Computational Analysis of Deposition and Translocation of Inhaled Nicotine and Acrolein in the Human Body with E-cigarette Puffing Topographies.
Recently, toxicants such as formaldehyde and acrolein were detected in electronic cigarette (EC) aerosols. It is imperative to conduct research and provide sufficient quantitative evidence to address the associated potential health risks. However, it is still a lack of informative data, i.e., high-resolution local dosimetry of inhaled aerosols in lung airways and other systemic regions, due to the limited imaging resolutions, restricted operational flexibilities, and invasive nature of experimental and clinical studies. In this study, an experimentally validated multiscale numerical model, i.e., Computational Fluid-Particle Dynamics (CFPD) model combined with a Physiologically Based Toxicokinetic (PBTK) model is developed to predict the systemic translocation of nicotine and acrolein in the human body after the deposition in the respiratory system. In-silico parametric analysis is performed for puff topography influence on the deposition and translocation of nicotine and acrolein in human respiratory systems and the systemic region. Results indicate that the puff volume and holding time can contribute to the variations of the nicotine and acrolein plasma concentration due to enhanced aerosol deposition in the lung. The change in the holding time has resulted in significant difference in the chemical translocation which was neglected in a large group of experimental studies. The capability of simulating multiple puffs of the new CFPD-PBTK model paves the way to a valuable computational simulation tool for assessing the chronic health effects of inhaled EC toxicants.


Fractal surfaces of proteins.
Fractal surfaces can be used to characterize the roughness or irregularity of protein surfaces. The degree of irregularity of a surface may be described by the fractal dimension D. For protein surfaces defined with probes in the range of 1.0 to 3.5 angstroms in radius, D is approximately 2.4 or intermediate between the value for a completely smooth surface (D = 2) and that for a completely space-filling surface (D = 3). Individual regions of proteins show considerable variation in D. These variations may be related to structural features such as active sites and subunit interfaces, suggesting that surface texture may be a factor influencing molecular interactions.


Gram-Positive Bacterial Infections: Research Priorities, Accomplishments, and Future Directions of the Antibacterial Resistance Leadership Group.
Antimicrobial resistance in gram-positive bacteria remains a challenge in infectious diseases. The mission of the Gram-Positive Committee of the Antibacterial Resistance Leadership Group (ARLG) is to advance knowledge in the prevention, management, and treatment of these challenging infections to improve patient outcomes. Our committee has prioritized projects involving methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) due to the scope of the medical threat posed by these pathogens. Approved ARLG projects involving gram-positive pathogens include (1) a pharmacokinetics/pharmacodynamics study to evaluate the impact of vancomycin dosing on patient outcome in MRSA bloodstream infection (BSI); (2) defining, testing, and validating innovative assessments of patient outcomes for clinical trials of MRSA-BSI; (3) testing new strategies for "step-down" antibiotic therapy for MRSA-BSI; (4) management of staphylococcal BSIs in neonatal intensive care units; and (5) defining the impact of VRE bacteremia and daptomycin susceptibility on patient outcomes. This article outlines accomplishments, priorities, and challenges for research of infections caused by gram-positive organisms.


Vastus medialis obliquus atrophy: does it exist in patellofemoral pain syndrome?
Quadriceps atrophy and in particular atrophy of the vastus medialis obliquus (VMO) muscle have been frequently related with patellofemoral pain syndrome (PFPS), despite very little objective evidence. Patients with PFPS exhibit atrophy of the VMO in comparison with healthy controls. Case-control study; Level of evidence, 3. Forty-six patients with PFPS and 30 healthy control persons with similar age, gender, body mass index, and activity index distributions underwent magnetic resonance imaging (MRI) of the quadriceps. The muscle size was determined by calculating the cross-sectional area of the total quadriceps and its components. The cross-sectional area (CSA) of the VMO was significantly smaller in the PFPS group than in the control group (16.67 ± 4.97 cm(2) vs 18.36 ± 5.25 cm(2)) (P = .040). A tendency was noted for a smaller total quadriceps CSA for the PFPS patients at midthigh level (66.99 ± 15.06 cm(2) vs 70.83 ± 15.30 cm(2)) (P = .074). This is the first study to examine VMO size in PFPS patients by MRI. Patients with patellofemoral problems exhibited atrophy of the VMO. Although it is not clear whether this atrophy is a result or a cause of PFPS, the results of this study do show that atrophy of the VMO is a contributing factor in PFPS. Longitudinal, prospective studies are needed to establish the cause-effect relation of VMO atrophy and PFPS.


A missense mutation in the human connexin50 gene (GJA8) underlies autosomal dominant "zonular pulverulent" cataract, on chromosome 1q.
CZP1, a locus for autosomal dominant "zonular pulverulent" cataract, previously had been linked with the Duffy blood-group-antigen locus on chromosome 1q. Here we report genetic refinement of the CZP1 locus and show that the underlying mutation is present in GJA8, the gene for connexin50. To map the CZP1 locus we performed linkage analysis using microsatellite markers on two distantly related branches of the original Ev. pedigree, which now spans eight generations. Significantly positive two-point LOD score (Z) values were obtained for markers D1S2669 (maximum Z [Zmax] = 4.52; maximum recombination frequency [thetamax] = 0) and D1S514 (Zmax = 4.48; thetamax = 0). Multipoint analysis gave Zmax = 5.22 (thetamax = 0) at marker D1S2669. Haplotyping indicated that CZP1 probably lies in the genetic interval D1S2746-(20.6 cM)-D1S2771. Sequence analysis of the entire protein-coding region of the GJA8 gene from the pedigree detected a C-->T transition in codon 88, which introduced a novel MnlI restriction-enzyme site that also cosegregated with the cataract. This missense mutation is predicted to result in the nonconservative substitution of serine for a phylogenetically conserved proline (P88S). These studies provide the first direct evidence that GJA8 plays a vital role in the maintenance of human lens transparency and identify the genetic defect believed to underlie the first inherited disease to be linked to a human autosome.


Management of anorectal injuries in children: an eighteen-year experience.
Anorectal injuries (ARI) are rare in childhood and yet occur due to sexual abuse and firearm injuries in developed countries. The labeling of ARI remains controversial in spite of a number of divergent reports over the past decade. We evaluated the surgical indications for primary repair of ARI without stoma, and also the potential risk factors affecting morbidity and mortality in children with ARI. Between 1983 and 2001, 41 children were diagnosed as ARI in our institution due to blunt or penetrating trauma. There were 17 male and 24 female patients. Causes of anorectal injury were blunt injuries in the majority of cases (56 %). Vagina and extremity fractures were the organs most frequently associated with ARI. There was isolated ARI in 49 % of cases. Intraperitoneal organ injury was found in 3 patients (7 %). The distribution of injury location according to the classification of ARI in our children was as follows: 10 % in G I, 32 % in G II, 51 % in G III, and 10 % in G V. Primary repair without colostomy was performed in 51 % of cases. Primary repair and diversion of faecal stream by loop colostomy was required in 20 (49 %) patients. Postoperative septic complications occurred in 29 % of cases. Some potential risk factors such as trauma mechanism and associated organ injury were not significantly correlated to postoperative septic complications, while other risk factors such as mode of treatment, time of operative intervention and contamination were significantly related to postoperative septic complications (p < 0.05). The sensitivity of trauma scoring systems for the estimation of postoperative complication occurrence was significant for ISS (p < 0.05) and ARI score (p < 0.05). The relative risk of developing a postoperative septic complication was higher than 2 for patients with ARI grade III, ISS > 15, primary repair + colostomy group, and time of operative intervention > 8 hours. A child in the colostomy + primary repair group died on the first postoperative day from rapidly progressing septicaemia and multiple organ failure (2.4 %). The management of ARI can be carried out by primary repair procedure without colostomy in the majority of cases if the needed selectivity is established.


Advancing the accessibility of psychotherapy: learning from our international colleagues.
Although the Affordable Care Act has theoretically made access to mental health care possible for all patients, the United States continues to lag behind other countries with respect to the provision of psychotherapeutic treatments. In the United Kingdom, for example, substantial resources have been committed to increase the availability of effective psychotherapies, particularly for depression and anxiety disorders. This development required a significant deployment of resources, with more than one billion dollars committed over the course of 7 years (2008-2015). Over 6,000 therapists have been trained and are currently being deployed in specialized local services to treat patients with depression and anxiety. A second phase of the initiative aims to bring psychotherapeutic treatment to patients with schizophrenia, bipolar disorder, and borderline personality disorder. Psychotherapy advocates in the United States may be more successful in advocating for such treatments by using similar methods to influence legislators and insurers.


Phenotypic plasticity in Periplaneta americana photoreceptors.
Plasticity is a crucial aspect of neuronal physiology essential for proper development and continuous functional optimization of neurons and neural circuits. Despite extensive studies of different visual systems, little is known about plasticity in mature microvillar photoreceptors. Here we investigate changes in electrophysiological properties and gene expression in photoreceptors of the adult cockroach, Periplaneta americana, after exposure to constant light (CL) or constant dark (CD) for several months. After CL, we observed a decrease in mean whole-cell capacitance, a proxy for cell membrane area, from 362 ± 160 to 157 ± 58 pF, and a decrease in absolute sensitivity. However, after CD, we observed an increase in capacitance to 561 ± 155 pF and an increase in absolute sensitivity. Small changes in the expression of light-sensitive channels and signaling molecules were detected in CD retinas, together with a substantial increase in the expression of the primary green-sensitive opsin (GO1). Accordingly, light-induced currents became larger in CD photoreceptors. Even though normal levels of GO1 expression were retained in CL photoreceptors, light-induced currents became much smaller, suggesting that factors other than opsin are involved. Latency of phototransduction also decreased significantly in CL photoreceptors. Sustained voltage-activated K+ conductance was not significantly different between the experimental groups. The reduced capacitance of CL photoreceptors expanded their bandwidth, increasing the light-driven voltage signal at high frequencies. However, voltage noise was also amplified, probably because of unaltered expression of TRPL channels. Consequently, information transfer rates were lower in CL than in control or CD photoreceptors. These changes in whole-cell capacitance and electrophysiological parameters suggest that structural modifications can occur in the photoreceptors to adapt their function to altered environmental conditions. The opposing patterns of modifications in CL and CD photoreceptors differ profoundly from previous findings in Drosophila melanogaster photoreceptors.


