A proautophagic antiviral role for the cellular prion protein identified by infection with a herpes simplex virus 1 ICP34.5 mutant.
The cellular prion protein (PrP) often plays a cytoprotective role by regulating autophagy in response to cell stress. The stress of infection with intracellular pathogens can stimulate autophagy, and autophagic degradation of pathogens can reduce their replication and thus help protect the infected cells. PrP also restricts replication of several viruses, but whether this activity is related to an effect on autophagy is not known. Herpes simplex virus 1 (HSV-1) effectively counteracts autophagy through binding of its ICP34.5 protein to the cellular proautophagy protein beclin-1. Autophagy can reduce replication of an HSV-1 mutant, Δ68H, which is incapable of binding beclin-1. We found that deletion of PrP in mice complements the attenuation of Δ68H, restoring its capacity to replicate in the central nervous system (CNS) to wild-type virus levels after intracranial or corneal infection. Cultured primary astrocytes but not neurons derived from PrP(-/-) mice also complemented the attenuation of Δ68H, enabling Δ68H to replicate at levels equivalent to wild-type virus. Ultrastructural analysis showed that normal astrocytes exhibited an increase in the number of autophagosomes after infection with Δ68H compared with wild-type virus, but PrP(-/-) astrocytes failed to induce autophagy in response to Δ68H infection. Redistribution of EGFP-LC3 into punctae occurred more frequently in normal astrocytes infected with Δ68H than with wild-type virus, but not in PrP(-/-) astrocytes, corroborating the ultrastructural analysis results. Our results demonstrate that PrP is critical for inducing autophagy in astrocytes in response to HSV-1 infection and suggest that PrP positively regulates autophagy in the mouse CNS.


[Heart failure: expressions of personal knowledge about the disease].
This qualitative study characterized individuals with heart failure (HF) according to their sociodemographic, health, and treatment profiles and analyzed their knowledge on the disease and its treatment. A total of 42 volunteers with HF were interviewed at a cardiology hospital in São Paulo using a semi-structured questionnaire; the data were subjected to content analysis. The sample comprised mostly males and individuals older than 45 years old; the sample was classified as functional class II with associated comorbidities and was subjected to pharmacological treatment. The type of knowledge exhibited by the sample was illustrative, diagnostic, and explanatory, and many different meanings were attributed to the disease. Most volunteers did not know the names, doses, or frequencies of use of their medications. Non-pharmacological treatment was identified as related to the information provided by the healthcare professionals about nutrition and salt and water intake. The results pave the road for systematic educational interventions that can improve the coping with and management of this disease.


Pilomatrix carcinoma of the lacrimal caruncle: a case report.
A 45-year-old man presented with a 3-month history of a mass located in the caruncle of his right eye. An incisional biopsy had been performed one month prior by another specialist, and the histopathology report showed basal cell carcinoma. The mass was completely excised with a 2 mm safety margin, and the large conjunctival defect was reconstructed with one sheet of amniotic membrane allograft. A histological diagnosis of pilomatrix carcinoma was established. To prevent recurrence after surgery, we added bevacizumab (25 mg/mL, 1.25 mg/mL per drop) eye drops four times per day for three months. At the one-year follow-up, the patient showed no evidence of local recurrence or distant metastasis after initial excision and remains under close follow-up. Pilomatrix carcinoma should be considered in the differential diagnosis of a caruncular mass.


Measuring angiogenic cytokines, circulating endothelial cells, and endothelial progenitor cells in peripheral blood and cord blood: VEGF and CXCL12 correlate with the number of circulating endothelial progenitor cells in peripheral blood.
Circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) are thought to play an important role in the vascularization of damaged tissues and cancers. These cells are also required for tissue-engineered blood vessels and to help skin substitutes revascularize more efficiently. A standard approach to the phenotyping and enumeration of CEC and EPC is key to the development of new therapies, and the identification of biomarkers within the blood that regulate their levels may be important for the treatment of cancer. We have devised an improved multiparameter flow cytometric assay for CEC and circulating EPC enumeration. This assay uses antibodies recognizing CD133 and CD34 to identify EPC and CEC, respectively, and incorporates specific markers CD144 and vascular endothelial growth factor receptor 2 (VEGFR-2) for both CEC and EPC cells. In peripheral blood (PB), mean CEC numbers were 55 +/- 95 mL(-1) and mean EPC numbers were 44 +/- 58 mL(-1) (n = 60). We also found a significant correlation of both plasma VEGF (r = 0.90, p < 0.001) and CXCL12 (r = 0.84, p < 0.001) with EPCs, but not CECs. The cytokines also correlated with each other (r = 0.85, p < 0.001). In umbilical cord blood (UCB) we found on average 13 times more CEC (719 +/- 338 mL(-1)) and 7 times more EPC (299 +/- 245 mL(-1)) than in PB. However, serum VEGF and CXCL12 levels in UCB did not correlate with either EPC or CEC numbers. These results suggest a major role for VEGF and CXCL12 in the control of marrow-derived EPCs in adult PB and provide normal data for comparison with patient populations.


Experimental investigation of the initial regime in fingering electrodeposition: dispersion relation and velocity measurements.
Recently a fingering morphology, resembling the hydrodynamic Saffman-Taylor instability, was identified in the quasi-two-dimensional electrodeposition of copper. We present here measurements of the dispersion relation of the growing front. The instability is accompanied by gravity-driven convection rolls at the electrodes, which are examined using particle image velocimetry. While at the anode the theory presented by Chazalviel et al. [J. Electroanal. Chem. 407, 61 (1996)] describes the convection roll, the flow field at the cathode is more complicated because of the growing deposit. In particular, the analysis of the orientation of the velocity vectors reveals some lag of the development of the convection roll compared to the finger envelope.


