users (aged ≥ 55 years) consistently exhibited a significantly lower risk of hyperlipidemia than the non-TMX users and control participants (adjusted HRs, 0.79 and 0.82 from models 1 and 2, respectively). Within the 8-year follow-up period, patients with breast cancer and 366 to 1500 days of TMX therapy and > 1500 days of TMX therapy had significantly lower risks of hyperlipidemia compared with patients with ≤ 365 days of TMX therapy (adjusted HR, 0.54; 95% CI, 0.50-0.59; adjusted HR, 0.21; 95% CI, 0.18-0.24, respectively). In Asian patients with breast cancer, TMX use was associated with reduced risks of hyperlipidemia.


Purification and characterization of four isoforms of Himalayan mistletoe ribosome-inactivating protein from Viscum album having unique sugar affinity.
Ribosome-inactivating proteins having antitumor and immunomodulatory properties constitute the active principle of widely used mistletoe therapy in Europe. This is the first report of the four isoforms of Himalayan mistletoe ribosome-inactivating proteins (HmRips) from Viscum album parasitized on wild apple inhabiting NW Himalayas. HmRips were purified by affinity chromatography and four isoforms were separated by ion-exchange chromatography. HmRip 1, 2, 3, and 4 have isoelectric points of 6.6, 6.1, 5.2, and 4.7, respectively. Disulfide linked toxin and lectin subunits of HmRip 1 and 2 isoforms have molecular weights of 28 and 34kDa while those of HmRip 3 and 4 have 28 and 32kDa. The isoforms lacked blood group specificity and showed positive activity with seven mammalian erythrocyte types but did not show any activity with avian erythrocyte type. Lectin activity of HmRips remained unchanged for a wide range of temperatures (0-65 degrees C) and pH (3-9). Unlike other type II Rips, the HmRip 1, 2, and 4 showed unique affinity towards l-rhamnose, meso-inositol, and l-arabinose while HmRip 3 has specificity to gal/galNAc. Sugar binding studies with 22 sugars also suggested that the C-4 hydroxyl of galactose might be the critical site involved in sugar binding of HmRips. Type II Rips are known to be galactoside specific and do not have affinity for l-rhamnose and meso-inositol. However, HmRip 1, 2, and 4 having equal affinity for galactose and l-rhamnose do not strictly fit into any of the four structural classes of the lectins and represent a new class of type II Rips and plant lectins.


Drastic Reduction of Turnaround Time After Implementation of a Fully Automated Assay for RAS-BRAF Mutations in Colorectal Cancer: A Pilot Prospective Study in Real-life Conditions.
In some situations, there is a need for rapid mutation tests for guiding clinical decisions and starting targeted therapies with minimal delays. In this study we evaluated the turnaround time before and after the implementation of a fully automated multiplex assay for KRAS and NRAS/BRAF mutation tests (Idylla™ platform, Biocartis) in metastatic colorectal cancer. The objective of this project was to compare the turnaround times in 2017-2018 with the fully automated multiplex assay to the 2016 results with previous methods. Centers with a number of tests for metastatic colorectal cancer > 100 yearly and a usual turnaround time ≥ 3 weeks for mutation detection were selected. Results of 505 KRAS tests and 369 NRAS/BRAF tests were transmitted by 10 centers. The mean turnaround time from test prescription to reception of results was reduced from 25.8 days in 2016 to 4.5 days in 2017-2018. In conclusion, this pilot project shows that the Idylla™ platform for testing KRAS and NRAS/BRAF mutations allows an optimized turnaround time from test prescription to reception of results.


Targeting Iron-Sulfur Clusters in Cancer: Opportunities and Challenges for Ferroptosis-Based Therapy.
Iron dysregulation is a hallmark of cancer, characterized by an overexpression of genes involved in iron metabolism and iron-sulfur cluster (ISC) biogenesis. Dysregulated iron homeostasis increases intracellular labile iron, which may lead to the formation of excess cytotoxic radicals and make it vulnerable to various types of regulated cell death, including ferroptosis. The inhibition of ISC synthesis triggers the iron starvation response, increasing lipid peroxidation and ferroptosis in cancer cells treated with oxidative stress-inducing agents. Various methods, such as redox operations, iron chelation, and iron replacement with redox-inert metals, can destabilize or limit ISC formation and function, providing potential therapeutic strategies for cancer treatment. Targeting ISCs to induce ferroptosis represents a promising approach in cancer therapy. This review summarizes the state-of-the-art overview of iron metabolism and ferroptosis in cancer cells, the role of ISC modulation in ferroptosis, and the potential of targeting ISCs for ferroptosis induction in cancer therapy. Further research is necessary to develop and validate these strategies in clinical trials for various cancers, which may ultimately lead to the development of novel and effective treatments for cancer patients.