Transforming growth factor-beta1 promoter polymorphism C-509T is associated with asthma.
Transforming growth factor-beta1 (TGF-beta1) is increased in the lungs of individuals with asthma and may modulate airway inflammation and remodeling. Some genetic studies have found that a C-to-T single-nucleotide polymorphism (C-509T) in the TGF-beta1 gene promoter may be associated with altered gene expression and asthma phenotype. To build on these data, we performed a case-control association study at this locus involving 527 subjects with asthma and 170 control subjects without asthma. All individuals were white. Genotyping at 49 unlinked polymorphisms indicated that a subset of case subjects and all control subjects were well matched and without evidence of population stratification. Logistic regression was used to model the effects of age, sex, and genotype on case-control status. The diagnosis of asthma was positively associated with the T allele and TT genotype under a codominant model (odds ratio, 2.98; 95% confidence interval, 1.45 to 6.25; p = 0.003). Total serum IgE, eosinophil count, and FEV1% predicted levels were not associated with this polymorphism. Furthermore, we show that the C-509T polymorphism alters TGF-beta1 promoter-reporter activity and promoter interactions with the transcription factor Yin Yang 1. We conclude that the T allele of C-509T is associated with the diagnosis of asthma and may enhance TGF-beta1 gene transcription.


'Seeing' proximal representations: Testing attitudes to the relationship between vision and images.
Corrections applied by the visual system, like size constancy, provide us with a coherent and stable perspective from ever-changing retinal images. In the present experiment we investigated how willing adults are to examine their own vision as if it were an uncorrected 2D image, much like a photograph. We showed adult participants two lines on a wall, both of which were the same length but one was closer to the participant and hence appeared visually longer. Despite the instruction to base their judgements on appearance specifically, approximately half of the participants judged the lines to appear the same. When they took a photo of the lines and were asked how long they appeared in the image their responses shifted; now the closer line appeared longer. However, when they were asked again about their own view they reverted to their original response. These results suggest that many adults are resistant to imagining their own vision as if it were a flat image. We also place these results within the context of recent views on visual perspective-taking.


Immunomodulatory liposomes targeting liver macrophages arrest progression of nonalcoholic steatohepatitis.
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic macrophage inflammation, steatosis and fibrosis. Liposomes injected intravenously passively target hepatic myeloid cells and have potential to deliver immunomodulatory compounds and treat disease. We investigated targeting, delivery, immunomodulation and efficacy of liposomes in mice with diet-induced NASH. Liposome-encapsulated lipophilic curcumin or 1,25-dihydroxy-vitamin D3 (calcitriol) were injected intravenously into mice with diet-induced NASH. Liver and cell liposome uptake was assessed by in vivo imaging and flow cytometry. Immunomodulation of targeted cells were assessed by RNA transcriptome sequencing. NASH was assessed by histological scoring, serum liver enzymes and fasting glucose/insulin and liver RNA transcriptome sequencing. Liposomes targeted lipid containing MHC class-II+ hepatic dendritic cells in mice and humans. Delivery of liposomal curcumin to hepatic dendritic cells shifted their inflammatory profile towards a regulatory phenotype. Delivery of liposomal curcumin or calcitriol to mice with diet-induced NASH led to reduced liver inflammation, fibrosis and fat accumulation, and reduced insulin resistance. RNA transcriptome sequencing of liver from treated mice identified suppression of pathways of immune activation, cell cycle and collagen deposition. Liposomes are a new strategy to target lipid rich inflammatory dendritic cells and have potential to deliver immunomodulatory compounds to treat NASH.


Combination of propofol and remifentanil target-controlled infusion for laryngeal mask airway insertion in children.
The addition of remifentanil to propofol administration can improve the conditions for insertion of laryngeal mask airways (LMAs). However, the extent to which remifentanil reduces propofol requirements when both drugs are administered concomitantly via target-controlled infusion (TCI) in pediatric patients has not been adequately demonstrated. The purpose of this study was to determine the target concentration of propofol that is required for LMA insertion at three different remifentanil target concentrations (0, 2.5, and 5 ng kg(-1) min(-1)) during TCI in children. A total of 67 children, aged 2 to 12 years, were included, and anesthesia was conducted with TCI of propofol and remifentanil using the STELPUMP program. The children were assigned to three groups in a randomized, double-blind manner: propofol with saline (control group), propofol with 2.5 ng mL(-1) of remifentanil (low-remifentanil group), and propofol with 5.0 ng ml(-1) of remifentanil (high-remifentanil group). The EC(50) of propofol for LMA insertion at each target-concentration of remifentanil was determined using Dixon's up-and-down method, and the EC(50) of propofol in each group was compared using the Kruskal-Wallis ANOVA by rank test. The EC(50) for propofol was 5.18 mcg mL(-1) in the control group, 4.81 mcg ml(-1) in the low-remifentanil group, and 4.36 mcg mL(-1) in the high-remifentanil group, which was significantly different between the control group and the high-remifentanil group only (P<0.001). A higher target concentration of remifentanil significantly reduced the propofol target concentration for LMA insertion during TCI of both drugs in children, but low concentrations of remifentanil failed to reduce the propofol requirement.


Prehospital rapid sequence induction by emergency physicians: is it safe?
To determine if there were differences in practice or intubation mishap rate between anaesthetists and accident and emergency physicians performing rapid sequence induction of anaesthesia (RSI) in the prehospital setting. All patients who underwent RSI by a Helicopter Emergency Medical Service (HEMS) doctor from 1 May 1997 to 30 April 1999 were studied by retrospective analysis of in-flight run sheets. Intubation mishaps were classified as repeat attempts at intubation, repeat drug administration and failed intubation. RSI was performed on 359 patients by 10 anaesthetists (202 patients) and nine emergency physicians (157 patients). Emergency physicians recorded a larger number of patients as having Cormack and Lehane grade 3 or 4 laryngoscopy than anaesthetists (p<0.0001) but were less likely to use a gum elastic bougie to assist intubation (p=0.024). Patients treated by emergency physicians did not have a significantly different pulse, blood pressure, oxygen saturation or end tidal CO2 to patients treated by anaesthetists at any time after intubation. Emergency physicians were more likely to anaesthetise patients with a Glasgow Coma Score >12 than anaesthetists (p=0.003). There were two failed intubations (1%) in the anaesthetist group and four (2.5%) in the emergency physician group. Repeat attempts at intubation and repeat drug administration occurred in <2% of each group. RSI performed by emergency physicians was not associated with a significantly higher failure rate or an increased number of intubation mishaps than RSI performed by anaesthetists. Emergency physicians were able to safely administer sedative and neuromuscular blocking drugs in the prehospital situation. It is suggested that emergency physicians can safely perform rapid sequence induction of anaesthesia and intubation.


Would disfluency by any other name still be disfluent? Examining the disfluency effect with cursive handwriting.
When exposed to words presented under perceptually disfluent conditions (e.g., words written in Haettenschweiler font), participants have difficulty initially recognizing the words. Those same words, though, may be better remembered later than words presented in standard type font. This counterintuitive finding is referred to as the disfluency effect. Evidence for this disfluency effect, however, has been mixed, suggesting possible moderating factors. Using a recognition memory task, level of disfluency was examined as a moderating factor across three experiments using a novel cursive manipulation that varied on degree of legibility (easy-to-read cursive vs. hard-to-read cursive). In addition, list type and retention interval between study and test were manipulated. Across all three experiments, cursive words engendered better memory than type-print words. This memory effect persisted across varied list designs (blocked vs. mixed) and a longer (24-hour) retention interval. A small-scale meta-analysis across the three experiments suggested that the cursive disfluency effect is moderated by level of disfluency: easy-to-read cursive words tended to be better remembered than hard-to-read cursive words. Taken together, these results challenge extant accounts of the disfluency effect. The theoretical and practical implications of these findings are discussed.


Stilbene Compounds Inhibit Tumor Growth by the Induction of Cellular Senescence and the Inhibition of Telomerase Activity.
: Cellular senescence is a state of cell cycle arrest characterized by a distinct morphology, gene expression pattern, and secretory phenotype. It can be triggered by multiple mechanisms, including those involved in telomere shortening, the accumulation of DNA damage, epigenetic pathways, and the senescence-associated secretory phenotype (SASP), and so on. In current cancer therapy, cellular senescence has emerged as a potent tumor suppression mechanism that restrains proliferation in cells at risk for malignant transformation. Therefore, compounds that stimulate the growth inhibition effects of senescence while limiting its detrimental effects are believed to have great clinical potential. In this review article, we first review the current knowledge of the pro- and antitumorigeneic functions of senescence and summarize the key roles of telomerase in the regulation of senescence in tumors. Second, we review the current literature regarding the anticancer effects of stilbene compounds that are mediated by the targeting of telomerase and cell senescence. Finally, we provide future perspectives on the clinical utilization of stilbene compounds, especially resveratrol and pterostilbene, as novel cancer therapeutic remedies. We conclude and propose that stilbene compounds may induce senescence and may potentially be used as the therapeutic or adjuvant agents for cancers with high telomerase activity.


Coordination of early neural tube development by BDNF/trkB.
Neurotrophins signal through members of the trk family of tyrosine kinase receptors and are known to regulate several neuronal properties. Although initially characterized by their ability to prevent naturally occurring cell death of subsets of neurons during development, neurotrophins can also regulate the proliferation and differentiation of precursor cells. Here we report a novel involvement of neurotrophins in early development of the neural tube. We demonstrate that a functional trkB receptor is expressed by motor neuron progenitors in the ventral neural tube and that treatment of ventral neural tube explants with the trkB ligand Brain-Derived Neurotrophic Factor (BDNF) leads to a significant increase in the number of motor neurons. The only BDNF expression detectable at this stage is by a subset of ventrally projecting interneurons in the dorsal neural tube; ablating this region in vivo leads to a reduction of motor neuron numbers. This loss can be prevented by simultaneous treatment with BDNF. We propose that BDNF produced by dorsal interneurons stimulates proliferation and/or differentiation of motor neuron progenitors after anterograde axonal transport and release in proximity to the trkB-expressing motor neuron precursors, thereby coordinating development between dorsal and ventral regions of the neural tube.


