Cost-effectiveness analysis of atezolizumab in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen: a United Kingdom health care perspective.
Cost-effectiveness of atezolizumab, as a treatment for advanced non-small-cell lung cancer (NSCLC) patients who cannot receive a platinum-containing regimen,was still unknown. Our objective was to evaluate the cost-effectiveness of atezolizumab vs. chemotherapy in this indication from the perspective of UK healthcare system. From the global, randomised, open-label, phase III IPSOS trial, clinical inputs and patient characteristics were obtained. A partitioned survival model with three health states was built: Progression-free survival, progressed disease and death. A lifetime time horizon was applied, with an annual discount rate of 3.5%. Additionally, the willingness-to-pay threshold of £50,000/QALY was utilized. Primary outcomes were quality-adjusted life-year (QALY), costs, and incremental cost-effectiveness ratio (ICER). Sensitivity, scenario, and subgroup analyses were used to assess the reliability of base-case results. Price simulations were carried out in order to provide information for the pricing strategy at specific willingness-to-pay threshold. In the base-case analysis, atezolizumab resulted in a gain of 0.28 QALYs and an ICER of £94,873/QALY compared to chemotherapy, demonstrating no cost-effectiveness. Price simulation results revealed that atezolizumab would be preferred at a price lower than £2,215 (a reduction of 41.8%) at the willingness-to-pay threshold of £50,000. Sensitivity, scenario and subgroup analyses revealed these conclusions were generally robust, the model was most sensitive to the price of atezolizumab and subsequent medication. Furthermore, atezolizumab was found to be more cost-effective for patients displaying a positive PD-L1 expression, with an ICER of £72,098/QALY as compared to chemotherapy. Atezolizumab is not cost-effective for patients with advanced NSCLC ineligible for platinum-containing regimen, potential price reduction is necessary.


Promoting physical activity among South Asian women with coronary heart disease and diabetes: what might help?
People of South Asian origin have higher mortality and morbidity from coronary heart disease (CHD) and diabetes than those of European origin. However, physical activity, of established value in primary and secondary prevention, appears lower among South Asians. To explore influences on, and attitudes towards, physical activity among South Asian women with CHD and diabetes to inform secondary prevention strategies. Exploratory qualitative study with women aged 26-70 years of varying South Asian ethnicity, religion and socio-economic background with CHD and/or non-insulin-dependent diabetes were recruited from primary care practices in the UK. The beneficial use of physical activity to improve and limit progression of their disease was largely unrecognized by the women interviewed. They were uncertain what type and level of physical activity was appropriate and safe for them. They operated their own threshold for physical activity in relation to their condition, which they were afraid to exceed. Specific guidance from health professionals was lacking. Respondents emphasized the cultural importance of being active day to day, rather than the 'Western' concepts of organized exercise. However, women's principal motivations and attitudes towards physical activity, to loose weight, socialize and maintain independence, were culturally similar to 'majority' populations. Better health professional guidance on appropriate physical activity, its health benefits and its safety is needed for this highly at-risk group. Promoting informal moderate-intensity physical activity may help. Strategies should avoid any tendency to overemphasize cultural barriers noting greater similarities than differences between cultural groups.


Transvenous, intracardial cardioversion for the treatment of postoperative atrial fibrillation.
Atrial fibrillation (AF) following cardiac surgery is an important factor contributing to postoperative morbidity. Transvenous, intracardial cardioversion (TIC) has been shown to be effective in the treatment of chronic AF, but is an invasive and cost-intensive procedure. However, TIC would definitely be a beneficial approach if recurrence of AF following TIC is low and pharmacological treatment could be avoided. Thus, we hypothesised that TIC would be superior to conventional treatment with amiodarone with respect to the conversion rate and recurrence of AF. We compared TIC and conventional amiodarone therapy in a prospective, randomised and controlled trial in patients who developed AF following cardiac surgery. Twenty-three patients developed AF out of a total of 76 patients who gave written informed consent. Eighteen of these AF patients could be randomised into two equally sized groups to receive either an ALERT pulmonary artery catheter and TIC, or a standard pulmonary artery catheter and treatment with amiodarone. Haemodynamic parameters were registered before intervention to exclude pulmonary hypertension or fluid overload. Rates of cardioversion were compared by a Likelyhood ratio test. Out of the nine ALERT patients, AF in five cases converted to sinus rhythm (SR) with a median of two shocks (6 J). After 24 hours however, only two patients remained in sinus rhythm. On the other hand, six of the nine patients treated with amiodarone were still in SR after 24 hours. Whereas no difference was detectable in the conversion rate, persistence of SR following TIC was low. Thus, TIC without antiarrhythmic treatment is not recommendable for the treatment of postoperative AF.


Hydrogen Production from Barley Straw and Miscanthus by the Hyperthermophilic Bacterium, Cadicellulosirupter bescii.
This work aimed to evaluate the feasibility of biohydrogen production from Barley Straw and Miscanthus. The primary obstacle in plant biomass decomposition is the recalcitrance of the biomass itself. Plant cell walls consist of cellulose, hemicellulose, and lignin, which make the plant robust to decomposition. However, the hyperthermophilic bacterium, Caldicellulosiruptor bescii, can efficiently utilize lignocellulosic feedstocks (Barley Straw and Miscanthus) for energy production, and C. bescii can now be metabolically engineered or isolated to produce more hydrogen and other biochemicals. In the present study, two strains, C. bescii JWCB001 (wild-type) and JWCB018 (ΔpyrFA Δldh ΔcbeI), were tested for their ability to increase hydrogen production from Barley Straw and Miscanthus. The JWCB018 resulted in a redirection of carbon and electron (carried by NADH) flow from lactate production to acetate and hydrogen production. JWCB018 produced ~54% and 63% more acetate and hydrogen from Barley Straw, respectively than its wild-type counterpart, JWCB001. Also, 25% more hydrogen from Miscanthus was obtained by the JWCB018 strain with 33% more acetate relative to JWCB001. It was supported that the engineered C. bescii, such as the JWCB018, can be a parental strain to get more hydrogen and other biochemicals from various biomass.


Can nature's design be improved upon? High strength, transparent nacre-like nanocomposites with double network of sacrificial cross links.
The preparation of a high-strength and highly transparent nacre-like nanocomposite via layer-by-layer assembly technique from poly(vinyl alcohol) (PVA) and Na+-montmorillonite clay nanosheets is reported in this article. We show that a high density of weak bonding interactions between the polymer and the clay particles: hydrogen, dipole-induced dipole, and van der Waals undergoing break-reform deformations, can lead to high strength nanocomposites: sigmaUTS approximately 150 MPa and E' approximately 13 GPa. Further introduction of ionic bonds into the polymeric matrix creates a double network of sacrificial bonds which dramatically increases the mechanical properties: sigmaUTS approximately 320 MPa and E' approximately 60 GPa.


How Quorum Sensing Connects Sporulation to Necrotrophism in Bacillus thuringiensis.
Bacteria use quorum sensing to coordinate adaptation properties, cell fate or commitment to sporulation. The infectious cycle of Bacillus thuringiensis in the insect host is a powerful model to investigate the role of quorum sensing in natural conditions. It is tuned by communication systems regulators belonging to the RNPP family and directly regulated by re-internalized signaling peptides. One such RNPP regulator, NprR, acts in the presence of its cognate signaling peptide NprX as a transcription factor, regulating a set of genes involved in the survival of these bacteria in the insect cadaver. Here, we demonstrate that, in the absence of NprX and independently of its transcriptional activator function, NprR negatively controls sporulation. NprR inhibits expression of Spo0A-regulated genes by preventing the KinA-dependent phosphorylation of the phosphotransferase Spo0F, thus delaying initiation of the sporulation process. This NprR function displays striking similarities with the Rap proteins, which also belong to the RNPP family, but are devoid of DNA-binding domain and indirectly control gene expression via protein-protein interactions in Bacilli. Conservation of the Rap residues directly interacting with Spo0F further suggests a common inhibition of the sporulation phosphorelay. The crystal structure of apo NprR confirms that NprR displays a highly flexible Rap-like structure. We propose a molecular regulatory mechanism in which key residues of the bifunctional regulator NprR are directly and alternatively involved in its two functions. NprX binding switches NprR from a dimeric inhibitor of sporulation to a tetrameric transcriptional activator involved in the necrotrophic lifestyle of B. thuringiensis. NprR thus tightly coordinates sporulation and necrotrophism, ensuring survival and dissemination of the bacteria during host infection.


Patterns of organization and management in private and public substance abuse treatment programs.
As an organizational field, substance abuse treatment clearly includes a remarkable range of organizations. Yet only in the past two decades has there been research interest in the organizational context in which treatment is delivered. The goal of this article is to promote the concept of organizational field by summarizing findings from an ongoing research program and by examining the organizational structure, service delivery, and patterns of innovation adoption in two large samples of substance abuse treatment programs in the United States. Among highlighted findings, there are notable differences between the public and private sectors in structural and staffing characteristics, as well as in the characteristics of clients receiving substance abuse treatment. With regard to the use of evidence-based practices, our findings suggest that pharmacotherapies are more likely to be adopted in private centers, whereas notably effective voucher approaches are more common in public centers. Future research directions are discussed.


Successive action of meprin A and neprilysin catabolizes B-type natriuretic peptide.
Natriuretic peptides such as B-type natriuretic peptide (BNP) are important cardioprotective hormones with essential functions in sodium excretion, water balance and blood pressure regulation. Consequently, the catabolism of these peptides is in the focus of clinical research. In previous studies, we demonstrated that BNP, in contrast to the structurally related atrial and C-type natriuretic peptide, was not hydrolyzed by neprilysin (NEP). Because membrane preparations of several organs of NEP-knockout mice rapidly degrade BNP, the aim of this study was to identify BNP-catabolizing peptidases responsible for this fast clearance. Using kidney membranes of wild-type and NEP-knockout mice, as well as several peptidase inhibitors, we monitored the catabolism of BNP and analyzed its degradation products. We identified meprin A, a multimeric metalloprotease expressed in the brush borders of kidney proximal tubules, to initially truncate mouse BNP in the N terminus to mBNP7-32, a BNP metabolite with conserved biological activity. Consequently, in vivo experiments with the meprin inhibitor actinonin successfully elevated plasma BNP concentration in rats. We further demonstrated that the generation of mBNP7-32 is the prerequisite to catabolize BNP and identified NEP as the peptidase degrading the truncated BNP. Thus, the cooperative, successive action of the 2 transmembranal peptidases meprin A and NEP is crucial for rapid renal BNP inactivation. Therefore, the inhibition of meprin A could be a potent tool for increasing circulating BNP levels.