Stereoselective L-[3H]quinuclidinyl benzilate-binding sites in nervous tissue of Aplysia californica: evidence for muscarinic receptors.
The muscarinic antagonist L-[3H]quinuclidinyl benzilate (L-[3H]QNB) binds with a high affinity (Kd = 0.77 nM) to a single population of specific sites (Bmax = 47 fmol/mg of protein) in nervous tissue of the gastropod mollusc, Aplysia. The specific L-[3H]QNB binding is displaced stereoselectively by the enantiomers of benzetimide, dexetimide, and levetimide. The pharmacologically active enantiomer, dexetimide, is more potent than levetimide as an inhibitor of L-[3H]QNB binding. Moreover, the muscarinic cholinergic ligands, scopolamine, atropine, oxotremorine, and pilocarpine are effective inhibitors of the specific L-[3H]QNB binding, whereas nicotinic receptor antagonists, decamethonium and d-tubocurarine, are considerably less effective. These pharmacological characteristics of the L-[3H]QNB-binding site provide evidence for classical muscarinic receptors in Aplysia nervous tissue. The physiological relevance of the dexetimide-displaceable L-[3H]QNB-binding site was supported by the demonstration of the sensitivity of the specific binding to thermal denaturation. Specific binding of L-[3H]QNB was also detected in nervous tissue of another marine gastropod, Pleurobranchaea californica. The characteristics of the Aplysia L-[3H]QNB-binding site are in accordance with studies of numerous vertebrate and invertebrate tissues indicating that the muscarinic cholinergic receptor site has been highly conserved through evolution.


Cholecystokinin-immunoreactive cells form symmetrical synaptic contacts with pyramidal and nonpyramidal neurons in the hippocampus.
The ultrastructural features and synaptic relationships of cholecystokinin (CCK)-immunoreactive cells of rat and cat hippocampus were studied using the unlabeled antibody immunoperoxidase technique and correlated light and electron microscopy. CCK-positive perikarya of variable shape and size were distributed in all layers and were particularly concentrated in stratum pyramidale and radiatum: the CCK-immunoreactive neurons were nonpyramidal in shape and the three most common types had the morphological features of tufted, bipolar, and multipolar cells. Electron microscopic examination revealed that all the CCK-positive boutons established symmetrical (Gray's type II) synaptic contacts with perikarya and dendrites of pyramidal and nonpyramidal neurons. The origin of some of the boutons was established by tracing fine collaterals that arose from the main axon of two CCK-immunostained cells and terminated in the stratum pyramidale; these collaterals were then examined in the electron microscope. The axon of one such neuron exhibited a course parallel to the pyramidal layer and formed pericellular nets of synaptic boutons upon the perikarya of pyramidal neurons. This pattern of axonal arborization is very similar to that of some of the basket cells, previously suggested to be the anatomical correlate for pyramidal cell inhibition. Typical dendrites of pyramidal cells also received symmetrical synaptic contacts from CCK-immunoreactive boutons, and some of these boutons could be shown to originate from a local neuron in stratum radiatum. Many CCK-immunoreactive cells received CCK-labeled boutons upon their soma and dendritic shafts. Synaptic relationship, established by multiple "en passant" boutons, was observed between CCK-positive interneurons of the stratum lacunosum-moleculare and radiatum. The soma and dendrites of the CCK-immunostained neurons also received symmetrical and asymmetrical synapses from nonimmunoreactive boutons. These results indicate that the CCK-immunoreactive neurons participate in complex local synaptic interactions in the hippocampus.


A Bufadienolide-Enriched Fraction of Bryophyllum pinnatum Inhibits Human Myometrial Contractility In Vitro.
Bryophyllum pinnatum has been used since the 1970s to prevent premature labour, first in anthroposophic hospitals and, more recently, also in the main Swiss perinatal centres. However, it is not known which compounds in B. pinnatum leaves contribute to the tocolytic effect. Here we studied the effects of a flavonoid-enriched fraction, the corresponding flavonoid aglycon mixture, a bufadienolide-enriched fraction, and B. pinnatum leaf press juice on human myometrial contractility in vitro. The strength (area under the curve and amplitude) and frequency of contractions were recorded using strips of human myometrium mounted in an organ bath system. Cell viability assays were performed with the human myometrium hTERT-C3 and PHM1 - 41 cell lines. Repeated addition of the flavonoid-enriched fraction, flavonoid aglycon mixture, bufadienolide-enriched fraction, or B. pinnatum leaf press juice led to a progressive decrease of contraction strength, without jeopardising the vitality of myometrium strips. The bufadienolide-enriched fraction was the most active, since 1 µg/mL of the bufadienolide-enriched fraction lowered the area under the curve to 40.1 ± 11.8% of the initial value, whereas 150 µg/mL of the flavonoid-enriched fraction, 6.2 µg/mL of the flavonoid aglycon mixture, and 10 µg/mL of the B. pinnatum leaf press juice were required to achieve comparable inhibition. A progressive increase of contraction frequency was observed, except in the case of the flavonoid aglycon mixture, which did not affect frequency. None of the test substances decreased myometrial cell viability, even at concentrations of 500 µg/mL of the flavonoid-enriched fraction, 40 µg/mL of the flavonoid aglycon mixture, 3.8 µg/mL of the bufadienolide-enriched fraction, and 75 µg/mL of the B. pinnatum leaf press juice, i.e., higher than those used in the myometrium experiments. Given the concentrations of flavonoids in the flavonoid-enriched fraction and B. pinnatum leaf press juice, and of bufadienolides in the bufadienolide-enriched fraction and B. pinnatum leaf press juice, it appears that bufadienolides may be mainly responsible for the relaxant effect.