Uromodulin storage diseases: clinical aspects and mechanisms.
The recent discovery of mutations in the uromodulin gene ( UMOD ) in patients with medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD) provides the opportunity for a revision of pathogenic aspects and puts forth the basis for a renewed classification. This review focuses on clinical, pathological, and cell biology advances in UMOD -related pathological states, including a review of the associated clinical conditions described to date in the literature. Overall, 31 UMOD mutations associated with MCKD2 and FJHN (205 patients) and 1 mutation associated with GCKD (3 patients) have been described, with a cluster at exons 4 and 5. Most are missense mutations causing a cysteine change in uromodulin sequence. No differences in clinical symptoms between carriers of cysteine versus polar residue changes have been observed; clinical phenotypes invariably are linked to classic MCKD2/FJHN. A common motif among all reports is that many overlapping symptoms between MCKD2 and FJHN are present, and a separation between these 2 entities seems unwarranted or redundant. Cell experiments with mutant variants indicated a delay in intracellular maturation and export dynamics, with consequent uromodulin storage within the endoplasmic reticulum (ER). Patchy uromodulin deposits in tubule cells were found by means of immunohistochemistry, and electron microscopy showed dense fibrillar material in the ER. Mass spectrometry showed only unmodified uromodulin in urine of patients with UMOD mutations. Lack of uromodulin function(s) is associated with impairments in tubular function, particularly the urine-concentrating process, determining water depletion and hyperuricemia. Intracellular uromodulin trapping within the ER probably has a major role in determining tubulointerstitial fibrosis and renal failure. We propose the definition of uromodulin storage diseases for conditions with proven UMOD mutations.


[Effect of phenylalanine and alpha-tocopherol on ubiquinone and ubichromenol metabolism in the liver of E-avitaminotic rats in vitro].
When incubating the liver pulp of vitamin E-deficiency rats with 2-14C-sodium acetate and phenylalanine for an hour the content and radioactivity of ubiquinone and ubichromenol increase as compared to the control level. In this respect phenylalanine in in a dose of 60 and 120 mumol per 1 g of the liver pulp is most effective. Under conditions of these experiments incubation for 3 h causes no noticable changes in the content and metabolism of ubiquinone and ubichromenol in the liver pulp of vitamin E-deficiency rats as compared to the control level. Introduction of different amounts of alpha-tocopherol into the incubation medium results 3 h after an increase in concentration and radioactivity of ubiquinone, the alpha-tocopherol dose of 116 nmol being the most effective. An increase in the concentration and radioactivity of ubichromenol occurs at lower doses of exogenous alpha-tocopherol (58 nmol). All the used doses of alpha-tocopherol cause a decrease in intensity of radio-label incorporation into the unsaponifiable fraction of vitamin E-deficiency rat liver incubated for 3 h. Phenylalanine also results in a decrease of these values with the system incubation for an hour and produces no changes in them in the 3 h incubation. The results of the experiments give grounds to suppose the presence of interrelation between alpha-tocopherol and biosynthesis of ubiquinone and ubichromenol in the rat liver.


Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy.
It is well known that dysfunction of the apoptotic pathway confers apoptosis resistance and results in a low sensitivity of human cancer cells to therapeutic agents. A novel strategy to overcome the resistance is to target the apoptotic pathway directly. To identify molecular targets in the apoptotic pathway that are differentially regulated in cancer and normal cells, we have examined the levels of apoptotic effectors and inhibitors in human tumor and normal cell lines as well as in cancer and normal tissues. These include three pancreatic cancer lines (BXPC-3, MIA PaCa-2, and Panc-1), four breast cancer cell lines (MDA-MB-231, MDA-MB-435, MDA-MB-361, and MCF-7), and colon carcinoma line (SW620). Additionally, breast carcinoma tissue specimens were examined. Compared with normal human fibroblast and mammary epithelial cell lines, we detected high basal levels of caspase-3 and caspase-8 activities and active caspase-3 fragments in the tumor cell lines and cancer tissues in the absence of apoptotic stimuli. Furthermore, the tumor cells expressed high levels of survivin and XIAP, two members of the inhibitor of apoptosis (IAP) protein family. When the activity of these IAPs was blocked by expression of dominant-negative mutant survivin (survivinT34A) and XIAP-associated factor 1, respectively, apoptosis was induced in tumor but not normal cell lines. Moreover, down-regulation of both survivin and XIAP significantly enhanced tumor-cell apoptosis as compared with inhibition of either survivin or XIAP alone. These results suggest that up-regulated IAP expression counteracts the high basal caspase-3 activity observed in these tumor cells and that apoptosis in tumor cells but not normal cells can be induced by blocking IAP activity. Therefore, IAPs are important molecular targets for the development of cancer-specific therapeutic approaches.


Influence of dietary beta-glucan on growth performance, nonspecific immunity, and resistance to Streptococcus suis infection in weanling pigs.
Three experiments, using 344 pigs, were conducted to evaluate the influence of beta-glucan on growth performance, neutrophil and macrophage function, haptoglobin production, and resistance to Streptococcus suis challenge in weanling pigs. In Exp. 1, 144 pigs were used to evaluate the influence of .1% dietary beta-glucan in a soybean meal- or milk protein-based diet on growth performance and neutrophil function. Pigs fed beta-glucan from d 7 to 14 after weaning had lower ADFI (P < .01) and, although not significant, ADG was lower for pigs fed beta-glucan than for pigs fed control diets. However, no differences were observed in growth performance or neutrophil function for pigs fed control or diets containing beta-glucan from d 7 to 35 after weaning. Experiment 2 was a 28-d growth assay in which pigs were fed a diet with or without .1% beta-glucan, containing 7.5% spray-dried plasma protein and 25% dried whey from d 0 to 14 after weaning. Pigs then were fed corn-soybean mealbased diets containing 2.5% spray-dried blood meal and 10% dried whey. No differences in growth performance were observed. Experiment 3 was a 35-d assay to evaluate growth performance, neutrophil and macrophage function, and plasma haptoglobin concentration. Pigs were challenged on d 28 postweaning with intravenous S. suis. In Exp. 3, pigs were fed diets without or with .025 or .05% beta-glucan. Dietary beta-glucan did not influence neutrophil or macrophage function. However, pigs fed diets containing .025% beta-glucan had increased (P < .05) ADG and ADFI and were heavier (P < .05) on d 28 after weaning than pigs fed the control diet. No differences in feed efficiency (G/F) were detected between treatments. Pigs fed beta-glucan had decreased (P < .10) plasma haptoglobin on d 14, 21, and 28 after weaning. However, Fisher's Exact test revealed that more (P < .04) pigs fed a diet containing .025% beta-glucan died by d 12 after challenge with S. suis. In conclusion, these data suggest the existence of a complex interaction involving growth performance and resistance to S. suis in pigs fed .025% beta-glucan.


Neutrophils in multiple sclerosis are characterized by a primed phenotype.
Neutrophils are armed with proteases with indiscriminate histotoxic potential, and to minimize tissue injury, their activation involves priming with inflammatory mediators before cells are fully activated in a second step. Here, we show that neutrophils in multiple sclerosis patients are more numerous and exhibit a primed state based on reduced apoptosis, higher expression of TLR-2, fMLP receptor, IL-8 receptor and CD43, enhanced degranulation and oxidative burst as well as higher levels of neutrophil extracellular traps in serum. The chronic inflammatory environment in multiple sclerosis probably underlies this inappropriate neutrophil priming, which may result in enhanced neutrophil activation during infection.


[Parameters of spectral-temporal maps of signal averaged ECG in patients with ischemic heart disease and chronic heart failure].
Signal averaged ECG was registered in 57 patients with chronic heart failure due to ischemic heart disease and either accelerating or stable class III effort angina. Analysis of parameters of spectral-temporal maps showed that high local activity in terminal portion of ventricular and atrial complexes reflected heterogeneity of depolarization of atrial and ventricular myocardium. These changes correlated with presence of atrial and ventricular late potentials and could be used as markers of electrical instability of the myocardium.


Cold-adapted protease enables quantitation of surface proteins in the absence of membrane trafficking.
We report here an improved method for analyzing protein surface expression utilizing a cold-adapted trypsin. Preservation of activity of the enzyme at 0-4°C permits modification of the protease method of surface analysis to temperatures at which trafficking of mammalian plasmalemmal proteins is blocked. This is an important advantage over established trypsin-cleavage protocols. Moreover, the method is less time-consuming than surface biotinylation.


Do patients with invasive lobular breast cancer benefit in terms of adequate change in surgical therapy from a supplementary preoperative breast MRI?
Breast magnetic resonance imaging (MRI) has been introduced in the preoperative management of invasive lobular breast cancer (ILC). We analysed if MRI leads to adequate changes in surgical management. We carried out a single-centre retrospective confirmatory analysis of 92 patients with ILC and a preoperative breast MRI. By applying a blinded tumour board method, we analysed if surgical procedures were altered due to breast MRI. In case of alteration, we analysed whether the change was adequate according to the postoperative pathology findings. We considered an adequate rate of change>5% to be a clinically relevant benefit. A change in surgical therapy due to the MRI findings occurred in 23 of 92 patients (25%). According to the postoperative pathology findings, this change was adequate for 20 of these patients (22%; 95% confidence interval [CI] 14%-31%, P<0.0001). An overtreatment occurred for three patients (3%; 95% CI 0%-6%) who underwent a mastectomy following the results of breast MRI. Patients with larger tumours did likely benefit more from preoperative breast MRI. Patients with ILC might benefit from a preoperative breast MRI. Possible harm from overtreatment should be minimised by diligent use of preoperative histological clarification.


Microvascular and Structural Alterations of the Macula in Early to Moderate Glaucoma: An Optical Coherence Tomography-Angiography Study.
In glaucoma, macular optical coherence tomography (OCT) typically shows a thinning of the three inner segments and OCT-angiography (OCTA) a reduction of the vascular density (VD). It is still unclear if glaucoma directly affects macular VD. This retrospective study included 31 glaucoma patients of early and moderate stage (GS1, GS2, Mills et al.) and 39 healthy individuals. Macular segments' thickness and superficial and deep plexus vascular density (VD) were obtained using spectral-domain OCT and OCTA, respectively. One-way analysis of variance (ANOVA) was used to compare healthy controls and glaucoma patients according to their glaucoma stage. Using correlation analyses, the association between glaucoma and either OCT or OCTA parameters was evaluated. A glaucoma stage-stratified linear regression analysis was then performed. Inner macular segment and whole retinal thickness were reduced in GS1 and GS2 patients compared to healthy controls (e.g., ganglion cell layer GCL: controls: 47.9 ± 7.4, GS1: 45.8 ± 5.1, GS2: 30.6 ± 9.4, ANOVA: p < 0.0001). Regarding OCTA-parameters, the VD of both segmentation levels was reduced in glaucoma patients, particularly when comparing GS2 patients with controls (superficial plexus: p = 0.004) and GS2 with GS1 (p = 0.0008). Linear regression revealed an association between these parameters and the presence of glaucoma (for superior plexus: R2 = 0.059, p = 0.043). Finally, a correlation between macular segment thickness and VD was observed, but with a strength increasing with glaucoma severity (GCL and superior plexus VD: controls: R2 = 0.23, GS1 R2 = 0.40, GS2 R2 = 0.76). Despite the glaucoma-independent correlation between macular segment thickness and VD, disease severity strengthens this correlation. This consideration suggests that glaucoma directly influences OCT and OCTA parameters individually.