Decision making in periodontics: a review of outcome measures.
Clinical decisions regarding selection of appropriate periodontal therapy is a multifactorial process involving the assimilation of information from clinical experiences, relevant research, and patient preferences for anticipated outcomes. In order to select the treatment which is most beneficial to patients, a rational, systematic approach to decision making is needed. Clinical experience is a key factor in decision making, but one not easily controlled for. Research to date has focused on clinical or proximate outcomes as a measurement of treatment efficacy, but few of these studies provide the highest level of evidence. While Quality of Life issues play an important role in treatment selection, patient-based outcomes have not been well researched in dentistry. This paper outlines a method clinicians can use to evaluate treatment efficacy studies. In addition, the evidence from longitudinal periodontal treatment efficacy studies is reviewed and the use of patient-based outcome measures is examined.


Vascular endothelial cadherin shedding is more severe in sepsis patients with severe acute kidney injury.
Vascular endothelial cadherin (VE-cadherin) is a membrane protein that is the major component of adherens junctions between endothelial cells. It is crucial for regulating vascular integrity, endothelial permeability, and angiogenesis. During inflammatory processes, VE-cadherin is shed into circulation (sVE-cadherin). Plasma sVE-cadherin is elevated in sepsis, malignancy, autoimmune diseases, and coronary atherosclerosis. However, the relationship between specific organ failures, especially severe acute kidney injury (AKI) defined by requirement for renal replacement therapy (AKI-RRT), and plasma sVE-cadherin levels in severe sepsis has not been well studied. The present study is a prospective study of critically ill adults with sepsis and acute respiratory failure (age ≥ 18 years) enrolled in the Validating Acute Lung Injury markers for Diagnosis (VALID) study. Plasma sVE-cadherin was measured at study enrollment. Primary analysis focused on the association between sVE-cadherin levels and the development of AKI, AKI-RRT, other organ dysfunction as defined by Brussels organ failure scores, pulmonary versus non-pulmonary sepsis, acute respiratory distress syndrome (ARDS), and in-hospital mortality. Of 228 severe sepsis patients included, 80 (35%) developed AKI-RRT. Plasma sVE-cadherin levels at enrollment were significantly higher in patients with AKI-RRT compared with patients without AKI-RRT (p = 0.003). Plasma sVE-cadherin levels by quartile were significantly higher in severe sepsis patients with acute kidney injury stage 3 (p = 0.044) as defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Patients with greater than 2 organ failures had higher plasma sVE-cadherin levels than patients with 2 or fewer organ failures (p < 0.001). In a multivariable analysis, plasma sVE-cadherin was independently associated with AKI-RRT (odds ratio 6.44 per log increase in plasma sVE-cadherin, 95% CI 1.126-36.847, p = 0.036). Plasma sVE-cadherin levels were significantly higher in patients with non-pulmonary sepsis compared to pulmonary sepsis (p < 0.001). Shedding of sVE-cadherin is associated with severe acute kidney injury and with more severe organ dysfunction in patients with sepsis, suggesting that breakdown of endothelial adherens junctions may contribute to the pathogenesis of organ dysfunction in sepsis. Further studies of sVE-cadherin as a biomarker of disease severity in clinical sepsis are needed to better elucidate the role of VE-cadherin shedding in sepsis-induced severe organ dysfunction.


Armed Conflict and Early Childhood Development in 12 Low- and Middle-Income Countries.
Despite 1 in 10 children being affected by armed conflicts, there is limited evidence on the effects of conflicts on early childhood development (ECD), an important Sustainable Development Goals indicator. We aimed to elucidate the relationship between exposure to conflicts and ECD. We conducted a multinational observational study using population-based data on 27 538 children 36 to 59 months old from Demographic and Health Surveys from 12 low- and middle-income countries merged with prospective data on conflicts from Uppsala Conflict Data Program. We estimated the association between 1 to 5 consecutive years of exposure to conflicts within 50 km and ECD after inverse probability of treatment weighting. Mediators of the relationship between conflicts and ECD were identified. We also estimated the association between conflicts and individual domains of ECD. Exposure to conflicts was associated with a 5.9% decrease (95% confidence interval -7.5% to -4.3%) in the probability of a child being developmentally on track from the first year of exposure. This was compounded after the second year, with 5 consecutive years of exposure associated with a 10.4% decrease in the probability of a child being developmentally on track (95% confidence interval -13.7% to -7.2%). A lack of access to early childhood education was a significant mediator into the fifth year of exposure. Among individual ECD domains, socioemotional development was disproportionately impaired. Exposure to nearby conflicts is associated with an increased probability of delayed ECD, especially with chronic exposure. Children in affected areas should be provided psychosocial support and early childhood education from an early stage.


Interactions of Self-Assembled Bletilla Striata Polysaccharide Nanoparticles with Bovine Serum Albumin and Biodistribution of Its Docetaxel-Loaded Nanoparticles.
: Amphiphilic copolymers of stearic acid (SA)-modified Bletilla striata polysaccharides (BSPs-SA) with three different degrees of substitution (DSs) were synthesized. The effects of DS values on the properties of BSPs-SA nanoparticles were evaluated. Drug state, cytotoxicity, and histological studies were carried out. The affinity ability of bovine serum albumin (BSA) and the BSPs-SA nanoparticles was also characterized utilizing ultraviolet and fluorescence spectroscopy. Besides, the bioavailability and tissue distribution of docetaxel (DTX)-loaded BSPs-SA nanoparticles were also assessed. The results demonstrated that the DS increase of the hydrophobic stearic acid segment increased the negative charge, encapsulation efficiency, and drug-loading capacity while decreasing the critical aggregation concentration value as well as the release rate of docetaxel from the nanoparticles. Docetaxel was encapsulated in nanoparticles at the small molecules or had an amorphous status. The inhibitory capability of DTX-loaded BSPs-SA nanoparticles against 4T1 tumor cells was superior to that of Duopafei®. The ultraviolet and fluorescence results exhibited a strong binding affinity between BSPs-SA nanoparticles and bovine serum albumin, but the conformation of bovine serum albumin was not altered. Additionally, the area under the concentration⁻time curve (AUC₀⁻∞) of DTX-loaded BSPs-SA nanoparticles was about 1.42-fold higher compared with Duopafei® in tumor-bearing mice. Docetaxel levels of DTX-loaded BSPs-SA nanoparticles in some organs changed, and more docetaxel accumulated in the liver, spleen, and the tumor compared with Duopafei®. The experimental results provided a theoretical guidance for further applications of BSPs-SA conjugates as nanocarriers for delivering anticancer drugs.


Effect of inhibitor of tumor necrosis factor-alpha on experimental otitis media with effusion.
Tumor necrosis factor (TNF)-alpha is important in the pathogenesis of otitis media with effusion (OME). The purpose of this study was to determine the effect of TNF-alpha antagonist on the outcome of lipopolysaccharide (LPS)-induced OME in rats. Otitis media was induced by injecting Pseudomonas aeruginosa LPS transtympanically. Another (combination) group was pretreated with TNF-alpha antagonist, soluble TNF receptor type I (sTNF RI), before transtympanic injection of LPS. Saline and phosphate-buffered saline solutions were used as controls. Twelve hours after the transtympanic injection, otoscopic examination and aspiration of middle ear effusion (MEE) were done. The temporal bones in each group were examined histopathologically, and the vascular permeability of the middle ear mucosa was measured by the Evans blue vital dye technique. In the LPS and combination groups, MEE developed in 90% and 0% of ears, respectively. The combination group showed less inflammation, less mucosal thickening, and significantly decreased vascular permeability as compared to the LPS group. Transtympanic administration of sTNF RI appears to suppress the development of LPS-induced OME. This study suggests that TNF-alpha antagonist, along with antibiotics, may have an adjunctive role in the future treatment of MEE.


miR-7-5p inhibits cell migration and invasion in glioblastoma through targeting SATB1.
MicroRNAs (miRNAs/miRs) have been revealed to influence the development and progression of glioblastoma. Although a number of miRNAs are abnormally expressed in glioblastoma it is not clear whether they are a factor associated with glioblastoma pathogenesis. In the present study, miR-7-5p was identified as being aberrantly downregulated in glioblastoma tissues and cell lines. miR-7-5p overexpression significantly decreased the migratory and invasive capacity of the cells, while miR-7-5p silencing had the opposite effect. In addition, a luciferase assay confirmed that special AT rich sequence binding protein 1 (SATB1) was a direct target gene of miR-7-5p in glioblastoma. The overexpression of SATB1 in glioblastoma was revealed to promote cell migration and invasion. In addition, SATB1 overexpression may weaken the inhibitory effect of miR-7-5p on cell migration and invasion. miR-7-5p overexpression reversed the effects of SATB1 on cell migration and invasion in glioblastoma cells. In conclusion, miR-7-5p may be a useful therapeutic target for the diagnosis and treatment of patients with glioblastoma.


Theory and practice in the development of a multisorbent passive dosimeter system.
A new family of passive dosimeters has been developed to allow the use of multiple sorbents and analytical techniques suited to a wide range of sampling situations. The dosimeter hardware has been designed to be reusable with interchangeable sorbent capsule refills to provide low cost per test. Capsules have been designed both for conventional solvent desorption and to be used with a newly developed rapid thermal desorber capable of automation for multiple samples. The development of the system is described together with laboratory tests and results and the effects of environmental parameters.


Mechanism of action of human calcitonin gene-related peptide in rabbit heart and in human mammary arteries.
We investigated the effects of human calcitonin gene-related peptide (CGRP) on isolated rabbit hearts to evaluate the mechanisms responsible for the vasodilatory action of the peptide on the coronary district, monitoring contemporaneously the effects on left ventricular pressure (LVP) and heart rate (HR). We also evaluated the reactivity of the human internal mammary artery (IMA) to excitatory drugs acting with different mechanisms and the inhibitory response to CGRP in comparison with the commonly used vasodilatory agents. The peptide induced a slight inhibitory effect on the basal coronary perfusion pressure (CPP), whereas it was ineffective on the inotropism and chronotropism. A more detectable coronary vasodilation was evident when CPP was increased by spasmogenic agents [vasopressin, methoxamine, Bay K 8644, and prostaglandin F2 alpha (PGF2 alpha)]. This inhibitory effect was dose dependent (10(-11)-10(-8) M) and apparently not specific, occurring to the same extent on different stimuli. Forskolin (10(-8) M), an adenylate-cyclase activator, and indomethacin (1.4 x 10(-5) M), a cyclooxygenase inhibitor, did not modify the spasmolytic activity of CGRP on precontracted coronary smooth muscle. The experiments performed on the segments of IMA, used for myocardial revascularization of patients affected by coronary diseases, have shown an evident spasmolytic action of CGRP on increased vascular tone induced by KCl (90 mM), noradrenaline (10(-5) M), serotonin (10(-6) M), and angiotensin II (10(-6) M). These inhibitory responses of CGRP on the spasmogenic compounds disappeared when the endothelial function of IMA, validated by the acetylcholine test, was abolished by mechanical ablation. A series of IMA segments was incubated (30 min) with N(G)-monomethil-L-arginine (L-NMMA), which inhibits nitric oxide (NO) synthase. In these experiments, the peptide failed to induce the vasodilation, suggesting that its action may be related to synthesis of NO. All these results show that CGRP is able to induce a potent vasodilatory action on different vessels of humans (internal mammary artery) and animals (rabbit coronary arteries). In particular the data obtained from IMA demonstrated that the vasorelaxant effect was related to synthesis of NO, one of the most studied endothelium-derived relaxing factors (EDRFs).