Ultra-diffuse hydrothermal venting supports Fe-oxidizing bacteria and massive umber deposition at 5000 m off Hawaii.
A novel hydrothermal field has been discovered at the base of Lōihi Seamount, Hawaii, at 5000 mbsl. Geochemical analyses demonstrate that 'FeMO Deep', while only 0.2 °C above ambient seawater temperature, derives from a distal, ultra-diffuse hydrothermal source. FeMO Deep is expressed as regional seafloor seepage of gelatinous iron- and silica-rich deposits, pooling between and over basalt pillows, in places over a meter thick. The system is capped by mm to cm thick hydrothermally derived iron-oxyhydroxide- and manganese-oxide-layered crusts. We use molecular analyses (16S rDNA-based) of extant communities combined with fluorescent in situ hybridizations to demonstrate that FeMO Deep deposits contain living iron-oxidizing Zetaproteobacteria related to the recently isolated strain Mariprofundus ferroxydans. Bioenergetic calculations, based on in-situ electrochemical measurements and cell counts, indicate that reactions between iron and oxygen are important in supporting chemosynthesis in the mats, which we infer forms a trophic base of the mat ecosystem. We suggest that the biogenic FeMO Deep hydrothermal deposit represents a modern analog for one class of geological iron deposits known as 'umbers' (for example, Troodos ophilolites, Cyprus) because of striking similarities in size, setting and internal structures.


Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials.
To analyse the benefits and harms of statins in patients with chronic kidney disease (pre-dialysis, dialysis, and transplant populations). Meta-analysis. Cochrane Central Register of Controlled Trials, Medline, Embase, and Renal Health Library (July 2006). Randomised and quasi-randomised controlled trials of statins compared with placebo or other statins in chronic kidney disease. Two reviewers independently assessed trials for inclusion, extracted data, and assessed trial quality. Differences were resolved by consensus. Treatment effects were summarised as relative risks or weighted mean differences with 95% confidence intervals by using a random effects model. Fifty trials (30 144 patients) were included. Compared with placebo, statins significantly reduced total cholesterol (42 studies, 6390 patients; weighted mean difference -42.28 mg/dl (1.10 mmol/l), 95% confidence interval -47.25 to -37.32), low density lipoprotein cholesterol (39 studies, 6216 patients; -43.12 mg/dl (1.12 mmol/l), -47.85 to -38.40), and proteinuria (g/24 hours) (6 trials, 311 patients; -0.73 g/24 hour, -0.95 to -0.52) but did not improve glomerular filtration rate (11 studies, 548 patients; 1.48 ml/min (0.02 ml/s), -2.32 to 5.28). Fatal cardiovascular events (43 studies, 23 266 patients; relative risk 0.81, 0.73 to 0.90) and non-fatal cardiovascular events (8 studies, 22 863 patients; 0.78, 0.73 to 0.84) were reduced with statins, but statins had no significant effect on all cause mortality (44 studies, 23 665 patients; 0.92, 0.82 to 1.03). Meta-regression analysis showed that treatment effects did not vary significantly with stage of chronic kidney disease. The side effect profile of statins was similar to that of placebo. Most of the available studies were small and of suboptimal quality; mortality data were provided by a few large trials only. Statins significantly reduce lipid concentrations and cardiovascular end points in patients with chronic kidney disease, irrespective of stage of disease, but no benefit on all cause mortality or the role of statins in primary prevention has been established. Reno-protective effects of statins are uncertain because of relatively sparse data and possible outcomes reporting bias.


Clinical trial safety and mortality analyses in patients receiving etanercept across approved indications.
Assessment of associations between etanercept treatment and rare adverse events has been limited by the size of clinical trial populations. The authors examined the collective safety of etanercept in clinical trials across approved indications. Forty-nine U.S. and non-U.S. trials of etanercept, involving up to 13,977 patients for approved indications, with final trial reports as of May 2006, were selected from the Amgen Inc. clinical trials database. Exposure-adjusted rates of serious infections, opportunistic infections, malignancies, and deaths were reported by trial, indication, and dosage. Rates of serious infections were generally similar between etanercept and controls. Overall rates of opportunistic infections and tuberculosis were low. The standardized incidence ratio (SIR) (95% CI) for malignancy was 1.00 (0.83-1.19) for all etanercept patients across all indications. The SIR for lymphoma for patients with rheumatoid arthritis was 3.45 (1.83-5.89); all other indications reported SIRs similar to those observed in the general population. The SIRs for cutaneous squamous cell carcinoma in patients with psoriasis relative to the general population with high or low sun exposure were 2.09 (1.27-3.22) and 4.96 (3.03-7.66), respectively. SIRs were less than 1.0 for all other indications regardless of sun exposure. Rates of melanoma and basal cell carcinoma were not significantly different from those in the general population. There was no increase in mortality associated with etanercept use relative to control populations. These data support the overall tolerability of etanercept across approved indications.


Transition metal-free stereospecific access to (E)-(1-fluoro-2-arylvinyl)phosphine borane complexes.
This work describes the first transition metal-free stereospecific synthesis of (E)-(1-fluoro-2-arylvinyl)phosphine boranes through the addition of diarylphosphine-boranes to gem-bromofluoroalkenes in the presence of a base at room temperature. The reaction proceeds well under very mild conditions and tolerates a variety of functionalities. Scope and limitations of the reaction are discussed. Mechanistic investigations have been undertaken and revealed that the reaction takes place through an SRN1 mechanism. The formation of the fluorinated vinyl radical has been evidenced by electron paramagnetic resonance (EPR) experiment.


Sural and radial sensory responses in healthy adults: diagnostic implications for polyneuropathy.
We prospectively performed sural and radial sensory nerve conduction studies in 92 healthy subjects, aged between 21 and 88 years, both to determine the lower limits of normal (LLN) and to assess the effects of age and body mass index (BMI) on the sural and radial sensory nerve action potential (SNAP) amplitudes and on the sural/radial amplitude ratio (SRAR). Using the nonparametric bootstrap method to calculate 95% confidence intervals, we found that the 5% LLN values for sural and radial SNAPs were 14 microV and 25.5 microV in subjects aged < or =39 years, 7 microV and 17.4 microV in subjects aged 40-59 years, and 3 microV and 12 microV in subjects aged > or =60 years. The 5% LLN for SRAR for all patients was 0.21. Sural and radial SNAP amplitudes but not SRAR were strongly and inversely correlated with age and BMI. These age-adjusted normal values and revised SRAR will aid in the electrodiagnosis of polyneuropathy.