Isolation of the second Bacillus thuringiensis RNA polymerase that transcribes from a crystal protein gene promoter.
A crystal protein gene of Bacillus thuringiensis subsp. kurstaki HD-1-Dipel is transcribed in vivo from two overlapping promoters that are activated at different times during sporulation. We reported earlier (K. L. Brown and H. R. Whiteley, Proc. Natl. Acad. Sci. USA 85:4166-4170, 1988) that an RNA polymerase containing a sigma subunit with an apparent Mr of 35,000 can transcribe in vitro from the promoter utilized from early to midsporulation. We now report the isolation of an RNA polymerase containing a sigma subunit with an Mr of ca. 28,000; this polymerase activates transcription in vitro from the promoter used from mid- to late sporulation. This form of RNA polymerase also directs transcription in vitro from promoters preceding two other crystal protein genes and a gene coding for a spore coat protein. On the basis of a comparison of the four promoters, we propose the following consensus sequence for the -10 region recognized by RNA polymerase containing the Mr-28,000 sigma subunit: 5'-TNATANNaTGag-3'. No consensus sequence could be derived for the -35 region. When the N-terminal amino acid sequence of the sigma 28 polypeptide was aligned with the amino acid sequences of known sigma subunits, significant homology was found with the N terminus of the mature form of the sigma K subunit of RNA polymerase isolated from sporulating cells of Bacillus subtilis.


Divergent personalities influence the myogenic regulatory genes myostatin, myogenin and ghr2 transcript responses to Vibrio anguillarum vaccination in fish fingerlings (Sparus aurata).
Myogenic regulators of muscle development, metabolism and growth differ between fish species in a context-specific manner. Commonly, the analysis of environmental influences on the expression of muscle-related gene regulators in teleosts is based on differences in swimming performance, feeding behaviour and stress-resistance, but the evaluation of behavioural phenotyping of immune and stress-related responsiveness in skeletal muscle is still scarce. Here we challenge proactive and reactive fingerlings of gilthead sea bream (Sparus aurata), one of the most commonly cultured species in the Mediterranean area, with highly pathogenic O1, O2α and O2β serotypes of Vibrio anguillarum, a widespread opportunistic pathogen of marine animals, to analyse skeletal muscle responses to bath vaccination. Transcripts related to inflammation (interleukin 1β, il1β; tumour necrosis factor-α, tnfα; and immunoglobulin M, igm), and muscle metabolism and growth (lipoprotein, lpl; myostatin, mstn-1; myogenin; and growth hormone receptors type I and II, ghr1 and ghr2, respectively) were analysed. Biochemical indicators of muscle metabolism and function (creatine kinase, CK, aspartate aminotransferase, AST; esterase activity, EA; total antioxidant status, TAC and glucose) were also determined. Our results indicate that proactive, but not reactive, fish respond to Vibrio vaccination by increasing the expression levels of mstn-1, myogenin and ghr2 transcripts at short-/medium- term (1 to 3 days' post vaccination). No effect of vaccination was observed in immune indicators or biochemical parameters in either phenotypes, except for elevated levels of EA in reactive fish one-week post vaccination. This suggests that behavioural divergence should be taken into account to evaluate the crosstalk between immune, metabolic and growth processes in muscle of immune-challenged fish.


Cellular Prion Protein Mediates Pancreatic Cancer Cell Survival and Invasion through Association with and Enhanced Signaling of Notch1.
Up-regulation of human prion protein (PrP) in patients with pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. However, the underlying molecular mechanism of PrP-mediated tumorigenesis is not completely understood. In this study, we found that PDAC cell lines can be divided into either PrP high expresser or PrP low expresser. In addition to filamin A (FLNA), PrP interacts with Notch1, forming a PrP/FLNA/Notch1 complex. Silencing PrP in high-expresser cells decreases Notch1 expression and Notch1 signaling. These cells exhibited decreased proliferation, xenograft growth, and tumor invasion but show increased tumor apoptosis. These phenotypes were rescued by ectopically expressed and activated Notch1. By contrast, overexpression of PrP in low expressers increases Notch1 expression and signaling, enhances proliferation, and increases tumor invasion and xenograft growth that can be blocked by a Notch inhibitor. Our data further suggest that PrP increases Notch1 stability likely through suppression of Notch proteosome degradation. Additionally, we found that targeting PrP combined with anti-Notch is much more effective than singularly targeted therapy in retarding PDAC growth. Finally, we show that coexpression of PrP and Notch1 confers an even poorer prognosis than PrP expression alone. Taken together, our results have unraveled a novel molecular pathway driven by interactions between PrP and Notch1 in the progression of PDAC, supporting a critical tumor-promoting role of Notch1 in PrP-expressing PDAC tumors.


TRH mobilizes membrane calcium in thyrotropic cells as monitored by chlortetracycline.
Chlortetracycline (CTC), a probe of membrane-bound divalent cations, was used to study the action of thyrotropin-releasing hormone (TRH) in mouse pituitary thyrotropic tumor (TtT) cells in culture. Cellular fluorescence of CTC was caused by both Ca2+- and Mg2+-CTC complexes and was influenced by the concentration of these cations in the incubation medium. TRH, but not other peptides, caused a rapid, transient, and concentration-dependent decrease in the CTC fluorescence intensity; half-maximal effect occurred with 10--30 nM TRH. The decrement in fluorescence intensity caused by TRH was not due to enhanced loss of CTC from the cells. The decrease in fluorescence elicited by TRH was specific for Ca2+-CTC complexes because preincubation of the cells with 1 mM EGTA or 1 mM EDTA plus 2.05 mM Mg2+ abolished the response, whereas preincubation with 1 mM EDTA plus 2.05 mM Ca2+ permitted the usual TRH response. Antimycin A and carbonyl cyanide m-chlorophenylhydrazone decreased cellular ATP content to 37 +/- 1 and 32 +/- 1% of control, respectively, and abolished the TRH-induced decrease in CTC fluorescence. We conclude that TRH displaced Ca2+ from an energy-dependent, membrane-bound pool(s) within TtT cells and that this may be one mechanism by which the concentration of intracellular free Ca2+ is raised so that is couples stimulation by TRH to TSH secretion.


Changes in the isoprenoid pathway in syndrome X.
This study assessed the changes in digoxin and some other metabolites of the isoprenoid pathway in metabolic syndrome X presenting with multiple lacunar state. There was an increase in plasma HMG CoA reductase activity with a consequent increase in serum digoxin, which caused a reduction in RBC membrane Na+-K+ ATPase activity. There was an increase in serum tryptophan and its metabolites and a decrease in tyrosine and its metabolites. Serum magnesium was decreased with consequent alteration in the metabolism of glycosaminoglycans and glycolipids. Increase in dolichol, another product of the isoprenoid pathway resulted in alteration in glycoprotein metabolism. Changes in the composition of membrane glycosaminoglycans, glycoproteins and cholesterol:phospholipid ratio were also observed in this disorder leading to decreased lysosomal stability. Decrease in ubiquinone, another isoprenoid metabolite resulted in alteration in the free radical generation. Membrane Na+-K+ ATPase inhibition due to digoxin, altered membrane structure, increased tryptophan catabolites and decreased tyrosine catabolites can lead on to increased intracellular calcium and reduced intracellular magnesium which can account for the symptoms of syndrome X.


Elevated EDAR signalling promotes mammary gland tumourigenesis with squamous metaplasia.
Ectodysplasin A receptor (EDAR) is a death receptor in the Tumour Necrosis Factor Receptor (TNFR) superfamily with roles in the development of hair follicles, teeth and cutaneous glands. Here we report that human Oestrogen Receptor (ER) negative breast carcinomas which display squamous differentiation express EDAR strongly. Using a mouse model with a high Edar copy number, we show that elevated EDAR signalling results in a high incidence of mammary tumours in breeding female mice. These tumours resemble the EDAR-high human tumours in that they are characterised by a lack of oestrogen receptor expression, contain extensive squamous metaplasia, and display strong β-catenin transcriptional activity. In the mouse model, all of the tumours carry somatic deletions of the third exon of the CTNNB1 gene that encodes β-catenin. Deletion of this exon yields unconstrained β-catenin signalling activity. We also demonstrate that β-catenin activity is required for transformed cell growth, showing that increased EDAR signalling creates an environment in which β-catenin activity can readily promote tumourigenesis. Together, this work identifies a novel death receptor oncogene in breast cancer, whose mechanism of transformation is based on the interaction between the WNT and Ectodysplasin A (EDA) pathways.


Outbreeding depression varies among cohorts of Ipomopsis aggregata planted in nature.
Outbreeding depression in progeny fitness may arise from disruption of local adaptation, disruption of allelic coadaptation, or a combination of these "environmental" and "physiological" mechanisms. Thus the minimum spatial scale over which outbreeding depression arises should depend on the spatial scale of gene dispersal and (with an environmental mechanism) of change in selection regimes. We previously reported substantial outbreeding depression in lifetime fitness of progeny resulting from crosses among parents separated by 100 m in natural populations of the herbaceous plant Ipomopsis aggregata. In this paper we explore the effect of crossing distance on fitness in two additional experiments begun in 1987 and 1990. We planted seed progeny derived from partial diallel crossing designs in randomized blocks in maternal environments and scored emergence of seedlings, survival, and eventual flowering of individuals over the subsequent six to eight years. Nested within each diallel design were crossing distances of 1 m, 10 m, and 100 m. Compared to 1-m and 10-m progeny, 100-m progeny of the 1987 diallel suffered a significant reduction in seedling emergence, and both 1-m and 100-m progeny that survived to flower achieved lower lambda-values on average than 10-m progeny. Total outbreeding depression suffered by 100-m relative to 10-m progeny was approximately 10%, compared to approximately 30% in our earlier study of I. aggregata. Progeny of 10-m crosses also outperformed 1-m and 100-m progeny of the 1990 diallel by approximately 5%, but no difference among crossing distance treatments was significant. Thus, the magnitude of outbreeding depression in 100-m crosses varied among experiments. This is not surprising given likely spatial and temporal variation in gene flow and selection regimes, different population histories, and different parental and progeny environments. Characterizing outbreeding depression on the shortest spatial scales over which it is expressed, as well as its variation and causes, is worthwhile because it promises to shed light on the earliest stages of angiosperm speciation.