Raltegravir susceptibility and fitness progression of HIV type-1 integrase in patients on long-term antiretroviral therapy.
HIV type-1 (HIV-1) protease (PR), reverse transcriptase (RT) and integrase (IN) share the same precursor polyprotein and there is much evidence to suggest functional interactions between IN and RT. We aimed to elucidate whether long-term highly active antiretroviral therapy (HAART) targeting PR and RT could influence raltegravir susceptibility and the fitness of IN. HIV-1 IN sequences from 45 heavily antiretroviral-experienced patients with longitudinal samples separated by a median of 10 years were obtained to estimate the rate of nucleotide substitution. IN recombinant viruses were generated from five selected patients. Phenotypic susceptibility to raltegravir was tested in vitro. Changes in viral replication capacity were assayed by growth kinetics and competition of intrapatient IN recombinant viruses. The amino acid substitution rate within IN was 0.06% per year during long-term antiretroviral treatment. Some substitutions had previously been associated with resistance to different IN inhibitors. Despite this, neither the early- nor late-derived IN recombinant viruses showed an increase in phenotypic susceptibility to raltegravir. Moreover, IN recombinant viruses corresponding to IN samples after 10 years of HAART had a replication capacity that was similar to or better than IN recombinant viruses from baseline samples. HIV-1 IN from longitudinal samples taken from patients treated with IN inhibitor-sparing regimens showed no evidence of genotypic or phenotypic resistance to raltegravir. Additionally, long-term pressure with PR and RT inhibitors did not impair the fitness of HIV-1 IN. These data suggest that current antiretroviral regimens do not diminish the fitness of IN or influence raltegravir efficacy.


Developing Vaccines for SARS-CoV-2 and Future Epidemics and Pandemics: Applying Lessons from Past Outbreaks.
The COVID-19 pandemic is a stark reminder of the heavy toll that emerging infectious diseases (EIDs) with epidemic and pandemic potential can inflict. Vaccine development, scale-up, and commercialization is a long, expensive, and risky enterprise that requires substantial upfront planning and offers no guarantee of success. EIDs are a particularly challenging target for global health preparedness, including for vaccine development. Insufficient attention has been given to challenges, lessons learned, and potential solutions to support and sustain vaccine industry engagement in vaccine development for EIDs. Drawing from lessons from the most recent Ebola epidemic in the Democratic Republic of the Congo, as well as the 2009 H1N1 influenza, 2014-2016 Ebola, and 2015-16 Zika outbreaks preceding it, we offer our perspective on challenges facing EID vaccine development and recommend additional solutions to prioritize in the near term. The 6 recommendations focus on reducing vaccine development timelines and increasing business certainty to reduce risks for companies. The global health security community has an opportunity to build on the current momentum to design a sustainable model for EID vaccines.


Renal dysfunction is common among adults after palliation for previous tetralogy of Fallot.
Long-term survival after tetralogy of Fallot (TOF) repair is excellent. However, little is published regarding late noncardiac complications. This study aimed to determine the prevalence and risk factors for renal dysfunction among adults after TOF repair. For this study, 56 adult patients with complete repair of TOF were identified, and their charts were retrospectively reviewed. An estimated glomerular filtration rate (eGFR) for each patient was calculated using the Modification of Diet in Renal Disease formula (MDRD). Using each patient's eGFR, he or she was classified into stages based on the National Kidney Foundation chronic kidney disease (CKD) staging. Clinical parameters were compared among patients with and those without renal dysfunction to identify risk factors for renal impairment. The median estimated eGFR rate for the cohort was 78 ml/min/1.73 m(2). Based on the National Kidney Foundation CKD staging system, 54 % of the patients had at least stage 2 chronic renal disease. The risk factors identified were hypertension (p < 0.01), type 2 diabetes mellitus (p < 0.05), longer follow-up evaluation (p < 0.005), older age at complete repair (p < 0.05), and use of daily diuretics (p < 0.05). After repair of TOF, renal dysfunction is common at late follow-up evaluation. The study findings show the importance of routine assessment of renal function and the need to limit or avoid future episodes of acute kidney injury in this at-risk population.


Relating Ultrastable Glass Formation to Enhanced Surface Diffusion via the Johari-Goldstein β-Relaxation in Molecular Glasses.
Glasses are materials essential for modern technology; they are usually prepared by cooling liquids. Recently, novel ultrastable glasses (SGs) with extraordinary thermodynamic and kinetic stability have been created by vapor deposition at appropriate substrate temperatures. However, the underlying mechanism for the formation of SGs is still not established. For most of the molecular SGs created so far, we demonstrate that the formation of SGs is closely related to the Johari-Goldstein β-relaxation from the fact that the lowest substrate temperatures possible for the formation of SGs match the secondary glass-transition temperatures, where the β-relaxation time reaches 103 s. Theoretically the β-relaxation time via the primitive relaxation time of the coupling model has proven capable of accounting for the enhancement of molecular mobility at the surface. Thus our findings provide evidence to support that the immense enhancement of molecular diffusion at the surface is critical for the formation of SGs. The result has implications in the design and fabrication of SGs.


Membrane fatty acid composition as a determinant of Listeria monocytogenes sensitivity to trans-cinnamaldehyde.
trans-Cinnamaldehyde, the major compound of cinnamon essential oil, is a potentially interesting natural antimicrobial food preservative. Although a number of studies have addressed its mode of action, the factors that determine bacterial sensitivity or tolerance to trans-cinnamaldehyde are poorly understood. We report the detailed characterization of a Listeria monocytogenes Scott A trans-cinnamaldehyde hypersensitive mutant defective in IlvE, which catalyzes the reversible transamination of branched-chain amino acids to the corresponding short-chain α-ketoacids. This mutant showed an 8.4 fold extended lag phase during growth in sublethal concentrations (4 mM), and faster inactivation in lethal concentrations of trans-cinnamaldehyde (6 mM). trans-Cinnamaldehyde hypersensitivity could be corrected by genetic complementation with the ilvE gene and supplementation with branched-chain α-ketoacids. Whole-cell fatty acid analyses revealed an almost complete loss of anteiso branched-chain fatty acids (BCFAs), which was compensated by elevated levels of unbranched saturated fatty acids and iso-BCFAs. Sub-inhibitory concentrations of trans-cinnamaldehyde induced membrane fatty acid adaptations predicted to reduce membrane fluidity, possibly as a response to counteract the membrane fluidizing effect of trans-cinnamaldehyde. These results demonstrate the role of IlvE in BCFA production and the role of membrane composition as an important determinant of trans-cinnamaldehyde sensitivity in L. monocytogenes.


[Bipolar disorders and metabolic syndrome: a clinical study in 185 patients].
This study aimed to evaluate the prevalence of metabolic syndrome (MetS) in Italian patients with bipolar disorder (BD) and to determine the sociodemographic and clinical correlates of MetS in this patient population. 185 subjects with BD I, II, NAS, cyclothymic disorder and schizoaffective disorder, bipolar subtype were included. Sociodemographic and clinical characteristics, lifestyle information (alcohol and smoking habits and rate of physical exercise) and comorbidity for cardiovascular diseases and diabetes were collected. Patients were assessed for MetS according to American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) criteria. MetS was present in 27.9% of the sample. Abdominal obesity was present in 48.9%, hypertension in 53.8%, high triglycerides in 36.6%, low HDL-C levels in 33.3% and fasting hyperglycemia in 11.5% of the sample. Of the investigated variables, age, duration of illness, rate of obesity and cardiovascular disease were higher in patients with MetS. MetS was also associated with the absence of physical activity. MetS is highly prevalent in Italian patients with BD. Our 27.9% prevalence rate is similar to the rates reported in other European studies and lower than that in US studies. Elderly and obese patients with BD are at particularly high risk for MetS. The absence of physical exercise is also associated to MetS.


[Safety and validity of port-less forceps in reduced-port surgery for laparoscopic resection of colorectal cancer].
The purpose of this study was to examine the safety and validity of reduced-port surgery( RPS) in comparison with conventional laparoscopic surgery for colorectal cancer. We investigated 64 cases of colorectal cancer( CRC) resected by laparoscopic surgery at our hospital in 2012, including 22 cases resected by RPS using 1 or more port-less forceps( Endo Relief, Hope Electronics, Japan). With regard to safety, Endo Relief yielded satisfactory outcomes in terms of the limitations of other needlescopic devices, such as lack of strength and risk of tissue injury, while maintaining countertraction. In addition to the original reasons for introducing RPS, such as lessening wound pain and improving the cosmetic outcome after surgery, the advantages of RPS for CRC are high cost efficiency and the possibility of using additional forceps to maintain triangulation or countertraction during laparoscopic surgery. Because it involves a port-less system, RPS facilitates the frequent reuse of forceps, thereby contributing to its high cost efficiency. In the introduction of RPS for laparoscopic colorectal resection, the use of port-less forceps for countertraction could be safe and effective.


Osteogenic protein-1 stimulates proliferation and differentiation of human bone cells in vitro.
The effect of recombinant human osteogenic protein-1 (OP-1) on proliferation and alkaline phosphatase (ALP) activity was studied using human bone cells in culture. TE85, osteosarcoma cells with osteoblastic characteristics and normal bone cells derived from mandible (HBM) were used. OP-1 stimulated 3H-thymidine incorporation in a dose dependent manner in TE85 (5-fold over vehicle control at 3-10 ng/ml) and HBM cells (1.8-fold at 100 ng/ml). In TE85 cells, OP-1 also increased cell number (2.4-fold over vehicle control at 3 ng/ml). OP-1 stimulated ALP activity in TE85 cells (4-fold over vehicle control at 30 ng/ml), but moderately inhibited ALP activity in HBM cells (to 67% of vehicle control at 100 ng/ml). Because 1,25(OH)2D3 has been shown to increase ALP activity in many cell types, we also studied if 1,25(OH)2D3 modulates the effects of OP-1 on ALP activity. In the presence of 10(-8) M 1,25(OH)2D3, a biphasic response occurred in TE85 and HBM cells with stimulation of ALP activity at low dose of OP-1 and inhibition at high dose. Thus, the effect of OP-1 on ALP activity appeared to be modulated by 1,25(OH)2D3. Our results suggest that OP-1 could be an important regulator of osteoblast proliferation and differentiation.