Long-term outcomes of successful chronic total occlusion percutaneous coronary interventions using the antegrade and retrograde approach.
To compare long-term clinical outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) using the retrograde and antegrade approach. There is limited long-term clinical outcomes data on the retrograde approach to CTO PCI. We performed a retrospective analysis of the long-term clinical outcomes of 193 consecutive patients who underwent successful CTO PCI at our institution between March 2008 and December 2011. Mean age was 63.6 ± 8.3 years. The target vessel was right coronary artery in 52.6%, left anterior descending artery in 24.5% and circumflex in 21.4% of cases. The retrograde approach was used in 41 patients (21.2%). The mean stent length was longer in the retrograde group (83 ± 32 vs. 64 ± 32 mm, P = 0.001). Two major procedural complications occurred, both in the retrograde group (P = 0.012). During a median follow-up of 2.0 years compared to the antegrade CTO PCI group, patients who underwent retrograde CTO PCI were more likely to undergo target lesion revascularization (TLR) (45.6% vs. 25.7%, P = 0.006). No significant difference was observed in the incidence of all-cause mortality, myocardial infarction, non-target vessel revascularization, or coronary artery bypass graft surgery between the 2 groups. On multivariate analysis, stent length was the only independent predictor of TLR during follow-up. Retrograde CTO PCI was associated with higher incidence of TLR, but similar incidence of death and myocardial infarction compared to antegrade CTO PCI. These findings likely reflect the higher complexity of CTO lesions treated with the retrograde approach.


'You are Okay': a support and educational program for children with mild intellectual disability and their parents with a mental illness: study protocol of a quasi-experimental design.
Children of parents with a mental illness or substance use disorder (COPMI) have an increased risk of developing social-emotional problems themselves. Fear of stigmatisation or unawareness of problems prevents children and parents from understanding each other. Little is known about COPMI with mild intellectual disabilities (ID), except that they have a high risk of developing social-emotional problems and require additional support. In this study, we introduce a program for this group, the effectiveness of which we will study using a quasi-experimental design based on matching. The program 'You are okay' consists of a support group for children and an online educational program for parents. The goal of the program is to increase children and parents' perceived competence with an aim to prevent social-emotional problems in children. Children between ten and twenty years old with mild ID (IQ between 50 and 85) and at least one of their parents with a mental illness will be included in the study. The children will receive part time treatment or residential care from an institute for children with mild ID and behavioural problems. Participants will be assigned to the intervention or the control group. The study has a quasi-experimental design. The children in the intervention group will join a support group, and their parents will be offered an online educational program. Children in the control group will receive care as usual, and their parents will have no extra offer. Assessments will be conducted at baseline, post-test, and follow up (6 months). Children, parents, and social workers will fill out the questionnaires. The 'You are okay' program is expected to increase children and parents' perceived competence, which can prevent (further) social-emotional problem development. Because the mental illness of parents can be related to the behavioural problems of their children, it is important that children and parents understand each other. When talking about the mental illness of parents becomes standard in children's treatment, stigmatisation and the fear for stigmatisation can decrease. Dutch Trial Register NTR4845 . Registered 9 October 2014.


N-terminal targeting of guanine nucleotide exchange factors (GEF) for ADP ribosylation factors (ARF) to the Golgi.
B2-1 (cytohesin-1) is a member of a group of proteins (including ARNO and ARNO3) that are all of similar size and domain composition. The three proteins contain an N-terminal coiled-coil domain, followed by a Sec7 and a pleckstrin homology (PH) domain. While it is well established that the Sec7 domain functions as a guanine nucleotide exchange factor (GEF) for ADP-ribosylation factors (ARFs) and the PH domain anchors the proteins to membrane phosphoinositols, the function of the N-terminal domain is unknown. Here we show that the N terminus of B2-1 (residues 1-54) is necessary and sufficient to target the protein to the Golgi. The Sec7+PH domains of B2-1 (residues 55-398) are not sufficient for Golgi localization. Further deletion analysis and point mutagenesis indicate that the coiled-coil domain within the N terminus is responsible for Golgi targeting. Furthermore, ARNO and ARNO3 N termini also have the same capability of targeting to the Golgi. We conclude that the N-terminal, (&agr;)-helical, coiled-coil domain is used to target this family of proteins to the Golgi complex.


Murine eosinophil granulocyte proliferation kinetics in acute and chronic eosinophilia.
Eosinophil proliferation kinetics have been determined by examining fraction-labeled mitoses (FLM) curves in femoral marrow of mice stimulated for eosinophil production. Mice with marrow eosinophilopoiesis increased as a result of infection with the parasite Schistosoma mansoni exhibited eosinophil cycle durations of 22 h. This time is not different from normal rates of murine eosinophil cell cycles. Acutely stimulated mice, however, with a rapid eosinophilia initiated by rechallenge with a soluble schistosome egg antigen preparation, had marrow eosinophil proliferative cycles of about 10 h. The long duration of eosinophil cell cycles in mice with an extensive commitment to the production of large numbers of eosinophil granulocytes suggests that several mechanisms regulate expansions of eosinophil granulocytopoiesis in vivo by hemopoietic marrow.


Association between nonalcoholic fatty liver disease and type 2 diabetes: A bidirectional two-sample mendelian randomization study.
The aim of this study was to explore the mutually causal relationship between NAFLD and type 2 diabetes. Based on the data obtained from GWAS, this study employed bidirectional two-sample MR analysis to investigate the causal relationship between NAFLD and type 2 diabetes, and also examined the causal relationship between liver fat accumulation and type 2 diabetes as well as the relationship between NAFLD and FPG, IR. In MR analysis of NAFLD and type 2 diabetes, when NAFLD as an exposure and type 2 diabetes as a result, the OR (95 % CI) was 1.10890 (1.00135-1.22801); in the reverse analysis, the OR value was not statistically significant. In MR analysis of NAFLD, FPG and IR, there was no statistical significance in both directions. In MR analysis of liver fat accumulation and type 2 diabetes, when liver fat as an exposure and type 2 diabetes as a result, the OR (95 % CI) was 1.17516 (1.02054-1.35321); in the reverse analysis, the OR value (95 % CI) was 1.06283 (1.02879-1.09799). There is a unidirectional causal relationship between NAFLD and type 2 diabetes. Furthermore, a bidirectional causal relationship exists between liver fat accumulation and type 2 diabetes.