Genome mosaicism is conserved but not unique in Pseudomonas aeruginosa isolates from the airways of young children with cystic fibrosis.
Pseudomonas aeruginosa strains from the chronic lung infections of cystic fibrosis (CF) patients are phenotypically and genotypically diverse. Using strain PAO1 whole genome DNA microarrays, we assessed the genomic variation in P. aeruginosa strains isolated from young children with CF (6 months to 8 years of age) as well as from the environment. Eighty-nine to 97% of the PAO1 open reading frames were detected in 20 strains by microarray analysis, while subsets of 38 gene islands were absent or divergent. No specific pattern of genome mosaicism defined strains associated with CF. Many mosaic regions were distinguished by their low G + C content; their inclusion of phage related or pyocin genes; or by their linkage to a vgr gene or a tRNA gene. Microarray and phenotypic analysis of sequential isolates from individual patients revealed two deletions of greater than 100 kbp formed during evolution in the lung. The gene loss in these sequential isolates raises the possibility that acquisition of pyomelanin production and loss of pyoverdin uptake each may be of adaptive significance. Further characterization of P. aeruginosa diversity within the airways of individual CF patients may reveal common adaptations, perhaps mediated by gene loss, that suggest new opportunities for therapy.


Synthesis and antimalarial activity of new amino analogues of amodiaquine.
Amodiaquine remains one of the most prescribed antimalarial 4-aminoquinoline. To assess the importance of the 4'-hydroxyl group and subsequent hydrogen bond in the antimalarial activity of amodiaquine (AQ), a series of new analogues in which this functionality was replaced by various amino groups was synthesized. The incorporation of a 3'-pyrrolidinamino group instead of the 3'-diethylamino function of AQ allowed the development of a parallel series of amopyroquine derivatives. The compounds were screened against both chloroquine (CQ)-sensitive and -resistant strains of Plasmodium falciparum and their cytotoxicity evaluated upon the MRC5 cell line. Antimalarial activity in a low nanomolar range was recorded showing that the 4'-hydroxy function can be successfully replaced by various amino substituents in terms of activity without any influence of the level of CQ-resistance of the strains. Furthermore the ability of the compounds to inhibit beta-hematin formation was measured in order to discuss the mechanism of action of these new compounds. Compounds 7d and 8d exhibit a high selectivity index and may be considered as promising leads for further development.


Suitability of tartrate-resistant acid phosphatase type 5b as a screening marker for bone mineral density in community-dwelling elderly individuals.
Osteoporosis is a common disorder in aging populations that imposes considerable health problems. Tartrate-resistant acid phosphatase type 5b (TRAP-5b) is derived from osteoclasts, and is involved in normal bone homeostasis. Recently, a novel assay system for TRAP-5b, the fragments absorbed immunocapture enzymatic assay method, has been developed. To evaluate the suitability of TRAP-5b as a screening marker for bone mineral density (BMD), we explored the correlations between serum TRAP-5b concentrations and laboratory findings, body mass index, or BMD in 462 community-dwelling elderly individuals (249 men and 213 women, age 73.4±6.5 years) who participated in a regular medical screening program. By multivariate linear regression analysis adjusted for confounding factors, TRAP-5b was significantly correlated with body mass index (β=-0.005, p=0.043), alkaline phosphatase, a marker for osteoid formation and calcification (β=0.001, p<0.001), and triglyceride (β=-0.097, p=0.016) in men, and with body mass index (β=-0.009, p=0.025), alkaline phosphatase (β=0.001, p<0.001), calcium (β=-0.059, p=0.039), and bone trabecular area ratio (β=-0.47, p=0.025) in women. In conclusion, the elevated serum level of TRAP-5b is independently correlated with the decreased BMD in women, but not in men. Because measurement of TRAP-5b is not affected by food intake, and blood samples can be collected at any time of the day, we suggest the suitability of serum TRAP-5b as a simple marker for the evaluation of BMD in women.


New drugs and vaccines for drug-resistant Mycobacterium tuberculosis infections.
Tuberculosis remains the most common cause of death due to a single infective organism. Despite the availability of a vaccine and chemotherapeutic options, the global disease burden remains relatively unaffected. The ability of the mycobacterial etiological agents to adopt a semidormant, phenotypically drug-resistant state requires that chemotherapy is both complex and lengthy. The emergence of drug resistance has raised the possibility of virtually untreatable tuberculosis. Furthermore, the currently used bacillus Calmette-Guerin vaccine has had mixed success in protecting susceptible populations. Given this backdrop, the need for novel anti-infectives and more effective vaccines is clearly evident. Recent progress, described herein, has seen the development and entry into clinical trials of several new drugs and vaccine candidates.


Bacteriophage Can Prevent Encrustation and Blockage of Urinary Catheters by Proteus mirabilis.
Proteus mirabilis forms dense crystalline biofilms on catheter surfaces that occlude urine flow, leading to serious clinical complications in long-term catheterized patients, but there are presently no truly effective approaches to control catheter blockage by this organism. This study evaluated the potential for bacteriophage therapy to control P. mirabilis infection and prevent catheter blockage. Representative in vitro models of the catheterized urinary tract, simulating a complete closed drainage system as used in clinical practice, were employed to evaluate the performance of phage therapy in preventing blockage. Models mimicking either an established infection or early colonization of the catheterized urinary tract were treated with a single dose of a 3-phage cocktail, and the impact on time taken for catheters to block, as well as levels of crystalline biofilm formation, was measured. In models of established infection, phage treatment significantly increased time taken for catheters to block (∼ 3-fold) compared to untreated controls. However, in models simulating early-stage infection, phage treatment eradicated P. mirabilis and prevented blockage entirely. Analysis of catheters from models of established infection 10 h after phage application demonstrated that phage significantly reduced crystalline biofilm formation but did not significantly reduce the level of planktonic cells in the residual bladder urine. Taken together, these results show that bacteriophage constitute a promising strategy for the prevention of catheter blockage but that methods to deliver phage in sufficient numbers and within a key therapeutic window (early infection) will also be important to the successful application of phage to this problem.


The Polish version of the short scale measuring health literacy in adolescence.
Background: Recent years saw the development of international tools for measuring health competencies understood as health literacy (HL). One of them is the short index Health Literacy for School-Aged Children (HLSAC) implemented by the members of the Health Behaviour in School-aged Children (HBSC) network. So far, when researching the properties of this instrument, less attention has been devoted to the correlation of HLSAC with other tools related to health. The aim of the paper is to present selected psychometric features of the HLSAC index in a sample of Polish pupils, supplemented by the preliminary analysis of its association with the health locus of control. Material and methods: The information collected relates to 630 junior secondary school students surveyed in Poland in 2016 as part of the HLSAC questionnaire pilot study. The Multidimensional Health Locus of Control (MHLC) scale by K. Wallston was used as the additional module for Poland. It differentiates among three dimensions of health control: internal, external - dependent on other people, and external - dependent on random factors. It was checked which HLC dimension correlates most strongly with HL. Results: It was demonstrated that the HLSAC scale consisting of 10 questions has a very good reliability in the Polish version (Cronbach alfa = 0.851) and a one-factor structure. Confirmatory factor analysis supported a unidimensional model (RMSEA = 0.082; CFI=0.922; TLI=0.877). The HLSAC most strongly correlates with the internal health locus of control (r=0.376; p<0.001), slightly less with the influence of other people (r=0.153; p<0.001), while the correlation with the random factor health locus of control is insignificant (p=0.947). It was found that there is a weak, however significant, positive correlation between family affluence and HLSAC (p=0.041). Conclusions: The analyses conducted demonstrated that the Polish version of HLSAC has good psychometric features. The relatively higher correlation between HLSAC and internal rather than external health locus of control was confirmed. The practical effect of the pilot study was to develop an improved version of the HLSAC scale, which has been recommended for the mainstream HBSC 2018 survey.


Individualized exercise prescription in non-alcoholic steatohepatitis: a case report.
The effect of an individualized exercise programme on a non-alcoholic steatohepatitis case is presented. Before entering the programme the patient was treated with conventional recommendations on diet plus aerobic exercise during fourteen years, without major improvements of his analytical parameters.Two years after including him in a tailored exercise programme, aimed to fulfil the recommendations of the American College of Sports Medicine, his blood markers of liver dysfunction and cardiometabolic risk tended to improve. Consequently, our data support the idea that in non-alcoholic steatohepatitis the exercise-based therapeutic interventions should be individualized taking into account the cardio-respiratory and muscular fitness of the patient, rather than using generic behavioural recommendations.


Dynamic coagulability after injury: Is delaying venous thromboembolism chemoprophylaxis worth the wait?
Severely injured patients often progress from early hypocoagulable to normal and eventually hypercoagulable states, developing increased risk for venous thromboembolism (VTE). Prophylactic anticoagulation can decrease this risk, but its initiation is frequently delayed for extended periods due to concerns for bleeding. To facilitate timely introduction of VTE chemoprophylaxis, we characterized the transition from hypo- to hypercoagulability and hypothesized that trauma-induced coagulopathy resolves within 24 hours after injury. Serial blood samples were collected prospectively from critically injured patients for 120 hours after arrival at an urban Level I trauma center. Extrinsic thromboelastometry maximum clot firmness was used to classify patients as hypocoagulable (HYPO, <49 mm), normocoagulable (NORM, 49-71 mm), or hypercoagulable (HYPER, >71 mm) at each time point. Changes in coagulability over hospital course, VTE occurrence, and timing of prophylaxis initiation were analyzed. 898 patients (median Injury Severity Score, 13; mortality, 12%; VTE, 8%) were enrolled. Upon arrival, 3% were HYPO (90% NORM, 7% HYPER), which increased to 9% at 6 hours before down-trending. Ninety-seven percent were NORM by 24 hours, and 53% were HYPER at 120 hours. Median maximum clot firmness began in the NORM range, up-trended gradually, and entered the HYPER range at 120 hours. Patients with traumatic brain injury (TBI) followed a similar course and were not more HYPO at any time point than those without TBI. Failure to initiate prophylaxis by 72 hours was predicted by TBI and associated with VTE development (27% vs 16%, p < 0.05). Regardless of injury pattern, trauma-induced coagulopathy largely resolves within 24 hours, after which hypercoagulability becomes increasingly more prevalent. Deferring initiation of chemoprophylaxis, which is often biased toward patients with intracranial injuries, is associated with VTE development. Prognostic study, level III; Therapeutic, level IV.