Enhanced low-Reynolds-number propulsion in heterogeneous viscous environments.
It has been known for some time that some microorganisms can swim faster in high-viscosity gel-forming polymer solutions. These gel-like media come to mimic highly viscous heterogeneous environment that these microorganisms encounter in-vivo. The qualitative explanation of this phenomena first offered by Berg and Turner [Nature (London) 278, 349 (1979)], suggests that propulsion enhancement is a result of flagellum pushing on quasi-rigid loose polymer network formed in some polymer solutions. Inspired by these observations, inertia-less propulsion in a heterogeneous viscous medium composed of sparse array of stationary obstacles embedded into a incompressible Newtonian liquid is considered. It is demonstrated that for prescribed propulsion gaits, including propagating surface distortions and rotating helical filament, the propulsion speed is enhanced when compared to swimming in purely viscous solvent. It is also shown that the locomotion in heterogenous viscous media is characterized by improved hydrodynamic efficiency. The results of the rigorous numerical simulation of the rotating helical filament propelled through a random sparse array of stationary obstructions are in close agreement with predictions of the proposed resistive force theory based on effective media approximation.


Lateral External-fixation Adjacent to Radial Nerve.
Introduction The aim of our study was to describe the injury pattern and outcomes of active-duty subjects that underwent humeral external fixation and to determine if the placement of external fixator pins outside of the radial nerve safe zones is correlated with injury to the radial nerve. Materials and methods We examined all US Service members treated with humeral external fixation at our facility from June 2005 through June 2015. The mechanism of injury, injury pattern, location of external fixation application, pre- and postoperative radial nerve function, presence or absence of radial nerve transection from injury or external fixation, anatomic location of pins in relation to the radial nerve safe zone, and final radial nerve outcomes were recorded. We defined the proximal safe zone as 5 cm distal to the acromion to 14.8 cm proximal to the lateral epicondyle, and we defined the distal safe zone as the proximal 70% of the transepicondylar width of the humerus when projected proximally from the lateral epicondyle. Results For our study, 123 patients were identified over our date range, and 16 subjects were included with documentation regarding nerve function/injury characteristics, appropriate radiographs, and active duty status. Around 80% of injuries resulted from a blast mechanism, and 80% of injury patterns included either an intraarticular or open fracture. The radial nerve safe zone was violated in 15 of the 16 subjects (94%). The one subject with a safe construct did not sustain a nerve injury. Complete preoperative documentation on nerve function was only available for half of the subjects. Two of five subjects known to have intact function prior to external fixation had a postoperative neurologic deficit (40%). Of eight subjects with unknown radial nerve function prior to external fixation, seven subjects had full nerve function at the final follow up, and one subject had partial sensory function only. Of the three subjects with impaired preoperative radial nerve function, two made a full recovery, and the third recovered sensory function only. Around 50% of all subjects required medical retirement. Conclusion External fixation of upper extremity injuries in combat is rarely absolutely indicated, often results in the placement of pins outside of the radial nerve safe zone, and is associated with up to a 40% incidence of radial nerve injury.


[Headache attributed to ischaemic stroke. An update on its semiology and diagnosis].
Headache is a common symptom in acute ischemic stroke which is often overlooked and undertreated because of focus in neurologic function, communication difficulties in stroke patients and the current diagnostic criteria of this type of headache. The present study aimed to determine the prevalence of Acute and Persistent Headache Attributed to Ischemic Stroke and to analyze the fulfillment of the criteria of the International Classification of Headaches (ICHD-IID). Prospective observational analytical cohort study. The study population consisted of patients with acute ischemic stroke admitted to the Stroke Unit of a tertiary care hospital over a period of 12 months. Two hundred and forty-four patients with acute ischemic stroke (59.8% males, mean age 71+12.8 years) were included. Headache at onset or at the first 72 hours was present in 23.2% and 12.5% of them presented persistent headache attributed to ischemic stroke. Only 62.5% of the headaches at stroke onset fulfilled the diagnostic criteria of ICHD-III. Headache after ischemic stroke is a common symptom. It was associated with female sex, posterior circulation stroke and low scores on the National Institutes of Health Stroke Scale (NIHSS). The current diagnostic criteria should be reviewed.


Hypervalent-Iodine-Mediated Formation of Epoxides from Carbon(sp2)-Carbon(sp3) Single Bonds.
We have developed an efficient method for direct formation of epoxide groups from carbon(sp2)-carbon(sp3) single bonds of β-keto esters; the reaction is mediated by the water-soluble hypervalent iodine(V) reagent AIBX (5-trimethylammonio-1,3-dioxo-1,3-dihydro-1λ5-benzo[d][1,2]iodoxol-1-ol anion). On the basis of the results of density functional theory calculations and experimental studies, we propose that the reaction proceeds by a two-stage mechanism involving dehydrogenation of the β-keto ester substrates and epoxidation of the resulting enone intermediates. The rate-limiting step is abstraction of the β'-C-H (calculated free energy of activation, 24.5 kcal/mol).


A comparative study of the toxicological aspects of vanadium pentoxide and vanadium oxide nanoparticles.
Indiscriminate use of vanadium oxide nanoparticles (NPs) in steel industries and their release during combustion of fossil fuels makes it essential to study their toxic potential. Herein, we assessed the toxicological effects of two types of in-house synthesized vanadium oxide NPs in Wistar rats exposed to NPs through inhalation route. V2O5 and VO2 NPs exhibited rod and spherical symmetry, respectively with a mean diameter of 50±20 and 30±10 nm. Assessment of bronchoalveolar lavage fluid parameters demonstrated that VO2 NP-exposed animals had higher levels of lactate dehydrogenase, gamma-glutamyl transpeptidase and alkaline phosphatase as compared to V2O5 NP-exposed animals. The levels of oxidative stress markers malondialdehyde and reduced glutathione also indicated higher toxic potential of VO2 NPs. Moreover, after 7-day recovery, the levels of the above parameters were closer to normal levels only in V2O5-exposed animals. Interestingly, histopathological and immune-histopathology analysis (TNF-α) of lung tissue showed higher damage and inflammatory response in VO2 NP-exposed animals, which persisted even after 7 days of recovery period. Surprisingly, the carcinogenic potential of vanadium oxide NPs came into light which was indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay as well as the decreased levels of p53 and Bax, in lung tissue of NP-exposed animals. Notably, the physiochemical characterization of NPs, especially the shape and the size, play a central role in shaping the toxicity of these NPs and thus should be extensively evaluated for outlining the regulatory guidelines.


[Strategies in approaches to requirements in the control of electromagnetic irradiation levels].
The authors present main principles and approaches used in elaboration of methodic documents to control electromagnetic levels in enterprises that work in radio frequency range. The article incorporates list of actual methodic documents specified in accordance with those principles and approaches.


Structural and functional characterization of HIV-1 cell fusion inhibitor T20.
The peptide drug T20 (enfuvirtide), derived from the C-terminal heptad repeat region of HIV-1 gp41, is the only membrane fusion inhibitor available for treatment of viral infection; however, its mechanism of action remains elusive and its structural basis is lacking. We focused on determining the crystal structure of T20 in complex with N39, a target mimic peptide derived from the N-terminal heptad repeat region of gp41. On the basis of the structural information, the mechanisms of action of T20 and its resistance were further characterized. A panel of peptides was synthesized. The T20/N39 complex was assembled for crystallization studies. Circular dichroism spectroscopy, isothermal titration calorimetry (ITC), native polyacrylamide gel electrophoresis (N-PAGE), and mutational analysis were applied to analyze the structural and functional properties. A crystal structure of six-helical bundle (6-HB) structure formed by T20 and N39 was determined with a resolution limit of 2.3 Å, which revealed the critical intrahelical and interhelical interactions underlying the mechanism of action of T20 and its resistance mutations. Although the structural properties in the C-terminal tryptophan-rich motif (TRM) of T20 and the fusion peptide proximal region (FPPR) of N39 could not be finely defined by the structure, the data from biophysical and mutational analyses verified the essential roles of the TRM and FPPR motifs for the binding and inhibitory activities of T20. For the first time, our studies provide a structural basis of T20, which help our understanding on the mechanisms of HIV-1 fusion and its inhibition.


Evaluation of a double centrifugation technique for the detection of Anoplocephala eggs in horse faeces.
Faecal samples of 250 horses from farms with a known history of tapeworm infection were examined comparatively for cestode eggs using a double centrifugation/combined sedimentation-floatation technique. From each faecal sample, three 5 g and three 15 g subsamples were processed, each using either saturated NaCl solution, specific gravity (sp. g.) 1.2 [NaCl]; concentrated sugar solution, sp. g. 1.26 [sugar]; or concentrated ZnSO4 solution, sp. g. 1.3 [ZnSO4] for floatation. In total, faeces from 187 horses ( = 74.8%) tested 'positive' for Anoplocephala eggs. Percentages of samples testing 'positive' for Anoplocephala ova were: 57.2% for 5 g faeces/NaCl, 66% for 15 g faeces/NaCl, 66% for 5 g faeces/sugar, 72.8% for 15 g faeces/sugar, 55.6% for 5 g faeces/ZnSO4, and 61.2% for 15 g faeces/ZnSO4, respectively. Processing of 15 g faecal samples resulted in a significant (P < 0.05; McNemar's χ2-test) increase in the percentage of Anoplocephala egg detection compared to processing of 5 g samples for all floatation solutions. By processing 15 g faecal samples using sugar solution for floatation, 97.3% of all samples that tested 'positive' for Anoplocephala eggs were identified; there was no significant difference between the rate of samples that tested 'positive' using 15 g faeces/sugar (72.8%) and the total rate of samples that tested 'positive' (74.8%). Conversely, percentages of 'positive' samples from other test combinations were significantly (P < 0.0001, McNemar's χ2-test) lower than the total rate of samples testing 'positive'. Processing faecal samples using sugar solution for floatation gave significantly (P < 0.05, Wilcoxon test) higher Anoplocephala egg counts than using NaCl and ZnSO4 solutions, for both 5 g and 15 g faecal samples. The double centrifugation technique using 15 g faecal samples and concentrated sugar solution for floatation appeared to offer an advantage for the detection of Anoplocephala eggs in horse faeces compared to the other test combinations.