Designing rigid carbon foams.
We use ab initio density functional calculations to study the stability, elastic properties and electronic structure of sp(2) carbon minimal surfaces with negative Gaussian curvature, called schwarzites. We focus on two systems with cubic unit cells containing 152 and 200 carbon atoms, which are metallic and very rigid. The porous schwarzite structure allows for efficient and reversible doping by electron donors and acceptors, making it a promising candidate for the next generation of alkali ion batteries. We identify schwarzite structures that act as arrays of interconnected spin quantum dots or become magnetic when doped. We introduce two interpenetrating schwarzite structures that may find their use as the ultimate super-capacitor.


Patient-reported outcomes used actively in cancer patients undergoing antineoplastic treatment: A mini-review of the Danish landscape.
Many studies using Patient-reported outcomes (PRO) data have been conducted to monitor symptoms and health-related quality of life during follow-up after cancer treatment. However new ways of using (e)PROs have emerged. We aimed to explore the Danish landscape of the use of PRO in a research setting, where PRO is used actively in cancer patients undergoing treatment, and give an overview of how it is embraced by patients and clinicians. A literature search was performed in June 2023, using the keywords Denmark, cancer, and patient-reported outcomes. An expert on literature searches identified the search terms, and double screening was performed at both abstract and screening levels and full-text stage. The software tool Covidence was used. 467 articles were retrieved and 19 studies were included. They described the type of ePRO instrument used and the application of active ePRO i.e. a dialogue tool in the clinical encounter, release of alerts to clinicians, and enhancement of self-management. Finally, a development in the use of active ePROs over time is elucidated and we show how it is embraced by patients and clinicians. This mini-review gives an overview of how ePRO solutions are tested in oncological research in Denmark and embraced by patients and clinicians. ePRO solutions in a Danish setting seem well-suited for self-management. However, if more impact is warranted, clinicians need to engage in reviewing and using ePROs. Moreover, for successful implementation, the integration of ePROs in electronic health records must be supported by IT specialists and management.


Mechanical prophylaxis and other modalities.
The efficacy of different mechanical prophylaxes against venous thromboembolism, such as aggressive early mobilization, elastic stockings, continuous passive motion, and external pneumatic compression, is discussed and placed in perspective. The published literature regarding dextran, hydroxychloroquine, and antithrombin III is reviewed and critically assessed in terms of efficacy and safety.


Proteinuria predicting outcome in renal disease: nondiabetic nephropathies (REIN).
About two thirds of patients on renal replacement therapy irreversibly lose their kidney function because of progressive nephropathies, such as diabetic nephropathy and nondiabetic chronic renal disease. Halting the progression of these patients to end-stage renal disease (ESRD) is instrumental to substantially decrease the need and cost for renal replacement therapy. A large number of experimental studies have demonstrated that chronic nephropathies share common pathogenic mechanisms that contribute to renal disease progression, even independently of the original etiology. Actually, a variety of insults may result in a common pathway of systemic hypertension, increased glomerular pressure and protein ultrafiltration, glomerular and tubular protein overload, chronic inflammation and, ultimately, scarring. Experimental and clinical data converge to indicate that in chronic renal disease increased protein traffic is nephrotoxic, proteinuria predicts disease progression, and proteinuria reduction is renoprotective. Initial clinical trials, mostly in patients with no or mild proteinuria, failed to demonstrate that ACE inhibition therapy is renoprotective in nondiabetic chronic nephropathies. Consistently, meta-analyses based on data generated by these trials failed to detect a specific, blood pressure-independent, renoprotective effect of ACE inhibition therapy. The Ramipril Efficacy In Nephropathy (REIN) study found that ACE inhibitors, by reducing urinary proteins, may contribute to improve the outcome of nondiabetic renal disease, and reduce the risk of progression to ESRD by about 50%. Cumulative meta-analyses, including the REIN study results, confirmed and extended these findings. Thus, well-designed trials in properly selected and carefully monitored study populations continue to be the best approach to test the efficacy of novel treatments. The meta-analyses may help confirming the consistency of these findings and their generalizability to larger cohorts of patients.


Knowledge of juvenile sex offender registration laws predicts adolescent sexual behavior.
Because juveniles can now be registered as sex offenders, we conducted a pilot study to investigate awareness of these policies and sexual behavior histories in a convenience sample of 53 young adults (ages 18 to 23, 79% women). These preliminary data revealed that 42% percent of participants were unaware that youth under the age of 18 can be registered as sex offenders, and when informed that they can be, participants were unaware of the breadth of adolescent sexual behavior that warrants registration. Furthermore, those unaware of juvenile registration policies, compared to those who were aware, were marginally more likely to have had sex prior to age 18. Thus, youth most at risk of registration were least aware of this possibility, suggesting that juvenile registration likely does little to deter many behaviors that are considered to be juvenile sex offenses.


Nitrofurantoin resistance mechanism and fitness cost in Escherichia coli.
The biological fitness cost of antibiotic resistance is a key parameter in determining the rate of appearance and spread of antibiotic-resistant bacteria. We identified mutations conferring nitrofurantoin resistance and examined their effect on the fitness of clinical Escherichia coli isolates. By plating bacterial cells on agar plates containing nitrofurantoin, spontaneous nitrofurantoin-resistant E. coli mutants were isolated. The fitness of susceptible and resistant strains was measured as growth rate in the presence and absence of nitrofurantoin in rich culture medium. Time-kill kinetics of the resistant mutants was compared with the susceptible strains. Resistance mutations were identified by DNA sequencing. Spontaneous resistant mutants of initially susceptible clinical E. coli appeared with a rate of 10(-7)/cell/generation, and these mutants showed a reduction in the growth rate compared with the susceptible parent strain. Similarly, comparison of a set of susceptible and resistant clinical isolates of E. coli showed that the average growth rate of the resistant mutants was approximately 6% lower than the susceptible strains. Furthermore, the bacterial growth rate in the presence of nitrofurantoin at therapeutic levels was greatly reduced even for nitrofurantoin-resistant mutants. The resistance-conferring mutations were identified in the nsfA and nfsB genes that encode oxygen-insensitive nitroreductases. Nitrofurantoin resistance confers a reduction in fitness in E. coli in the absence of antibiotic. In the presence of therapeutic levels of nitrofurantoin, even resistant mutants are so disturbed in growth that they are probably unable to become enriched and establish an infection.