Association of Krouse Classification for Sinonasal Inverted Papilloma With Recurrence: A Systematic Review and Meta-analysis.
The risk factors for the recurrence of sinonasal inverted papilloma are still unclear. To investigate the potential association between the Krouse classification and the recurrence rates of sinonasal inverted papilloma. The EMBASE and MEDLINE databases were searched for the period January 1, 1964, through September 30, 2016, using the following search strategy: (paranasal sinuses [Medical Subject Headings (MeSH) terms] OR sinonasal [all fields]) AND (inverted papilloma [MeSH terms] OR (inverted [all fields] AND papilloma [all fields]). The inclusion criteria were (1) studies including sinonasal inverted papilloma only and no other forms of papillomas, such as oncocytic papilloma; (2) minimum follow-up of 1 year after the surgery; and (3) clear report of cases (recurrence) and controls according to the Krouse classification system or deducible from the full-text article. Literature search was performed by 2 reviewers. Of the 625 articles retrieved in the literature, 97 full-text articles were reviewed. Observational cohort studies or randomized controlled trials were included, and the following variables were extracted from full-text articles: authors of the study, publication year, follow-up data, and number of cases (recurrence) and controls (no recurrence) in each of the 4 stages of the Krouse classification system. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Odds ratios (ORs) and 95% CIs were estimated, and data of included studies were pooled using a random-effects model. The main outcome was recurrence after surgical removal of sinonasal inverted papilloma according to each stage of the Krouse classification system. Thirteen studies comprising 1787 patients were analyzed. A significant increased risk of recurrence (51%) was highlighted for Krouse stage T3 disease when compared with stage T2 (pooled OR, 1.51; 95% CI, 1.09-2.09). No significant difference in risk of recurrence was found between Krouse stages T1 and T2 disease (pooled OR, 1.14; 95% CI, 0.63-2.04) or between stages T3 and T4 (pooled OR, 1.27; 95% CI, 0.72-2.26). Inverted papillomas classified as stage T3 according to the Krouse classification system presented a 51% higher likelihood of recurrence. Head and neck surgeons must be aware of this higher likelihood of recurrence when planning and performing surgery for sinonasal inverted papilloma.


Dynamics of Microbial Communities during the Removal of Copper and Zinc in a Sulfate-Reducing Bioreactor with a Limestone Pre-Column System.
Biological treatment using sulfate-reducing bacteria (SRB) is a promising approach to remediate acid rock drainage (ARD). Our purpose was to assess the performance of a sequential system consisting of a limestone bed filter followed by a sulfate-reducing bioreactor treating synthetic ARD for 375 days and to evaluate changes in microbial composition. The treatment system was effective in increasing the pH of the ARD from 2.7 to 7.5 and removed total Cu(II) and Zn(II) concentrations by up to 99.8% and 99.9%, respectively. The presence of sulfate in ARD promoted sulfidogenesis and changed the diversity and structure of the microbial communities. Methansarcina spp. was the most abundant amplicon sequence variant (ASV); however, methane production was not detected. Biodiversity indexes decreased over time with the bioreactor operation, whereas SRB abundance remained stable. Desulfobacteraceae, Desulfocurvus, Desulfobulbaceae and Desulfovibrio became more abundant, while Desulfuromonadales, Desulfotomaculum and Desulfobacca decreased. Geobacter and Syntrophobacter were enriched with bioreactor operation time. At the beginning, ASVs with relative abundance <2% represented 65% of the microbial community and 21% at the end of the study period. Thus, the results show that the microbial community gradually lost diversity while the treatment system was highly efficient in remediating ARD.


Bronchoalveolar lavage to diagnose respiratory infections.
Respiratory samples obtained by bronchoalveolar lavage (BAL) in infectious processes provide important microbiological and cytological information to manage this type of patient. Most of the clinical and experimental BAL investigations have been done in ventilator-associated pneumonia (VAP) and in immunosuppressed conditions. The impact of quantitative BAL bacterial cultures for managing VAP is still controversial. However, there is no doubt that this method provides sensitive and specific information on bacterial, viral, fungal, and noninfectious etiologies. The conclusion is that BAL has to be used in VAP depending on the clinical situation of the patient and taking into account the local expertise and laboratory facilities. In immunosuppressed patients with pulmonary infiltrates its utility has been clearly demonstrated. In this specific population the early use of the information provided by this method is related to a better outcome. In community-acquired pneumonia there is no strong information supporting its use. This technique has some side effects and contraindications that have been weighted individually in each patient.


Very brief focal ischemia simulating transient ischemic attacks (TIAs) can injure brain and induce Hsp70 protein.
This study examined very brief focal ischemia that simulates transient ischemic attacks (TIAs) that occur in humans. Adult rats were subjected to sham operations or 5 min, 10 min, or 2 h of middle cerebral artery (MCA) ischemia using the suture (thread) model. Hsp70 protein was induced 24 h, 48 h and 72 h later in neurons throughout the entire MCA territory in many but not all animals. Following 5- and 10-minute MCA occlusions, 9 of 32 animals (28%) had microinfarcts mostly in dorsal lateral striatum. Uncommon Hsp70 stained intracellular cytoplasmic inclusions, some of which co-localized with activated caspase-3, were detected in microglia, macrophages, astrocytes and oligodendrocytes. Hsp70 stained neurons were TUNEL negative at 24 h and 48 h whereas some Hsp70 stained neurons were TUNEL positive at 72 h after reperfusion. Hsp70 positive, activated "bushy" microglia and Hsp70 negative, activated "polarized" or rod-shaped microglia were located outside of the microinfarcts. Thus, experimental focal ischemia simulating TIAs can: induce Hsp70 protein throughout the ischemic vessel territory; produce Hsp70 protein positive glial inclusions; activate Hsp70 positive and negative microglia; and cause microinfarcts in some animals.


[Experimental venous thrombosis: preretinal PO2 before and after photocoagulation].
Experimental occlusion of a retinal vein leads to retinopathy in the affected drainage area. In some cases the formation of ischemic regions, where the retina is completely destroyed, is typical for the development of this retinopathy. Laser photocoagulation restores the physiological preretinal oxygen pressure in these hypoxic regions. It is possible that the rise in O2 pressure which has been observed is caused by destruction of pigment epithelium and the photoreceptor layer, as oxygen diffuses freely from the choroid to the inner retina without being consumed by the outer layers.


Ciliary neurotrophic factor enhances neuronal survival in embryonic rat hippocampal cultures.
First described as a survival factor for chick ciliary ganglion neurons, ciliary neurotrophic factor (CNTF) has recently been shown to promote survival of chick embryo motor neurons. We now report neurotrophic effects of CNTF toward three populations of rat hippocampal neurons, the first demonstration of effects of CNTF upon rodent CNS neurons in culture. CNTF elicited an increase in the neurofilament content of hippocampal cultures prepared from embryonic day 18 (E18) rat brain. This was accompanied by increases of 2-, 28-, and 3-fold in the number of GABAergic, cholinergic, and calbindin-immunopositive cells, respectively. CNTF totally prevented the 67% loss of GABAergic neurons that occurred in control cultures over 8 d. CNTF also increased high-affinity GABA uptake and glutamic acid decarboxylase activity. Effects of CNTF were in all cases dose dependent, with maximal stimulation at approximately 100 pg/ml. When addition was delayed for 3 d, CNTF failed to elicit increases either in the number of cholinergic neurons or in GABA uptake.


Speed-power based training in the elderly and its potential for daily movement function enhancement.
Resistance exercise is widely recommended strategy to improve functional ability and quality of life of the elderly. Novel resistance exercises approaches, such as flywheel exercise have recently emerged as superior alternatives to traditional methods. Eccentric exercise methods are well documented to elicit different and often the more pronounced effect on physical ability and function of the elderly. By reviewing the relevant scientific literature, we found that only limited studies have investigated the effects of flywheel exercise in the elderly, however, the results are very promising. Thus, more research is desired to explore the effect of flywheel exercise type in elderly individuals.


[Methodology for determining workforce in health nephrologic unit in ITALY. Update of lows].
Nephrology continues to be in transition. While rates of kidney diseases and injury continue to rise, changes in the general health care system and the delivery of kidney care make it unclear how increases in need will be translated into demand for nephrologists. The changes in the delivery system also raise questions as to the future roles and career paths for nephrologists. There a major interrelated workforce issues to be watched closely : how many nephrologists are needed ? The supply of nephrologists does not reflect the distribution of patients with kidney diseases or the activity and job description related to end stage renal disease (ESRD) patients. Looking forward, more needs to be done to systematically measure need and access, and to identify clinical areas and activity of high need for nephrologists. This review examines the laws that govern the measure of work and the needs of personnel of the Italian state and in particular in health care. Therefore, once the method is accepted and established, it will be possible communicate those findings to policy makers and fellows and to involve the politicians.


Comparison of the treatment results after conventional and myeloablative chemotherapy in patients with poor prognosis Ewing's sarcoma family tumors - single center experience.
To compare the survival of patients with poor prognosis Ewing's sarcoma family tumors (EFT) after conventional and myeloablative chemotherapy treated at our hospital in a period of 25 years. Fifty-seven patients were treated between 1985 and 2010. The patients were separated into 3 groups. Group A included patients (n=20) treated with conventional chemotherapy between 1985 and 1997. Group B patients (n=22) were treated with conventional chemotherapy protocols between 1997 and 2010; and group C patients (n=15) were treated in the same period of time with conventional chemotherapy and subsequent myeloablative chemotherapy with hematopoietic stem cell transplantation (HSCT). In group A patients the 5-year overall survival (OS) was 25% and the disease-free survival (DFS) 15%; in group B patients they were 27.27% and 18.8% (p=0.31) and in group C patients 33.3% and 20% (p=0.58), respectively. More intensive chemotherapy, including myeloablative chemotherapy plus HSCT, is a curative option for patients with poor-prognosis EFT, but the survival still remains unsatisfactory.