SarS Is a Repressor of Staphylococcus aureus Bicomponent Pore-Forming Leukocidins.
Staphylococcus aureus is a successful pathogen that produces a wide range of virulence factors that it uses to subvert and suppress the immune system. These include the bicomponent pore-forming leukocidins. How the expression of these toxins is regulated is not completely understood. Here, we describe a screen to identify transcription factors involved in the regulation of leukocidins. The most prominent discovery from this screen is that SarS, a known transcription factor which had previously been described as a repressor of alpha-toxin expression, was found to be a potent repressor of leukocidins LukED and LukSF-PV. We found that inactivating sarS resulted in increased virulence both in an ex vivo model using primary human neutrophils and in an in vivo infection model in mice. Further experimentation revealed that SarS represses leukocidins by serving as an activator of Rot, a critical repressor of toxins, as well as by directly binding and repressing the leukocidin promoters. By studying contemporary clinical isolates, we identified naturally occurring mutations in the sarS promoter that resulted in overexpression of sarS and increased repression of leukocidins in USA300 bloodstream clinical isolates. Overall, these data establish SarS as an important repressor of leukocidins and expand our understanding of how these virulence factors are being regulated in vitro and in vivo by S. aureus.


Total Antioxidant Capacity: Biochemical Aspects and Clinical Significance.
Despite the physiological role of oxidant molecules, oxidative stress (OS) could underlie several human diseases. When the levels of antioxidants are too low or too high, OS occurs, leading to damage at the molecular, tissue and cellular levels. Therefore, antioxidant compounds could represent a way to modulate OS and/or to maintain proper redox balance. This review provides an overview of the methods available to assess total antioxidant capacity (TAC) in biological systems to elucidate the correct terminology and the pathophysiological roles. The clinical context is fundamental to obtain a correct interpretation of TAC. Hence, we discuss metabolic syndrome and infertility, two clinical conditions that involve OS, including the potential prognostic role of TAC evaluation in monitoring antioxidant supplementation. This approach would provide more personalised and precise therapy.


Acute effects of the glucagon-like peptide 2 analogue, teduglutide, on intestinal adaptation in short bowel syndrome.
Neonatal short bowel syndrome following massive gut resection is associated with malabsorption of nutrients. The intestinotrophic factor glucagon-like peptide 2 (GLP-2) improves gut function in adult patients with short bowel syndrome, but its effect in pediatric patients remains unknown. Our objective was to test the efficacy of the long-acting synthetic human GLP-2 analogue, teduglutide (ALX-0600), in a neonatal piglet jejunostomy model. Two-day-old pigs were subjected to resection of 50% of the small intestine (distal part), and the remnant intestine was exteriorized on the abdominal wall as a jejunostomy. All pigs were given total parenteral nutrition for 7 days and a single daily injection of the following doses of teduglutide: 0.01 (n = 6), 0.02 (n = 6), 0.1 (n = 5), or 0.2 mg · kg · day (n = 6), and compared with placebo (n = 9). Body weight increment was similar for all 4 teduglutide groups but higher than placebo (P < 0.05). There was a dose-dependent increase in weight per length of the remnant intestine (P < 0.01) and fractional protein synthesis rate in the intestine was increased in the 0.2 mg · kg · day group versus placebo (P < 0.001); however, functional and structural endpoints including activity of digestive enzymes, absorption of enteral nutrients, and immunohistochemistry (Ki67, villin, FABP2, ChgA, and GLP-2R) were not affected by the treatment. Teduglutide induces trophicity on the remnant intestine but has limited acute effects on functional endpoints. Significant effects of teduglutide on gut function may require a longer adaptation period and/or a more frequent administration of the peptide. In perspective, GLP-2 or its analogues may be relevant to improve intestinal adaptation in pediatric patients with short bowel syndrome.


Poor, ill, and sometimes abandoned: tubercular children in Buenos Aires, 1880-1920.
Ill children with chronic diseases, such as tuberculosis, have faced difficult lives. Poverty proved a factor in their susceptibility to disease, their abandonment, and their treatment. When public health policies in Buenos Aires shifted from ignoring children to viewing them as victims who needed protection, government agencies, charitable organizations, public schools, and hospitals developed special programs that emphasized both prevention and cure of childhood tuberculosis. Argentine physicians and hygienists supported programs that were similar to those in Europe and the United States. Despite efforts, from 1880 to 1920, diagnosis of tuberculosis remained problematic, health professionals failed to prevent tuberculosis in children, and physicians were unable to cure the disease.


Imaging Newborn Granule Cells in Fixed Sections.
This protocol describes the harvesting of brain tissue from mice that have had the retroviral vector CAG-GFP injected into the dentate gyrus. Brain tissue from these mice is dissected, the tissue is fixed, and the sections are prepared. The fixed sections are imaged using fluorescent confocal microscopy, and newborn granule cells containing GFP are visualized and are characterized.


Streptococcus pneumoniae Attenuated Strain SPY1 with an Artificial Mineral Shell Induces Humoral and Th17 Cellular Immunity and Protects Mice against Pneumococcal Infection.
Streptococcus pneumoniae is a major pathogen leading to substantial morbidity and mortality in children under 5 years of age. Vaccination is an effective strategy to prevent S. pneumoniae infection. SPY1 is a pneumococcal vaccine candidate strain obtained in our previous study. To improve its stability and immunogencity, in this study, we constructed the SPY1ΔlytA strain that lacks autolysin activity and was coated with an artificial exterior surface calcium phosphate shell by in situ mineralization. The resulting strain SPY1ΔlytACaPi displayed enhanced thermal stability enabling storage at 37°C for 1 week. Furthermore, mucosal and subcutaneous immunization with the SPY1ΔlytACaPi strain induced better protective effects than SPY1ΔlytA in anti-colonization after challenging with 19F and anti-invasion by D39 in mice. Subcutaneous immunization with SPY1ΔlytACaPi elicited higher IgG level while mucosal immunization primarily elicited an immune response which is supposed to be related to Th17 cells. Taken together, the mineralized strain may be a promising candidate for an attenuated S. pneumoniae vaccine.


Vibrational local modes in DNA polymer.
Where the translational symmetry of a long polymer chain is interrupted, characteristic vibrations of the molecule are possible in which only those atoms at or relatively near the defect site partake of the motion. This contrasts with the more common vibrational states in which the motion propagates along the chain as a sound wave. Examples of readily producible local defects include broken bonds, missing atoms or groups, and extra links as are found, e.g., in thymine dimers. For each different defect, the spectrum of local mode frequencies is characteristic of its structure. Hence the local modes give direct information about the nature of the defect and can serve as a diagnostic signature of the polymer chain lesion. We have developed and are using algorithms and fortran code to predict the existence and nature of local modes based on their atomic structures. We have studied examples of different defects and found their eigen-frequencies and eigenvectors. For the simplest case of a broken hydrogen bond in a single A-T unit in a long homopolymer dA.dT chain, we display stereo views of the vibrating unit side-by-side with the undisturbed molecule for the three local modes occurring below 300 cm-1 in frequency.


[Influence of the soybean flavonoid supplement on the synthesis of nitric oxide (NO) in the patients with atherosclerosis].
66 patients of 40-77 age group with atherosclerosis were studied. The observation period made up 4 weeks. The patients were divided into two groups. Group I- experimental group (50 patients) and group II-control group (16 patients) The patients of both groups were given standard therapy, but the patients of group I were additionally given 200mg soybean flavonoid supplement (daily dose 100mg. in capsules two times a day after meals). Clinical observation showed that the patients had no adverse reactions due to intake of the natural food supplement. Compared to the control patients better dynamics of clinical signs was observed in experimental group: reduction of chest pain intensity, arrhythmia and breathlessness, increase of tolerance to physical load, manifested of normalisation arterial hypertension and reduction of heart rate. Biochemical analysis showed an antiatherogenic and hypolipidemic effect of the soybean flavonoid supplement. Statistically reliable increase of NO; reduction of general peripherial vascular resistance and improvement of systolic function. Therefore it can be concluded that given biologically active supplement can be used in the treatment of atherosclerosis as an effective therapeutic tool.


Proteinuria in 3 sequential pregnancies following a fourth renal transplant.
Pregnancy posttransplantation, particularly after kidney transplantation, is becoming common. It poses a challenge for transplant physicians, obstetricians and neonatologists due to the possible adverse maternal and foetal outcomes. The available experience on multiple pregnancies posttransplantation is limited. This case study reports 3 successful pregnancies - 5, 13 and 20 years after fourth renal transplantation resulting in vaginal deliveries at 37, 34 and 38 weeks - in a patient with reflux nephropathy. She developed hypertension, proteinuria and abnormal renal function during gestation with each pregnancy, all of which reversed after delivery. The reported case demonstrates successful foetal outcomes and reversible proteinuria, hypertension and allograft dysfunction possibly related to preeclampsia in the mother during her 3 successful pregnancies after a fourth renal transplant.


Stress-induced impairment in goal-directed instrumental behaviour is moderated by baseline working memory.
Acute stress has been found to impair goal-directed instrumental behaviour, a cognitively flexible behaviour that requires cognitive control. The current study aimed to investigate the role of individual differences in baseline and stress-induced changes in working memory (WM) on the shift to less goal-directed responding under stress. To this end, 112 healthy participants performed an instrumental learning task. In phase 1, participants learned instrumental actions that were associated with two different food rewards. In phase 2, one of these food rewards was devalued by eating until satiety. Before the extinction test in phase 3, participants were subjected to the Maastricht Acute Stress Test or a no-stress control procedure. Results showed that the effect of stress on instrumental behaviour is modulated by baseline, but not stress-induced changes in WM capacity. Specifically, only at low baseline WM capacity did stress induce a shift to less goal-directed behaviour. These findings highlight that our cognitive resources are limited and for those who already have limited resources at baseline taking into account motivational value is impaired under stress.


Cytological demonstration of features of Alzheimer's disease using brain smear technique.
The major diagnostic histopathological features of moderate to severe Alzheimer's disease (AD) are amyloid rich neurofibrillary tangles (NFTs) and neuritic plaques (NPs) containing beta A4 peptide. As the frequency of stereotactic brain biopsies is increasing, the diagnostic cytological features of AD are of relevance. Our study presents the brain smear features of five autopsied patients with moderate to severe AD both clinically and pathologically. NFTs and NPs were identified in 100% of smears. Amyloid neuropil threads (NTs), a more recently identified hallmark of AD, were also seen in all smears. Segmental beta A4 peptide deposition within vessels, clustering of plaques around capillaries, and NTs were more obvious by the smear technique than in histological sections.