APOE Genotypes, Lipid Profiles, and Associated Clinical Markers in a Finnish Population with Cardiovascular Disease Risk Factors.
The APOE ε4 allele predisposes to high cholesterol and increases the risk for lifestyle-related diseases such as Alzheimer's disease and cardiovascular diseases (CVDs). The aim of this study was to analyse interrelationships of APOE genotypes with lipid metabolism and lifestyle factors in middle-aged Finns among whom the CVD risk factors are common. Participants (n = 211) were analysed for APOE ε genotypes, physiological parameters, and health- and diet-related plasma markers. Lifestyle choices were determined by a questionnaire. APOE genotypes ε3/ε4 and ε4/ε4 (ε4 group) represented 34.1% of the participants. Genotype ε3/ε3 (ε3 group) frequency was 54.5%. Carriers of ε2 (ε2 group; ε2/ε2, ε2/ε3 and ε2/ε4) represented 11.4%; 1.9% were of the genotype ε2/ε4. LDL and total cholesterol levels were lower (p < 0.05) in the ε2 carriers than in the ε3 or ε4 groups, while the ε3 and ε4 groups did not differ. Proportions of plasma saturated fatty acids (SFAs) were higher (p < 0.01), and omega-6 fatty acids lower (p = 0.01) in the ε2 carriers compared with the ε4 group. The ε2 carriers had a higher (p < 0.05) percentage of 22:4n-6 and 22:5n-6 and a lower (p < 0.05) percentage of 24:5n-3 and 24:6n-3 than individuals without the ε2 allele. The plasma fatty-acid profiles in the ε2 group were characterized by higher SFA and lower omega-6 fatty-acid proportions. Their lower cholesterol values indicated a lower risk for CVD compared with the ε4 group. A novel finding was that the ε2 carriers had different proportions of 22:4n-6, 22:5n-6, 24:5n-3, and 24:6n-3 than individuals without the ε2 allele. The significance of the differences in fatty-acid composition remains to be studied.


The Predictive Value of Return to Work Self-efficacy for Return to Work Among Employees with Cancer Undergoing Chemotherapy.
Purpose The aim of the present study was to examine the predictive value of Return to Work Self-efficacy (RTWSE) on Return to Work (RTW) among employees undergoing chemotherapy for cancer and to examine the relative contribution of RTWSE as predictor variable compared to personal, health-related, illness- and treatment-related and work-related factors. Methods A sample of 114 sickness absent employees with various cancers (age 18-62) included in the study on average 33 days after initiating chemotherapy were followed for 15 months. Data sources included patient questionnaires (RTWSE, depression, fatigue, performance status), sociodemographic factors (age, sex, job type, and perceived support from the workplace), patient records (type of cancer, treatment intention, number of treatment modalities, time since diagnosis and time since initiation of chemotherapy), and Danish national registries (RTW and education). Associations between RTWSE at baseline and weeks until full RTW during 15-months follow-up were analyzed using Cox proportional hazards regression. Results In the univariate analysis, high RTWSE was associated with shorter time to RTW (Hazard Ratio (HR) 1.84, 95% confidence interval (CI) 1.12-3.03). In the multivariate model, RTWSE failed to reach statistical significance (HR 1.12, 95% CI 0.62-2.02), whereas female sex (HR 0.30, 95% CI 0.15-0.60) and receiving palliative treatment (HR 0.15, 95% CI 0.05-0.44) were significantly associated with later RTW. Conclusion Compared to other factors of significance, RTWSE was not the strongest predictor of RTW when examined among employees undergoing chemotherapy for cancer. Before using the RTWSE questionnaire to identify employees with cancer at risk of late RTW, it is important to recognize that the predictive value of RTWSE may be different for employees on sick leave due to cancer than for other sickness absence populations.


Stable knock-down of efflux transporters leads to reduced glucuronidation in UGT1A1-overexpressing HeLa cells: the evidence for glucuronidation-transport interplay.
Efflux of glucuronide is facilitated by the membrane transporters including BCRP and MRPs. In this study, we aimed to determine the effects of transporter expression on glucuronide efflux and cellular glucuronidation. Single efflux transporter (i.e., BCRP, MRP1, MRP3, or MRP4) was stably knocked-down in UGT1A1-overexpressing HeLa cells. Knock-down of transporters was performed by stable transfection of short-hairpin RNA (shRNA) using lentiviral vectors. Glucuronidation and glucuronide transport in the cells were characterized using three different aglycones (i.e., genistein, apigenin, and emodin) with distinct metabolic activities. BCRP knock-down resulted in significant reductions in excretion of glucuronides (42.9% for genistein glucuronide (GG), 21.1% for apigenin glucuronide (AG) , and 33.7% for emodin glucuronide (EG); p < 0.01) and in cellular glucuronidation (38.3% for genistein, 38.6% for apigenin, and 34.7% for emodin; p < 0.01). Knock-down of a MRP transporter led to substantial decreases in excretion of GG (32.3% for MRP1, 36.7% for MRP3, and 36.6% for MRP4; p < 0.01) and AG (59.3% for MRP1, 24.7% for MRP3, and 34.1% for MRP4; p < 0.01). Also, cellular glucuronidation of genistein (38.3% for MRP1, 32.3% for MRP3, and 31.1% for MRP4; p < 0.01) and apigenin (40.6% for MRP1, 32.4% for MRP3, and 34.6% for MRP4; p < 0.001) was markedly suppressed. By contrast, silencing of MRPs did not cause any changes in either excretion of EG or cellular glucuronidation of emodin. In conclusion, cellular glucuronidation was significantly altered by decreasing expression of efflux transporters, revealing a strong interplay of glucuronidation with efflux transport.