A biomechanical evaluation of firefighters' musculoskeletal loads when carrying self-contained breathing apparatus in walking and running.
Musculoskeletal loading data are needed to design ergonomic intervention for firefighters. This study aimed to quantify the firefighters' musculoskeletal loads during self-contained breathing apparatus (SCBA) carriage and evaluate the effectiveness of shoulder strap length variation for the prevention of SCBA-related injuries. Twelve firefighters (height: 174.6 ± 2.4 cm, mass: 67 ± 3.5 kg, BMI = 22 ± 1 kg/m2) participated the walking and running protocols with no SCBA equipped and three varying-strapped SCBAs conditions. Joint range of motion and surface electromyography (sEMG) were synchronously measured. Subsequently, joint kinematics was inputted for subject-specific musculoskeletal modeling to estimate muscle forces and joint reaction forces, while the sEMG was used to validate the model. Repeated measures analysis of variance was used for the main effects (p < 0.05). Independent samples t-test was performed to determine differences between walking and running. Walking with SCBA increased the rectus femoris force and hip reaction force by 34.92% [F = 53.629; p < 0.001; η2 = 0.317] and 34.71% [F = 53.653; p < 0.001; η2 = 0.517], the growth rate was 54.2% [F = 76.487; p < 0.001; η2 = 0.418] and 51.19% [F = 69.201; p < 0.001; η2 = 0.652] during running, respectively. Running with SCBA significantly increased the knee reaction force by 63.04% [F = 83.960; p < 0.001; η2 = 0.797], while only 18.49% increase during walking. Adjusting SCBA shoulder strap length significantly altered the rectus abdominis force and L4/L5 reaction force during walking and running. Results revealed that rectus femoris activity, hip and knee exertion was sensitive to SCBA carriage. The variation of shoulder strap length has potential to influence the risk of low back pain (LBP). The findings suggest that fire services promote targeting physical training at firefighters' hip and knee regions. Test firefighters in this study were not advisable to adjust their shoulder strap at loose-fitting condition. The compatibility design of the trunk morphology and SCBA back-mounted frame was suggested for the management of LBP.


A system approach to improving maternal and child health care delivery in Kenyan communities and primary care facilities: baseline survey on maternal health.
Maternal, fetal and neonatal mortality are 10 to 100 fold higher in many low-income compared to high-income countries. Reasons for these discrepancies include limited antenatal care and delivery outside health facilities. The study aimed at conducting a baseline survey to assess the current levels of maternal health indicators in six counties in Western Kenya. This was a cross sectional study conducted targeting women residing in Uasin-Gishu, ElgeyoMarakwet, TransNzoia, Bungoma, Busia and Kakamega counties who had given birth five years prior to the interview. Socio-demographic and maternal indicators were collected using forms adopted from KDHS 2009. Interviews were conducted in the homesteads between December 2015 and June 2016. A total of 6257 women participated in the study, median age 27 years IQR 23-32. Majority of the women had post-primary level of education, were married and 40% were members of an income-generating activity. 56.8% were using modern family planning method, 49% attended WHO recommended four plus antenatal clinic visits and only 20% attended in the first trimester. Majority, 85% had their most recent delivery in a health facility. Findings suggest that women are not attending recommended four plus antenatal clinic visits and even those that attend are few are during the first trimester.


Role of compartmentalized redox-active iron in hydrogen peroxide-induced DNA damage and apoptosis.
Jurkat cells in culture were exposed to oxidative stress in the form of continuously generated hydrogen peroxide, obtained by the addition of glucose oxidase to the medium. This treatment induced a rapid, dose-dependent increase in the ICIP (intracellular calcein-chelatable iron pool). Early destabilization of lysosomal membranes and subsequent nuclear DNA strand breaks were also observed, as evaluated by the Acridine Orange relocation test and the comet assay respectively. Somewhat later, these effects were followed by a lowered mitochondrial membrane potential, with release of cytochrome c and apoptosis-inducing factor. These events were all prevented if cells were pretreated with the potent iron chelator DFO (desferrioxamine) for a period of time (2-3 h) long enough to allow the drug to reach the lysosomal compartment following fluid-phase endocytosis. The hydrophilic calcein, a cleavage product of calcein acetoxymethyl ester following the action of cytosolic esterases, obviously does not penetrate intact lysosomal membranes, thus explaining why ICIP increased dramatically following lysosomal rupture. The rapid decrease in ICIP after addition of DFO to the medium suggests draining of cytosolic iron to the medium, rather than penetration of DFO through the plasma membrane. Most importantly, these observations directly connect oxidative stress and resultant DNA damage with lysosomal rupture and the release of redox-active iron into the cytosol and, apparently, the nucleus.


Surgical complexity score and role of laparoscopy in women with advanced ovarian cancer treated with neoadjuvant chemotherapy.
To evaluate surgical complexity scores (SCS) and minimally invasive surgery (MIS) at interval debulking surgery (IDS) in advanced epithelial ovarian cancer (EOC) patients receiving neoadjuvant chemotherapy (NACT). A multi-institutional study of NACT with IDS for advanced EOC was conducted. Demographic data were abstracted and SCS assigned based on IDS findings. Disease-specific overall survival (DSS) was defined as the time from completion of adjuvant chemotherapy to death due to disease. Cox proportional hazards regression models were used for univariate and multivariate survival analyses. 282 patients were identified; 80.5% had high-grade serous histology and 54.6% were <75 (median 63.9; range 34.1-84.8). Approximately 84% were optimally cytoreduced (61% R0; 23% <1 cm). In multivariate analyses, age 75+ (p ≤ 0.001), residual disease (>1 cm; p = 0.03), and SCS ≥ 3 (p = 0.04) were significantly predictive of worse DSS when morbidity and ASA score were also in the model. When optimally debulked was defined as R0, only age 75+ (<0.001) was significantly associated with decreased DSS. In the R0 cohort, SCS did not significantly predict DSS. However, subset analysis defining optimal ≤1 cm, revealed higher SCS was associated with a 1.6-fold increased risk of death (p = 0.02). Fifty-one patients underwent laparoscopic IDS. Twenty-four (47%) were converted to laparotomy to achieve optimal debulking in 21 patients (87.5%); while 25 had laparoscopic optimal cytoreduction (19/25 [76%] R0). In women with advanced EOC treated with NACT, older age, SCS ≥ 3, and residual disease >1 cm at IDS were predictors of worse survival. MIS appears safe and feasible with acceptable optimal cytoreduction rates.


Vascular patterning of the quail coronary system during development.
Recent studies have provided insights into specific events that contribute to vasculogenesis and angiogenesis in the developing coronary vasculature. This study focused on the developmental progression of coronary vascularization beginning with tube formation and ending with the establishment of a coronary arterial tree. We used electron microscopy, histology of serial sections, and immunohistochemistry in order to provide a comprehensive view of coronary vessel formation during the embryonic and fetal periods of the quail heart, a species that has been used in a number of studies addressing myocardial vascularization. Our data reveal features of progenitor cells and blood islands, tubular formation, and the anatomical relationship of a transformed periarterial tubular network and sympathetic ganglia to the emergence and branching of the right and left coronary arteries. We have traced the pattern of coronary artery branching and documented its innervation. Finally, our data include the relationship of fibronectin, laminin, and apoptosis to coronary artery growth. Our findings bring together morphological events that occur over the embryonic and fetal periods and provide a baseline for studies into the mechanisms that regulate the various events that occur during these time periods.


Control of tuberculosis during aerosol therapy administration.
In summary, despite the major benefits conferred by aerosol therapy, the risk of transmission of M tuberculosis remains a concern. The most effective approach to preventing nosocomial transmission of respiratory infections such as tuberculosis is to prevent disease in patients at risk, particularly those receiving aerosol therapy. Tuberculin skin tests should be applied to all HIV-infected persons and chemoprophylaxis administered to those with greater than or equal to 5mm reaction. Early detection and treatment of tuberculosis are essential to prevent transmission both inside and outside of health-care settings. Cough-reduction measures should be taken when giving pentamidine aerosol, and patients who do cough should cover their mouths. Proper ventilation of treatment areas with negative air pressure and at least 10 air changes per hour, and more if feasible, is essential. HEPA filters should be installed to cleanse exhaust air from treatment rooms, and air should not be recirculated. The use of UV light to disinfect air is recommended only for special situations. Finally, personal protective devices should be worn by health-care workers who are exposed to patients receiving aerosol therapy when other measures do not offer adequate protection.


The immobilization of enzymes on nylon structures and their use in automated analysis.
1. Glucose oxidase (EC 188.8.131.52) and urease (EC 220.127.116.11) were covalently attached through glutaraldehyde to low-molecular-weight nylon powder. 2. Immobilized derivatives of glucose oxidase and urease were prepared by cross-linking the respective enzymes within the matrix of a nylon membrane. 3. An improved process is described for the immobilization of glucose oxidase and urease on the inside surface of partially hydrolysed nylon tube. 4. Automated analytical procedures are described for the determination of glucose with each of the three immobilized glucose oxidase derivatives and for the determination of urea with each of the three immobilized urease derivatives. 5. The efficiencies of the three immobilized enzyme structures as reagents for the automated determination of their substrates were compared.


Networking Chemicals Flows: Efficiency-Value-Environment Functionalized Symbiosis Algorithms and Application.
Maximizing the network of chemical symbiosis can enhance economic benefits and reduce life cycle environmental impacts, which are pivotal for achieving sustainability in the chemical industry. This study designs two innovative symbiosis algorithms, the Longest Path Algorithm and the Maximum Symbiosis Algorithm, specifically for chemical industrial clusters (CICs). The algorithms are applied to a prototypical CIC encompassing 569 distinct raw materials and yielding 435 unique products alongside 55 byproducts. First, the study provides an exhaustive overview of the assorted chemicals and their intrinsic traits, flow patterns, and conventional relationships within the cluster. On that basis, the former algorithm reveals that the longest path constitutes 5 enterprises, embodying the entire disperse dyestuff industry chain; the latter algorithm identifies 218 pairs of symbiotic relationships, leading to an additional 0.91 million tonnes of symbiotic chemicals. These interrelations also yield substantial cost savings of 1.25 billion CNY (0.17 billion US dollar) and enhance life cycle benefits by 0.62 to 11.87 times compared to the present status. The efficacious application of these algorithms to the cluster reaffirms their capacity to meet the designated objectives. This study introduces a fresh interdisciplinary standpoint to optimize chemical manufacturing processes and contributes essential theoretical underpinning for implementing pollution and carbon reduction strategies in similar CICs.