The impact of evaluating platelet transfusion need by platelet mass index on reducing the unnecessary transfusions in newborns.
Almost 95% of the platelet transfusions (PTs) conducted in the neonatal intensive care unit (NICU) are prophylactic transfusions. Guidelines for prophylactic PTs are based on platelet counts, but not on platelet functions. Nowadays, in order to reduce unnecessary transfusions, utilizing platelet mass index (PMI) was investigated. The aim of study is to find out whether PTs performed in our NICU during last 2 years were in accordance with the current guideline and to evaluate whether the frequency of PTs should be reduced if PMI was considered. Forty-three infants who received 96 prophylactic PTs were enrolled in the study. The guideline utilized in our NICU advocate keeping the platelet count: (a) >100 000 in pre/post-operative, (b) >50 000 in unstable and (c) >20 000 in stable patients. According to PMI criteria, PT should be performed if PMI: (a) <800 in pre/post-operative, (b)<400 in unstable and (c) <160 in stable patients. In all, 53.2% of PTs should not be given if the decision was in accordance with the current guideline. If decision for every PT was made according to the current guideline and taking PMI into consideration, an additional 11.5% reduction in total PTs could be achived. We suggest that better compliance with the new guidelines which take platelet functions into account may yield lower transfusion rate, lower costs and better conservation of blood bank resources.


T cell responses to a Parietaria judaica pollen extract: comparison between Parietaria-sensitive patients, other atopics and healthy controls.
We investigated the in vitro proliferation of peripheral blood mononuclear cells (PBMC) from Parietaria-allergic subjects, atopic patients with other sensitizations and healthy controls to Parietaria judaica pollen extracts. PBMC from almost all 44 subjects, divided into five groups (Parietaria-, grass-, Parietaria and grass-, Dermatophagoides-sensitive patients and normal individuals) were able to proliferate in response to the extract without statistically significant differences between groups. Mean values of the stimulation indexes for the five groups were respectively: 10.73, 3.18, 5.50, 10,56, 9.28. The results of separation experiments showed that the responding cells were T lymphocytes. Mitogenic effect of the Parietaria pollen extract was excluded by the absence of proliferative PBMC response from cord blood of seven newborns. These results indicate that Parietaria-sensitive, other atopics and normal individuals have Parietaria-specific T cells able to proliferate in vitro to Parietaria allergens.


[1,2,4]Triazolo[1,5-a]pyridine as Building Blocks for Universal Host Materials for High-Performance Red, Green, Blue and White Phosphorescent Organic Light-Emitting Devices.
The electron-accepting [1,2,4]triazolo[1,5-a]pyridine (TP) moiety was introduced to build bipolar host materials for the first time, and two host materials based on this TP acceptor and carbazole donor, namely, 9,9'-(2-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-1,3-phenylene)bis(9H-carbazole) (o-CzTP) and 9,9'-(5-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-1,3-phenylene)bis(9H-carbazole) (m-CzTP), were designed and synthesized. These two TP-based host materials possess a high triplet energy (>2.9 eV) and appropriate highest occupied molecular orbital/lowest unoccupied molecular orbital levels as well as the bipolar transporting feature, which permits their applicability as universal host materials in multicolor phosphorescent organic light-emitting devices (PhOLEDs). Blue, green, and red PhOLEDs based on o-CzTP and m-CzTP with the same device configuration all show high efficiencies and low efficiency roll-off. The devices hosted by o-CzTP exhibit maximum external quantum efficiencies (ηext) of 27.1, 25.0, and 15.8% for blue, green, and red light emitting, respectively, which are comparable with the best electroluminescene performance reported for FIrpic-based blue, Ir(ppy)3-based green, and Ir(pq)2(acac)-based red PhOLEDs equipped with a single-component host. The white PhOLEDs based on the o-CzTP host and three lumophors containing red, green, and blue emitting layers were fabricated with the same device structure, which exhibit a maximum current efficiency and ηc of 40.4 cd/A and 17.8%, respectively, with the color rendering index value of 75.


Species variation in small molecule components of animal vitreous.
We characterized differences in biochemical composition of the vitreous of different animal species with respect to small molecule constituents. Vitreous samples were extracted from sheep, pig, Dutch Belted rabbits, and New Zealand white rabbits. The vitreous samples were investigated for acetylcholinesterase (AChE) activity and, in addition, were subjected to metabolomics determination using mass spectrometry. AChE activity varied across the species investigated with greater activity noted in larger animals. Principal component analysis demonstrated species differentiation in relation to metabolomic profile. Key peaks identified the importance of animal diet on small molecule composition of the vitreous. Our results highlighted principal and consistent differences in small molecule composition and enzymatic activity of the vitreous depending on species. Interesting differences were demonstrated, showing that diet potentially can impact on components of and metabolites contained within the vitreous. Material will be exchanged between vascular and retinal tissue with the vitreous compartment and as a nonvascular, slowly equilibrating "sink" might reflect changes in transporter activity. As a first step, understanding the differences in the metabolic profile of vitreous from different species may impact interpretation of such activity across different species.


Comparisons of psychosomatic health and unhealthy behaviors between cleanroom workers in a 12-hour shift and those in an 8-hour shift.
The General Health Questionnaire (GHQ12) and physical fitness tests were administered to 338 workers in clean rooms producing electronic parts in 12-h shifts. The results were compared to those in 95 workers in 8-h shifts and 284 daytime management, clerical and engineering workers. The 12-h shift workers complained of poor health, dissatisfaction with life and poor recuperation from fatigue more than the 8-h shift workers although the rates of complaints were highest in the daytime workers. The GHQ scores were similar in the two shift groups, and much better than those in the daytime workers. However, the 12-h shift workers showed significantly lower fitness levels than the 8-h shift workers, and the levels were even worse than the daytime workers who had higher mean age and BMI levels compared with the shift workers. The tendency to have sedentary freetime activities and larger alcohol and cigarette consumption were observed in the 12-h shift workers. The 12-h shift work may have contributed to the unhealthy behaviors resulting in lower physical fitness levels. Health promotion services at the workplace should devote greater attention to long-hour shift workers, together with devising the ways to improve working conditions and environments for reducing fatigue at work.


(-)-Epigallocatechin-3-Gallate Inhibits Colorectal Cancer Stem Cells by Suppressing Wnt/β-Catenin Pathway.
The beneficial effects of tea consumption on cancer prevention have been generally reported, while (-)-Epigallocatechin-3-gallate (EGCG) is the major active component from green tea. Cancer stem cells (CSCs) play a crucial role in the process of cancer development. Targeting CSCs may be an effective way for cancer intervention. However, the effects of EGCG on colorectal CSCs and the underlying mechanisms remain unclear. Spheroid formation assay was used to enrich colorectal CSCs from colorectal cancer cell lines. Immunoblotting analysis and quantitative real-time polymerase chain reaction were used to measure the alterations of critical molecules expression. Immunofluorescence staining analysis was also used to determine the expression of CD133. We revealed that EGCG inhibited the spheroid formation capability of colorectal cancer cells as well as the expression of colorectal CSC markers, along with suppression of cell proliferation and induction of apoptosis. Moreover, we illustrated that EGCG downregulated the activation of Wnt/β-catenin pathway, while upregulation of Wnt/β-catenin diminished the inhibitory effects of EGCG on colorectal CSCs. Taken together, this study suggested that EGCG could be an effective natural compound targeting colorectal CSCs through suppression of Wnt/β-catenin pathway, and thus may be a promising agent for colorectal cancer intervention.


Isolated sarcoidosis of accessory spleen in the greater omentum: A case report.
Sarcoidosis is a multisystemic disease of unknown origin characterized by the formation of non-caseating granulomas. Thoracic involvement is the most common presentation; however, sarcoidosis can involve almost any other organ. To the best of our knowledge there have been only 10 cases of splenic sarcoidosis reported in the English literature, with no reports of sarcoidosis of an accessory spleen. The present study reports a case of isolated sarcoidosis of an accessory spleen in the greater omentum, which was identified postoperatively in a 44-year-old female. Chest X-ray results were normal. Gastric endoscopy demonstrated an ulcer in the antrum, which was confirmed to be a signet-ring cell carcinoma via biopsy. Computed tomography of the abdomen revealed mild thickening of the posterior antrum, and a mass in the inferior pole of the left kidney. Intraoperatively, no masses were detected in the liver and spleen. Moreover, no enlarged lymph nodes were detected in the abdominal cavity, pelvic cavity, mesenteric and para-aorta. Following a radical distal gastrectomy and left radical nephrectomy, postoperative pathology demonstrated signet-ring cell carcinoma in the antrum, left renal clear cell cancer and a red lesion measuring 0.5×0.5 cm in the greater omentum, which was similar to the spleen in the splenic cavity and was regarded as an accessory spleen. Following exclusion of fungi and acid-fast bacilli as causative agents, sarcoidosis of the accessory spleen in the greater omentum was confirmed. The patient recovered uneventfully and was discharged on day 8 postoperation. The patient remained alive after two-year follow-up without sarcoidosis and malignant tumor recurrence. The present case demonstrated that, intraoperatively, comprehensive exploration should be conducted to exclude the accessory spleen, which may also suffer from sarcoidosis.


Computer-aided vaccine designing approach against fish pathogens Edwardsiella tarda and Flavobacterium columnare using bioinformatics softwares.
Edwardsiella tarda and Flavobacterium columnare are two important intracellular pathogenic bacteria that cause the infectious diseases edwardsiellosis and columnaris in wild and cultured fish. Prediction of major histocompatibility complex (MHC) binding is an important issue in T-cell epitope prediction. In a healthy immune system, the T-cells must recognize epitopes and induce the immune response. In this study, T-cell epitopes were predicted by using in silico immunoinformatics approach with the help of bioinformatics tools that are less expensive and are not time consuming. Such identification of binding interaction between peptides and MHC alleles aids in the discovery of new peptide vaccines. We have reported the potential peptides chosen from the outer membrane proteins (OMPs) of E. tarda and F. columnare, which interact well with MHC class I alleles. OMPs from E. tarda and F. columnare were selected and analyzed based on their antigenic and immunogenic properties. The OMPs of the genes TolC and FCOL_04620, respectively, from E. tarda and F. columnare were taken for study. Finally, two epitopes from the OMP of E. tarda exhibited excellent protein-peptide interaction when docked with MHC class I alleles. Five epitopes from the OMP of F. columnare had good protein-peptide interaction when docked with MHC class I alleles. Further in vitro studies can aid in the development of potential peptide vaccines using the predicted peptides.


Unique molecular characteristics of the environmental responses of mucosal macrophages.
Macrophages are thought to be the cells that initially respond to environmental information and transmit this information to other immune cells. We hypothesize that there is a "network system" consisting of various tissue macrophages; the macrophages respond to stimulation and transmit secondary information to neighboring cells, which is important for the maintenance of homeostasis. Macrophages exist in all animal organs as tissue macrophages, and their cellular characteristics may change as an adaption to tissue-specific environments. It is believed that mucosal macrophages are particularly important in the macrophage network system because mucosa exist where there is regular exposure to foreign substances. However, the molecular mechanism by which intestinal mucosal macrophages respond to the external environment is not yet clear. In this review the biological characteristics of mucosal macrophages are introduced and how they recognize and eradicate various foreign substances is discussed.