The host-pathogen interaction of human cyclophilin A and HIV-1 Vpr requires specific N-terminal and novel C-terminal domains.
Cyclophilin A (CypA) represents a potential key molecule in future antiretroviral therapy since inhibition of CypA suppresses human immunodeficiency virus type 1 (HIV-1) replication. CypA interacts with the virus proteins Capsid (CA) and Vpr, however, the mechanism through which CypA influences HIV-1 infectivity still remains unclear. Here the interaction of full-length HIV-1 Vpr with the host cellular factor CypA has been characterized and quantified by surface plasmon resonance spectroscopy. A C-terminal region of Vpr, comprising the 16 residues 75GCRHSRIGVTRQRRAR90, with high binding affinity for CypA has been identified. This region of Vpr does not contain any proline residues but binds much more strongly to CypA than the previously characterized N-terminal binding domain of Vpr, and is thus the first protein binding domain to CypA described involving no proline residues. The fact that the mutant peptide Vpr75-90 R80A binds more weakly to CypA than the wild-type peptide confirms that Arg-80 is a key residue in the C-terminal binding domain. The N- and C-terminal binding regions of full-length Vpr bind cooperatively to CypA and have allowed a model of the complex to be created. The dissociation constant of full-length Vpr to CypA was determined to be approximately 320 nM, indicating that the binding may be stronger than that of the well characterized interaction of HIV-1 CA with CypA. For the first time the interaction of full-length Vpr and CypA has been characterized and quantified. A non-proline-containing 16-residue region of C-terminal Vpr which binds specifically to CypA with similar high affinity as full-length Vpr has been identified. The fact that this is the first non-proline containing binding motif of any protein found to bind to CypA, changes the view on how CypA is able to interact with other proteins. It is interesting to note that several previously reported key functions of HIV-1 Vpr are associated with the identified N- and C-terminal binding domains of the protein to CypA.


Partial or complete antenatal steroids treatment and neonatal outcome in extremely low birth weight infants < or =1000 g: is there a dose-dependent effect?
To assess the outcome of extremely low birth weight (ELBW) infants < or =1000 g as it relates to antenatal steroids (ANS) therapy. A retrospective analysis of 124 infants born between January 1995 and December 1997. Infants born to mothers with pregnancy-induced hypertension, diabetes, and severe growth restriction were excluded. In all, 77 (62%) infants were exposed to ANS, of whom 31 (25%) received one to two doses (partial course), and 46 (37%) received three to four doses (complete course). A total of 47 infants (38%) were not exposed to ANS. Infants not exposed to ANS, who exhibited more HMD, PDA, and IVH, were administered more surfactants, and were more likely to die versus infants with complete ANS dosing. Regression models revealed a dose-dependent effect of ANS on HMD, surfactant use, IVH, and CLD or death, with a significant decrease in HMD with > or =2 ANS doses. ANS, in a dose-dependent way, are associated with improved outcome in ELBW infants < or =1000 g, with the best outcome seen after a complete course.


[Effects of high doses of genistein on mammary gland of female rat].
to evaluate the effects of high doses of genistein on the mammary glands of adult female rats. Twenty-eight days after oophorectomy, 50 adult female rats were divided into five groups, as follows: a control group (Ctrl), three rats that received genistein (GEN) at the doses of 46 mg/kg (GEN46;), 125 mg/kg (GEN125) and 250 mg/kg (GEN250); one group received conjugated equine estrogen at the dose of 50 µg/g (ECE50). The substances were administered daily for 30 consecutive days by gavage and in the last week of the period of treatment, colpocytological exams were carried out for seven consecutive days. After treatment, the animals were anesthetized, blood samples were collected for estradiol and progesterone determination and the first pair of inguinal mammary glands was removed and processed for histomorphometric analysis. Collected data were subjected to analysis of variance supplemented by the Tukey-Kramer test (p<0.05). the ctrl group and the ones treated with different doses of GEN showed atrophic mammary glands, whereas the glands were more developed in the ECE group, where numerous mammary ducts and alveoli were observed. Morphometry showed a larger area of mammary parenchyma in the ECE group (98.870.1 ± 550.4 µm²* per mm²; p<0.05) compared with other groups (Ctrl=36.875.6 ± 443.4; GEN46=37.001.7 ± 557.4; GEN125=36.480.8 ± 658.3 and GEN250=37.502.8 ± 669.3). The same occurred in the number of alveoli in the ECE group (33.2 ± 6.9* per mm²; p<0.05) compared to the other groups (Ctrl=10.4 ± 2.1, GEN46=11.2 ± 3.1; GEN125=11.6 ± 2.1 and GEN250=12.3 ± 2.3). The estradiol level was higher in the ECE group compared to the other groups (9.4 ± 1.7 pg/mL; p<0.05), whereas serum levels of progesterone were similar in all groups. the administration of genistein at high doses had no trophic effect on the mammary glands of rats.