Cultured Human Fibroblast Biostimulation Using a 940 nm Diode Laser.
Fibroblasts are the main cells involved in regeneration during wound healing. The objective was to determine the effect of 940 nm diode laser on cultured human fibroblasts using different irradiation regimens. The CCD-1064Sk human epithelial fibroblast cell line was treated with a 940 nm diode laser at different energy doses (power: 0.2-1 W and energy density: 1-7 J/cm²) using different transmission modes (continuous or pulsed). The effect on cell growth at 24 and 72 h post-treatment was examined by measuring the proliferative capacity, the impact on the cell cycle, and the effect on cell differentiation. fibroblast proliferative capacity was increased at 24 and 72 h post-treatment as a function of the energy dose. The greatest increase was observed with a power of 0.2 or 0.5 W and energy density between 1 and 4 J/cm²; no difference was observed between continuous and pulsed modes. There were no significant differences in cell cycle between treated groups and controls. α-actin expression was increased by treatment, indicating enhanced cell differentiation. The 940 nm diode laser has biostimulating effects on fibroblasts, stimulating proliferative capacity and cell differentiation without altering the cell cycle. Further researches are necessary to explore its potential clinical usefulness in wound healing.


An Efficient, Affordable Optically Stimulated Luminescent (OSL) Annealer.
Optically stimulated luminescent (OSL) dosimeters are devices used for measuring doses of ionizing radiation. Signal is stored within an OSL material so that when stimulated with light, light of a specific wavelength is emitted in proportion to the integrated ionizing radiation dose. Each interrogation of the material results in the loss of a small fraction of signal, thus allowing multiple interrogations leading to more accurate measurements of dose. In order to reuse a dosimeter, the residual signals from prior doses must be taken into account and subtracted from current readings, adding uncertainty to any future measurements. To reduce these errors when they become large, it is desirable to completely clear the stored signal or anneal the dosimeter. Traditionally, heating the material has accomplished this. In a commercially available dosimeter badge system, the OSL material Al2O3:C is incorporated into a plastic slide that would melt at the necessary high temperatures, which can reach 900 °C, required for annealing. Fortunately, due to the material's high sensitivity to light, OSLs can be optically annealed instead. In order to do this, an affordable OSL dosimeter annealer was designed with inexpensive, exchangeable blue, green, and white high intensity light-emitting diodes (LEDs). Several dosimeters were repeatedly annealed for recorded intervals and then read out. A single dosimeter was partially annealed through repeated interrogations with the LED array from a commercial reader. The signal loss due to the exposure to each light was analyzed to determine the practicality and efficiency of each color. The rate and extent of signal loss was dependent not only on the spectrum of annealing light but on the initial signal levels as well. These findings suggest that blue LEDs are the most promising for effective and rapid clearing of the OSL material Al2O3:C.


Protein X of Borna disease virus inhibits apoptosis and promotes viral persistence in the central nervous systems of newborn-infected rats.
Borna disease virus (BDV) is a neurotropic member of the order Mononegavirales with noncytolytic replication and obligatory persistence in cultured cells and animals. Here we show that the accessory protein X of BDV represents the first mitochondrion-localized protein of an RNA virus that inhibits rather than promotes apoptosis induction. Rat C6 astroglioma cells persistently infected with wild-type BDV were significantly more resistant to death receptor-dependent and -independent apoptotic stimuli than uninfected cells or cells infected with a BDV mutant expressing reduced amounts of X. Confocal microscopy demonstrated that X colocalizes with mitochondria and expression of X from plasmid DNA rendered human 293T and mouse L929 cells resistant to apoptosis induction. A recombinant virus encoding a mutant X protein unable to associate with mitochondria (BDV-X(A6A7)) failed to block apoptosis in C6 cells. Furthermore, Lewis rats neonatally infected with BDV-X(A6A7) developed severe neurological symptoms and died around day 30 postinfection, whereas all animals infected with wild-type BDV remained healthy and became persistently infected. TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining revealed a significant increase in the number of apoptotic cells in the brain of BDV-X(A6A7)-infected animals, whereas the numbers of CD3(+) T lymphocytes were comparable to those detected in animals infected with wild-type BDV. Our data thus indicate that inhibition of apoptosis by X promotes noncytolytic viral persistence and is required for the survival of cells in the central nervous system of BDV-infected animals.


Safety and esthetic outcomes of therapeutic mammoplasty using medial pedicle for early breast cancer.
Although therapeutic mammoplasty (TM) was introduced for treatment of localized ductal carcinoma in situ and invasive breast carcinoma (stages I and II) in females with large breast size, the suitability of medial pedicle TM for treatment of breast tumors at different locations has not been established. The objective of this study was to assess the safety and esthetic outcome of medial pedicle TM for breast tumors at different locations. The study was conducted from February 2012 to July 2014. Consecutive patients with early breast carcinoma with medium- and large-sized breasts, with or without ptosis, who were offered medial pedicle TM were included in the study. Patients who were not candidates for breast-conserving surgery or those with tumors located along the medial pedicle were excluded. All patients received immediate postoperative adjuvant chemoradiotherapy. Thirty patients with a mean age of 48.5 years received medial pedicle TM in the breast harboring the tumor or, additionally, the other breast (N=14). The tumors were in the upper (60.0%), lower (26.7%), and lateral (13.3%) quadrants. Minor complications occurred in five cases (5/30, 16.7%) in the ipsilateral and in two (2/14, 14.3%) contralateral breasts. No wound dehiscence or areolar necrosis was recorded. A total of 22 (73.3%) patients were scored as excellent cosmesis. After a median follow-up of 20 months, no locoregional recurrence or distant metastases were observed. TM using a medial pedicle is a safe and appealing technique among women with tumors at different locations.


Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances.
Rasmussen's encephalitis is a rare chronic neurological disorder, characterised by unilateral inflammation of the cerebral cortex, drug-resistant epilepsy, and progressive neurological and cognitive deterioration. Neuropathological and immunological studies support the notion that Rasmussen's encephalitis is probably driven by a T-cell response to one or more antigenic epitopes, with potential additional contribution by autoantibodies. Careful analysis of the association between histopathology and clinical presentation suggests that initial damage to the brain is mediated by T cells and microglia, suggesting a window for treatment if Rasmussen's encephalitis can be diagnosed early. Advances in neuroimaging suggest that progression of the inflammatory process seen with MRI might be a good biomarker in Rasmussen's encephalitis. For many patients, families, and doctors, choosing the right time to move from medical management to surgery is a real therapeutic dilemma. Cerebral hemispherectomy remains the only cure for seizures, but there are inevitable functional compromises. Decisions of whether or when surgery should be undertaken are challenging in the absence of a dense neurological deficit, and vary by institutional experience. Further, the optimum time for surgery, to give the best language and cognitive outcome, is not yet well understood. Immunomodulatory treatments seem to slow rather than halt disease progression in Rasmussen's encephalitis, without changing the eventual outcome.


Blood-glucose self-monitoring in insulin treated type 2 diabetes mellitus a cross-sectional study with an intervention group.
Up to the present there is controversy about blood-glucose self-monitoring in type 2 diabetes. In 842 insulin-treated type 2 diabetic patients (age 60.1 +/- 10.9, diabetes duration since diagnosis 12.6 +/- 7.6 years, relative HbA1c 1.83 +/- 0.39% [relative HbA1c = HbA1c/mean normal, HPLC, Diamat]) a cross-sectional study was conducted to assess blood-glucose self-monitoring and interactions with quality of diabetes care. There was a negative correlation (r = -0.17, p < 0.001) between the frequency of blood-glucose self-tests/week and HbA1c. Performing multivariate analysis the most important parameters associated with HbA1c (R-square = 0.10) were: The frequency of blood-glucose self-tests/week (c = -0.005, p < 0.001), the insulin-dosage/kg body weight (c = 0.001, p = 0.0032) and the participation in a 5-day structured treatment and teaching programme for patients with conventional insulin therapy (5-TTP, c = 0.085, p < 0.0001). Other factors investigated in the model (age, diabetes duration, number of insulin injections/day, sex) showed no associations. Performing a sub-group analysis in patients older than 60 years (n = 396) parameters associated with HbA1c (R-square = 0.16) were the participation in a 5-TTP (c = 0.09, p = 0.002) and the frequency of blood-glucose self-tests/week (c = -0.006, p = 0.0018) too. In an further subgroup analysis patients (n = 249) were investigated who have not participated in a 5-TTP. In this cohort there were no correlations and no associations between the frequency of blood-glucose self-monitoring and HbA1c. Then, an intervention was started: 33 out of the 249 patients participated in a 5-TTP. At the time of re-examination 1 year after participating in the 5-TTP, the relative HbA1c decreased from 1.84 +/- 0.38% to 1.61 +/- 0.30% (p = 0.007) and there was a strong association between the frequency of blood-glucose self-tests/week and HbA1c (c = -0.016, p = 0.0032, R-square = 0.25). Daily blood-glucose self-monitoring was statistically associated with better quality of metabolic control. Participation in a 5-TTP and regularly blood-glucose self-monitoring is mandatory for all insulin-treated patients with type 2 diabetes mellitus.


Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus.
To evaluate traditional and non-traditional risk factors for subclinical atherosclerosis in systemic lupus erythematosus (SLE). A prospective cohort of 78 patients with SLE without overt atherosclerotic disease was studied. SLE clinical and laboratory parameters, disease activity and damage, treatment and traditional risk factors for atherosclerosis were evaluated. At baseline (T1) and after five years' follow up (T2), the serum levels of anti-oxidised palmitoyl arachidonoyl phosphocholine (oxPAPC), anti-heat shock protein 65, and anti-beta(2)-glycoprotein I antibodies and C reactive protein were tested. At T2, intima-media thickness (IMT) was measured using duplex carotid sonography. Thickened intima, plaque, mean IMT (m-IMT), and maximum IMT (M-IMT) were assessed. A thickened intima was seen in 22/78 (28%) patients and plaque in 13/78 (17%). M-IMT and m-IMT were (mean (SD)) 0.77 (0.34) mm and 0.55 (0.15) mm, respectively. Patients with carotid abnormalities were significantly older, had higher blood pressure and total serum cholesterol levels, and had taken a higher prednisone cumulative dosage than those without any lesions. The carotid abnormalities were associated with renal disease and ECLAM >2 at T1, and with azathioprine treatment. In multivariate analysis, age and cumulative prednisone dose were associated with carotid abnormalities; age, hypertension, and anti-oxPAPC at T2 were correlated with higher M-IMT and m-IMT. In patients with SLE some non-traditional risk factors for atherosclerosis were identified, the most important of which was the cumulative prednisone dose. The role of some traditional risk factors, such as age and hypertension, was also confirmed. The predictive value of the new immunological and inflammatory markers of atherosclerosis seems to be masked by some disease related features.