Fosfomycin in treatment of chronic urinary tract infection.
A study was made of fosfomycin in the treatment of chronic urinary infection in 51 patients. 72% of the 67 bacteria isolated and tested in the laboratory with discs containing 50 mug of fosfomycin were found to be sensitive to the antibiotic. The majority of E. coli, Klebsiella, P. mirabilis and Ps. aeruginosa strains were sensitive to the antibiotic. Generally, 60 mg of fosfomycin/kgbody weight was administered intramuscularly 6-hourly for 7-15 days. A clinical and bacteriological cure was obtained in 39 patients (76%), and after 4-6 weeks in 31 patients (61%). Blood and urine fosfomycin levels were determined in seven patients, three with normal renal function, three with moderate renal insufficiency, and one with severe renal insufficiency. The antibiotic levels and elimination time maintained a clear relation with the degree of renal insufficiency.


Identification and characterization of a new human type 9 cGMP-specific phosphodiesterase splice variant (PDE9A5). Differential tissue distribution and subcellular localization of PDE9A variants.
Previously, four splice variants of human cGMP-specific phosphodiesterase (PDE) 9A (PDEs 9A1, 9A2, 9A3 and 9A4) have been identified. In this study, we have cloned a cDNA representing a new human PDE9A variant (PDE9A5). PDE9A5 encodes a protein of 492 amino acids, smaller than PDEs 9A1 and 9A2 but larger than PDEs 9A3 and 9A4. The exon structure of PDE9A5 is different from those of PDEs 9A1, 9A2, 9A3 and 9A4 in that, of the 20 exons of PDE9A gene, it lacks exons 2 and 5. PDE9A5 has been characterized in comparison with PDE9A1, the longest PDE9A variant. PDEs 9A5 and 9A1 have similar enzymatic properties. They both have a high affinity for cGMP with similar Km values (0.39 and 0.25 microM, respectively), although they have slightly different Vmax values (2.55 and 0.96 micromol/min/mg, respectively). They exhibit very similar divalent metal ion dependency and inhibitor sensitivity. Real-time quantitative PCR analysis shows that PDEs 9A5 and 9A1 exhibit differential tissue distribution. They are highly expressed in immune tissues (spleen, lymph node and thymus) and are more abundant in T cells than in B cells, neutrophils and monocytes. When transiently expressed in HEK293 cells, PDEs 9A5 and 9A1 proteins exhibit differential subcellular localization. PDE9A5 localizes exclusively in the cytoplasm, whereas PDE9A1 localizes in the nucleus only. The nuclear localization of PDE9A1 is dependent on a unique pat7 motif. By Western blot analysis, native PDE9A1 is detectable in the nucleus but not in the cytoplasm of T cells. Thus, to our knowledge, PDE9A1 is the only PDE isoform found to localize exclusively in the nucleus. We speculate that the physiological role of the PDE9A diversity may be imparting cGMP-metabolizing ability to specific cellular compartments in appropriate tissues.


Cell type-specific lectin staining of the tracheobronchial epithelium of the rat: quantitative studies with Griffonia simplicifolia I isolectin B4.
We compared lectin staining patterns to cell population densities, as determined by morphological criteria in rat airways. Eight lectins were studied: Griffonia simplicifolia I isolectin B4 (GSI-B4), Arachis hypogaea (PNA), Wisteria floribunda (WFA), Glycine maximus (SBA), Dolichos biflorus (DBA), Helix pomatia (HPA), Ulex europaeus (UEA-1), and Maclura pomifera (MPA). Two of the lectins strongly stained morphologically distinct cell subpopulations. GSI-B4 stained basal cells, and MPA stained non-ciliated bronchiolar (Clara) cells. The specificity and sensitivity of GSI-B4 as a marker for basal cells was examined. In the trachea, 35% of all cells were GSI-B4 positive; 84% of these were basal cells, 7% were unidentified cells, 5% were serous/mucous cells, and 4% were ciliated, brush, or inflammatory cells. Comparison to cell population density data strongly suggested that all basal cells were GSI-B4 positive. The segmental bronchus was a transitional area; GSI-B4 positive basal cells were present in the region closest to the lobar bronchus but were absent in the distal region; instead, MPA-positive Clara cells appeared. When dissociated tracheal cells were obtained by pronase digestion, 43% were GSI-B4 positive. These results show that GSI-B4 is a sensitive and relatively specific marker for basal cells in the rat trachea which can be used to study dissociated epithelial cells.


Sentinel lymph node mapping and staging in endometrial cancer: A Society of Gynecologic Oncology literature review with consensus recommendations.
The emphasis in contemporary medical oncology has been "precision" or "personalized" medicine, terms that imply a strategy to improve efficacy through targeted therapies. Similar attempts at precision are occurring in surgical oncology. Sentinel lymph node (SLN) mapping has recently been introduced into the surgical staging of endometrial cancer with the goal to reduce morbidity associated with comprehensive lymphadenectomy, yet obtain prognostic information from lymph node status. The Society of Gynecologic Oncology's (SGO) Clinical Practice Committee and SLN Working Group reviewed the current literature for preparation of this document. Literature-based recommendations for the inclusion of SLN assessment in the treatment of patients with endometrial cancer are presented. This article examines.


[The effect of blood serum proteins from the seal on the analgetic action of narcotic analgesics].
The protein fraction isolated from blood of seal, Phoca groenlandica, has been found to produce hyperalgesic effect on rats exposed to thermic or electrocutaneous nociceptive stimulation, but fail to affect writhes provoked by intraperitoneal injection of acetic acid solution on mice. When combined with morphine, the fraction lowered completely its narcotic analgetic action in the above mentioned tests. On the contrary, these same proteins combined with promedol or fentanil enhanced and prolonged analgetic effect of the latter. Tested in vitro the protein showed neither opioid nor anti-opioid activity. Therefore it is reasonable to suppose that neurophysiological activity of the isolated fraction is due to the peptides formed on enzymatic hydrolysis of proteins in vivo rather than these proteins as such.


A modeling approach to understanding OLED performance improvements arising from spatial variations in guest:host blend ratio.
Phosphorescent organic light emitting diodes (OLEDs) suffer from efficiency roll off, where device efficiency rapidly decays at higher luminance. One strategy to minimize this loss of efficiency at higher luminance is the use of non-uniform or graded guest:host blend ratios within the emissive layer. This work applies a multi-scale modeling framework to elucidate the mechanisms by which a non-uniform blend ratio can change the performance of an OLED. Mobility and exciton data are extracted from a kinetic Monte-Carlo model, which is then coupled to a drift diffusion model for fast sampling of the parameter space. The model is applied to OLEDs with uniform, linear, and stepwise graduations in the blend ratio in the emissive layer. The distribution of the guests in the film was found to affect the mobility of the charge carriers, and it was determined that having a graduated guest profile broadened the recombination zone, leading to a reduction in second order annihilation rates. That is, there was a reduction in triplet-triplet and triplet-polaron annihilation. Reducing triplet-triplet and triplet-polaron annihilation would lead to an improvement in device efficiency.


Mammalian cyanide detoxification with sulphane sulphur.
It has been understood for nearly a century that most of the cyanide entering mammals by either ingestion or inhalation of sublethal quantities is detoxified by combination with cyanide-reactive sulphur. The detoxifying reaction is primarily enzymic, and the enzymes that catalyse it, as well as those that catalyse reactions which generate the cyanide-reactive sulphane sulphur, have been isolated and studied extensively. However, analytical methods suitable for quantitative characterization of the physiological pool of sulphur available for this detoxification have only recently come under development. A new method is based on the evaluation of cyanide depletion under controlled, mild reaction conditions in the presence of a sulphurtransferase and cofactor. The use of differential pulse polarography with nested internal standards makes this a practical procedure for samples containing as little as a few nanomoles of cyanide-reactive material. As measured by this method, the sulphane sulphur concentration in mammalian liver tissue is in the fractional millimolar range, with even less in the bloodstream. Nevertheless, the specific binding of sulphane sulphur by serum albumin, and the rapid cyanolysis of the albumin-bound sulphur, may yet indicate a significant role for the sulphurtransferase capability of serum albumin in cyanide detoxification.


A TRAIL-Delivered Lipoprotein-Bioinspired Nanovector Engineering Stem Cell-Based Platform for Inhibition of Lung Metastasis of Melanoma.
Genetically engineered mesenchymal stem cells (MSCs), as non-viral gene delivery platforms, are rapidly evolving in tumor therapy due to their low immunogenicity and natural tumor-homing capacity. Methods: In this paper, we selected reconstituted high-density lipoprotein (rHDL), a lipoprotein-bioinspired nanovector with specific binding ability to scavenger receptor B type I (SR-BI) expressed on MSCs, as a transfection agent to genetically modify MSCs. pDNA encoding tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was used as a functional gene to be transfected into the nucleus of MSCs for TRAIL expression. Lauric acid-coupled polyethyleneimine (PEI-LA) as an amphiphilic cationic polymer was synthesized to electrostatically bind to pDNA, and then incorporated into rHDL to form rHDL/PEI-LA/pDNA nanoparticles. Results: The nanoparticles exhibited homogenous particle size and excellent serum stability in vitro. Meanwhile, this SR-BI-targeted rHDL performed efficient intracellular gene delivery, specific lysosome-independent mechanism of cellular uptake and high transfection of pDNA towards MSCs. Moreover, high TRAIL expression in MSCs was detected after rHDL-mediated transfection. In vitro and in vivo results indicated that genetically engineered MSCs could accurately target to B16F10 cells, thereby producing significant apoptosis-inducing effect on aggressive melanoma. Conclusion: TRAIL-expressing MSCs engineered by rHDL nanovector was an efficient and hypotoxic method for stem cells-based pulmonary melanoma metastasis-targeting therapy.


[Sports and their significance for the diabetic child].
The positive effect of physical exercise on the metabolism for those with diabetes has been well known for a long time. It pertains also for children with diabetes. In spite of this, children and adolescents with diabetes still have problems taking part in sport-activities. The reasons are poor information and education of physicians, teachers, parents and those with diabetes. Holiday-camps will be an useful help for children to learn how to adapt the metabolism by self-control of blood and urine-sugar. Then it will be easier to accommodate physical exercise during the day. The improvement of fitness is one of the positive effects of sport, but it is of no consequence for metabolic control. However, sport-activities are a helpful addition for therapeutic management.