Urinary excretion of orally administered oxalic acid in MYRJ 45-treated NMRI mice.
Polyoxyethylene(8)stearate (MYRJ 45) has been shown to cause bladder tumours in chronic feeding studies. During this study the effects of dietary MYRJ 45 on the urinary excretion of dietary oxalic acid were tested. Male NMRI mice were gradually adapted to 20% MYRJ 45 in their diet. The animals were then dosed, after a 6 h fast, with 2 microCi of [U-14C]oxalic acid either with 1 ml of water or 1 ml of 20% MYRJ 45 in water. The urinary and faecal excretion of the label were determined using the combustion method coupled with liquid scintillation counting. MYRJ 45 was observed to increase significantly the urinary absorption of 14C in male NMRI mice when compared to control mice dosed with oxalic acid and water. The increase was observed both in MYRJ 45-pretreated mice receiving the label with MYRJ 45 or with water and in control mice receiving the label in a 20% MYRJ 45 water solution. The result indicates that dietary MYRJ 45 significantly increases the urinary excretion of dietary oxalic acid in male NMRI mice. This increase may contribute to the bladder tumour formation by facilitating calcium oxalate crystalluria with potential bladder wall irritating effect in mice.


[Psychological Parameters of Adolescent Patients Prior to Obesity Treatment].
Overweight and obesity in children and adolescents are highly prevalent and persistent. Current weight loss treatments are rarely individualized and show only small to moderate efficacy. Only rarely, psychopathological parameters are considered. The present study evaluated the psychopathology of adolescents with overweight and obesity (N=201, ages 12-17 years) prior to obesity treatment. The data were analyzed for age and sex effects. Self-report questionnaires assessed general symptom burden, eating disorder and general psychopathology, weight-related self-stigmatization, and physical and mental quality of life. Girls showed higher rates of weight-related self-stigmatization and higher disordered eating behavior compared to boys. Older adolescents reported a lower quality of life compared to younger adolescents. In normative comparisons with population-based samples and norms, adolescents with overweight and obesity showed significantly adverse outcomes in all parameters. Thus, this study identified psychopathology as an important factor in adolescents with high weight status that may affect obesity treatment. Future studies should examine psychopathology more differentially and determine therapeutic resources in adolescent overweight and obesity.


Persistent immune alterations and comorbidities in splenectomized patients with Gaucher disease.
Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the gene encoding acid-β-glucosidase, resulting in functional disruptions in degradation of glycosphingolipids and lysosomal accumulation of the substrates. The most frequent clinical presentations of GD are thrombocytopenia, splenomegaly and bone pain. Prior to advent of enzyme replacement therapy, splenectomy was performed for complications of hypersplenism such as severe thrombocytopenia and transfusion dependency. Though there is evidence about worsening bone disease after splenectomy, there is no systematic study to assess its effects on the immune system in GD patients. In order to investigate the long-term immunological effects of splenectomy, we used flow cytometry to compare the immunophenotypes of GD patients who had undergone splenectomy (SGD) to those with intact spleen. The results show that SGD patients have significantly fewer CD27(+)/IgM(+) B-cells but more CD4(+)/CD45RO(+) and CD8(+)/CD45RO(+) T-cells. The most surprising finding was an almost complete absence of circulating dendritic cells in SGD patients. In addition, splenectomized subjects had comorbidities, the most common being monoclonal gammopathy of undetermined significance (MGUS). Taken together, these results highlight the persistence of multiple immune alterations and comorbidities coexisting in higher frequency in the SGD group and they are not affected by GD specific therapy.


Cost analysis for reimbursement-rate setting of hospital pharmaceutical services in Thailand.
OBJECTIVES This study aimed to develop a hospital pharmaceutical service model, together with a costing template for unit cost analysis and to analyse unit costs of hospital pharmaceutical services. METHODS The study was designed on the basis of activity-based costing. A model of the services was set up by consensus of the working group. Pharmaceutical services among the study hospitals were standardised. A Microsoft Excel-based costing template was developed. Finally, the costing template was used for the unit cost analysis. Sensitivity analysis and descriptive statistics were used for further analysis. KEY FINDINGS Four general and seven regional hospitals participated in the study. Hospital pharmaceutical services were divided into nine supporting activities and nine patient-service activities. Unit costs of drug dispensing per prescription by regional hospitals were approximately double that of general hospitals. In contrast, the cost of aseptic dispensing per item in regional hospitals was lower than those in general hospitals. In comparing the unit costs from standard labour costs with those from actual labour costs, both increases and decreases were found. CONCLUSIONS Costing and the use of Microsoft Excel can be applied to the development of a costing template for unit cost analysis of hospital pharmaceutical services. This programme can provide accurate unit costs for services. The results can be used when considering pharmacy service reimbursement, efficiency and service development.