[Expression of SV40Tag, Rb and IRS-1 in glioma detected by tissue microarray and their relation with tumorigenesis and progression of gliomas].
To determine the expression of SV40Tag, Rb and IRS-1 in gliomas and to identify their function in gliomagenesis and progression. Tissue microarrays were constructed containing 118 samples including human glioma and meningioma, experimental glioma, and normal human brain tissue. The expression of SV40Tag, Rb, IRS-1, SV40Tag combined with Rb, and SV40Tag combined with IRS-1 were assayed by immunofluorescence or immunohistochemical techniques. The expression ratio and level were analyzed. The expressions of SV40Tag, Rb and IRS-1 were detected in gliomas and benign brain tumors. Their positive expression rate in glioma was 65.9%, 64.6% and 48.8%, respectively, with a statistically non-significant difference between the malignant and benign brain tumors. The malignant degree was positively correlated with SV40Tag and IRS-1, but negatively correlated with Rb expression. The combined expression rate of SV40Tag and Rb was 51.2%, and the combined expression rate of SV40Tag and IRS-1 was 40.2%. In the normal human brain tissue only the expression of Rb (77.8%, 7/9) and IRS-1 (22.2%, 2/9) were detected, but expression of SV40Tag could not be observed. Our findings that no expression of SV40Tag was observed in normal human brain tissue indicates that expression of SV40Tag may play an important role in the pathogenesis of glioma. It may be assumed that after SV40 virus invading human body, Rb disfunction and IRS-1 activation promote the malignant transformation of cells, which could be one of important factors in pathogenesis and procession of glioms.


Ultrasound Combined with Microbubbles Enhances the Effects of Methylprednisolone in Lipopolysaccharide-Induced Human Mesangial Cells.
A novel drug delivery system mediated by ultrasound (US) combined with microbubbles (MBs) (US+MB) could improve local drug concentration to enhance its efficacy. To investigate the influence of US+MB on methylprednisolone (MP), the effect of US+MB combined with MP (US+MB+MP) on lipopolysaccharide (LPS)-induced human mesangial cells (HMCs) and the underlying mechanism were explored in this study. The results revealed that HMCs treated with LPS underwent significant proliferation and exhibited an increase in nuclear transcription factor-κB (NF-κB) and transforming growth factor-β1 (TGF-β1) expression and a decrease in cellular apoptosis. This effect was significantly inhibited by MP (30-100 μg/ml), US combined with MBs (3.22 × 107 and 8.05 × 107 bubbles/ml), and US combined with both MBs (1.29 × 107 bubbles/ml) and MP (12 μg/ml) (US+MB1+MP12). The effect of US+MB1+MP12 was better than the effect of 12 μg/ml of MP alone and was similar to the effect of 100 μg/ml of MP. Additionally, the intracellular free MP content was significantly higher in the US+MB1+MP12 group than in the MP12 group. US combined with MBs not only inhibited LPS-induced HMC proliferation and NF-κB and TGF-β1 expression and increased cellular apoptosis but also synergized with the pharmacologic effect of MP. The mechanism is partially due to the US-assisted MB local drug delivery and the anti-inflammatory effect induced by US combined with MBs.


Second Harmonic Generation Signals in Rabbit Sclera As a Tool for Evaluation of Therapeutic Tissue Cross-linking (TXL) for Myopia.
Methods to strengthen tissue by introducing chemical bonds (non-enzymatic cross-linking) into structural proteins (fibrillar collagens) for therapy include photochemical cross-linking and tissue cross-linking (TXL) methods. Such methods for inducing mechanical tissue property changes are being employed to the cornea in corneal thinning (mechanically weakened) disorders such as keratoconus as well as the sclera in progressive myopia, where thinning and weakening of the posterior sclera occurs and likely contributes to axial elongation. The primary target proteins for such tissue strengthening are fibrillar collagens which constitute the great majority of dry weight proteins in the cornea and sclera. Fortuitously, fibrillar collagens are the main source of second harmonic generation signals in the tissue extracellular space. Therefore, modifications of the collagen proteins, such as those induced through cross-linking therapies, could potentially be detected and quantitated through the use of second harmonic generation microscopy (SHGM). Monitoring SHGM signals through the use of a laser scanning microscopy system coupled with an infrared excitation light source is an exciting modern imaging method that is enjoying widespread usage in the biomedical sciences. Thus, the present study was undertaken in order to evaluate the use of SHGM microscopy as a means to measure induced cross-linking effects in ex vivo rabbit sclera, following an injection of a chemical cross-linking agent into the sub-Tenon's space (sT), an injection approach that is standard practice for causing ocular anesthesia during ophthalmologic clinical procedures. The chemical cross-linking agent, sodium hydroxymethylglycinate (SMG), is from a class of cosmetic preservatives known as formaldehyde releasing agents (FARs). Scleral changes following reaction with SMG resulted in increases in SHG signals and correlated with shifts in thermal denaturation temperature, a standard method for evaluating induced tissue cross-linking effects.


Application of the C(18)-carboxypropylbetaine specimen processing method to recovery of Mycobacterium avium subsp. paratuberculosis from ruminant tissue specimens.
The causative agent of Johne's disease is Mycobacterium avium subsp. paratuberculosis. This is a chronic, debilitating gastrointestinal disorder that affects ruminants and is responsible for significant economic loss. The specimen processing method that combines C(18)-carboxypropylbetaine (CB-18) treatment and lytic enzyme decontamination has been shown to improve the diagnosis of mycobacterioses. This processing method was applied to the isolation of M. avium subsp. paratuberculosis from ruminant tissue samples. The BACTEC 12B liquid culture system was used but was supplemented with 1% egg yolk emulsion, 4 microg of mycobactin J, and 0.5% pyruvate (12B/EMP) for use in conjunction with this method. The final concentration of antibiotics used was 10 microg of vancomycin, 30 microg of amphotericin B, and 20 microg of nalidixic acid (VAN) per ml. A 7H10-based solid medium was also used that included mycobactin J, pyruvate, and VAN but excluded the egg yolk emulsion (7H10/MPV). Several M. avium subsp. paratuberculosis isolates were examined during the evaluation of this processing method. It was observed that treatment with lytic enzymes stimulated the growth of M. avium subsp. paratuberculosis; however, the growth of one isolate was markedly inhibited due to the presence of vancomycin. Subsequently, the vancomycin concentration in the VAN formulation was reduced to 2 microg/ml. A blinded panel of 60 previously characterized tissue samples from bovine and bison were then processed and analyzed by smear and culture. Historically, 31 and 37 specimens were classified as positive by histology and culture, respectively. The overall sensitivity and specificity of smear relative to culture following CB-18 processing were 97.6 and 89.5%, respectively. The 12B/EMP/VAN liquid culture system recovered M. avium subsp. paratuberculosis from 39 specimens, whereas 7H10/MPV and Herrold's egg yolk media recovered M. avium subsp. paratuberculosis from 26 and 16 specimens, respectively. The average times to positive were 7.4 +/- 8.3, 29.9 +/- 2.6, and 24 +/- 0 days, respectively. The contamination rates were 4.8, 22.6, and 20.0%, respectively.


[Comparison of CD15, galectin-3 and HBME-1 expression in follicular thyroid neoplasms].
Estimation of malignancy in thyroid follicular neoplasms is a common diagnostic problem, thus revealing of differences in expression of some antigens in both benign and malignant lesions seems to be essential. The aim of this study is to evaluate the immunohistochemical expression of CD15, galectin-3 and HBME-1 in follicular adenomas and carcinomas. Samples of 38 follicular adenomas (23 "classical", 5 with intracapsular invasion, 10 oncocytic) and 15 follicular carcinomas (9 "classic", 6 oncocytic) were stained immunohistochemically with anti-CD15, galectin-3 and HBME-1. In the whole group we found statistically significant differences in CD15 expression between follicular adenomas and carcinomas. "Classic" follicular carcinomas (without oncocytic tumors) showed stronger CD15 and HBME- 1 expression than "classic" adenomas. Adenomas with intracapsular invasion differed from "classic" adenomas only in HBME-1 expression. In oncocytic tumors the expression of examined antigens was similar. 1. In the group of nonoxyphilic tumors positive reaction with HBME-1 was more common in adenomas with intracapsular invasion and carcinomas, but positive reaction with anti-CD15--only in carcinomas. We suggest that reactivity with these antibodies could mark malignancy. 2. Oncocytic tumors had similar expression of CD15 and HBME-1 and galectin-3.


Natural course of coronary artery calcium progression in Asian population with an initial score of zero.
We aimed to investigate the natural course of coronary artery calcium progression in an Asian population with a baseline coronary artery calcium (CAC) score of zero, and to determine subclinical coronary atherosclerosis. Four hundred fifty-nine subjects with at least two CAC scans with an initial score of zero were included. CAC progression (+) was defined by the development of any CAC (i.e., CAC > 0) during subsequent CT scans. Clinical characteristics and Framingham risk profiles were also recorded. Among 459 subjects, 106 (23.09%) experienced CAC progression during the average follow-up period of 5.71 ± 2.68 years. Older age, male gender, HDL-C, total cholesterol and higher Framingham risk score were independently associated with CAC progression. Framingham risk score had the better discriminative ability (AUC = 0.660) to predict CAC progression compared to the other parameters with a sensitivity of 75.24% and specificity of 53.95%. For the double zero score with coronary artery atherosclerosis prediction, older age, triglycerides, hypertension, and Framingham risk score were significantly associated with these events. Among these parameters, Framingham risk score may be a relatively acceptable parameter with high negative predictive (NPV = 96.4%) value to rule out double zero score with obstructive coronary artery atherosclerosis scenario with an optimum cut-off value of <16.9 (AUC =0.652, sensitivity of 57.69%; specificity of 68.82%). A baseline zero CAC score in asymptomatic Chinese population with low to intermediate risk have a low incidence for CAC progression within the 5-years period. For CAC progression prediction, Framingham risk score with the cutoff < 11.1 may help confirm subjects at low risk to improve cardiovascular risk stratification and reclassification in the field of preventive cardiology.


Wheezing as a sign of cor triatriatum sinister culminating in multiple organ failure.
Cardiac asthma or cardiac wheezing (CW) refers to a syndrome of dyspnea and wheezing that mimicks asthma clinically. Reported herein is the case of a 2-month-old boy who presented with refractory wheezing as a sign of cor triatriatum sinister (CTS) that culminated in overwhelming multiple organ failure in a short time. On the day of admission, oxygen saturation (SpO2 ) was <80%. Heart rate was 198 beats/min and respiratory rate 58 breaths/min. Chest radiogram showed pulmonary edema. Electrocardiogram showed right atrial enlargement and right ventricular hypertrophy. N-terminal pro-brain natriuretic peptide (NTproBNP) was very high at >20,000 pg/mL. Two-dimensional echocardiography with Doppler showed CTS, which was complicated with severe pulmonary arterial hypertension due to flagrant pulmonary venous obstruction. Cardiac surgery was undertaken, after which pulmonary edema subsided, SpO2 increased to ≥96%, and NTproBNP dropped to normal. He was discharged 11 days later, and was free of cardiac, pulmonary, renal, and neurological sequelae at 24 month follow up.