Managing chronic pain with encapsulated cell implants releasing catecholamines and endogenous opiods.
Spinal injections (intrathecal) of norepinephrine and/or opiod agonists are antinociceptive and when administered together may act in synergy. Spinal implants of adrenal chromaffin cells are an effective method for sustained delivery of the analgesic substances norepinephrine and enkephalin to the central nervous system (CNS). One method of packaging and implanting cell-loaded devices into the intrathecal space of recipients is by encapsulating the cell suspensions in a polymer membrane prior to implantation. Cells/tissue packaged within an encapsulating membrane obviate the need for immunosuppressive therapies in transplant recipients. In addition, device output can be quantified prior to implantation, and following the removal of the spinal implant. The ability to retrieve the devices with the present tubular configuration also confers an additional margin of safety over unencapsulated chromaffin cell implants. This paper reviews the research and clinical observations of cellular transplants containing adrenal chromaffin cells for relieving chronic pain. Encapsulated cell technology is discussed with an emphasis on our experiences developing pain-modulating clinical devices. The human-sized prototype devices were loaded with enzymatically isolated bovine chromaffin cells and maintained in vitro for 7 - 8 days in serum-free media. Two days prior to implantation, each device was assayed by static incubation to measure catecholamine and met-enkephalin output, and qualified devices (n = 6) were implanted into the sheep subarachnoid space for 6 weeks. Following a 6 week in life period, the retrieval forces of prototype devices were measured during removal from the subarachnoid space. Static incubation of the devices immediately following retrieval and after a 24 hour re-incubation period were used to quantify norepinephrine and met-enkephalin secretion profiles. This study demonstrated the safety, retrievability and maintenance of pharmacologically active encapsulated chromaffin cell-loaded devices with human implant dimensions.


Shiga Toxin-Producing Escherichia Coii in Slaughtered Pigs and Pork Products.
During the years 2015-2016, 83 faecal samples were collected at slaughter from pigs reared in farms located in Central-Northern Italy. During the years 2014-2016 a total of 562 pork products [465 not-readyto-eat (NRTE) and 97 ready-to-eat (RTE) products] were collected from retail outlets, large retailers and processing plants. The samples were analysed according to ISO TS 13136:2012. Out of 83 swine faecal samples, 77 (92.8%) resulted stx-positive by real time polymerase chain reaction (PCR), 5 stx2+ and 1 stx1+ Shiga toxin-producing Escherichia coli (STEC) strains were isolated. Among the 465 NRTE samples, 65 (14.0%) resulted stx-positive by real time PCR and 7 stx2+ STEC strains were isolated. The stx2 gene was detected more frequently than the stx1 gene both in faecal samples (90.4 vs 8.4%) and in NRTE pork products (13.3 vs 1.3%). All the RTE samples included in the analysis resulted stx-negative. Among the samples resulted positive for stx and eae genes, serogroup-associated genes were detected at high frequency: O26 resulted the most frequent in faecal samples (81.3%) and O145 in pork products (88.1%). The O157 serogroup resulted positive in 83.3 and 78.1% of pork products and faecal samples, respectively. Despite the frequent detection by real time PCR of genes indicating the possible presence of STEC strains belonging to the six serogroups, the bacteriological step did not confirm the isolation of any such strains.


Presentation of a foreign peptide on the surface of tomato bushy stunt virus.
A 13-amino-acid peptide derived from the V3 loop of human immunodeficiency virus (HIV-1) glycoprotein 120 (gp120) was attached as a C-terminal gene fusion to the coat protein of tomato bushy stunt virus (TBSV). The architecture of this plant virus permitted external display of the foreign sequence 180 times on the surface of the chimaeric virus particle. The chimaera replicated to a level similar to wild-type TBSV and the foreign sequence was retained through six sequential passages in plants. The HIV epitope was detected on the surface of the virus capsid by a V3-specific monoclonal antibody and by human sera from HIV-1-positive patients, demonstrating the potential of using plant-derived chimaeric particles for diagnostic purposes. Chimaeric virus also induced a specific immune response to the foreign HIV epitope when injected into NMRI mice.


No simple answers: ethical conflicts in pediatric heart transplantation.
Ethical issues in pediatric heart transplantation are encountered daily in the work of the transplant coordinator. Issues such as use of resources in a just world, less-than-ideal candidates, and informed consent are challenges to the transplant professional. This article explores those issues using the language of ethics to analyze the conflicts they present. Resolutions will not necessarily be offered, as there are no simple answers.


The development of a genome wide SNP set for the Barnacle goose Branta leucopsis.
Migratory birds are of particular interest for population genetics because of the high connectivity between habitats and populations. A high degree of connectivity requires using many genetic markers to achieve the required statistical power, and a genome wide SNP set can fit this purpose. Here we present the development of a genome wide SNP set for the Barnacle Goose Branta leucopsis, a model species for the study of bird migration. We used the genome of a different waterfowl species, Mallard Anas platyrhynchos, as a reference to align Barnacle Goose second generation sequence reads from an RRL library and detected 2188 SNPs genome wide. Furthermore, we used chimeric flanking sequences, merged from both Mallard and Barnacle Goose DNA sequence information, to create primers for validation by genotyping. Validation with a 384 SNP genotyping set resulted in 374 (97%) successfully typed SNPs in the assay, of which 358 (96%) were polymorphic. Additionally, we validated our SNPs on relatively old (30 years) museum samples, which resulted in a success rate of at least 80%. This shows that museum samples could be used in standard SNP genotyping assays. Our study also shows that the genome of a related species can be used as reference to detect genome wide SNPs in birds, because genomes of birds are highly conserved. This is illustrated by the use of chimeric flanking sequences, which showed that the incorporation of flanking nucleotides from Mallard into Barnacle Goose sequences lead to equal genotyping performance when compared to flanking sequences solely composed of Barnacle Goose sequence.


Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma: correlation with microvessel density.
Cyclooxygenases (COX) are key enzymes for conversion of arachidonic acid to prostaglandins. Nitric oxide synthase (NOS) is the enzyme responsible for formation of nitric oxide. Both have constitutive and inducible isoforms. The inducible isoforms (iNOS and COX-2) are of great interest as regulators of tumor angiogenesis, tumorigenesis and inflammatory processes. This study was to clarify their role in pancreatic adenocarcinomas. We investigated the immunohistochemical iNOS and COX-2 expression in 40 pancreatic ductal adenocarcinomas of different grade and stage. The results were compared with microvessel density and clinicopathological data. Twenty-one (52.5%) of the cases showed iNOS expression, 15 (37.5%) of the cases were positive for COX-2. The immunoreaction was heterogeneously distributed within the tumors. Staining intensity was different between the tumors. No correlation between iNOS and COX-2 expression was seen. There was no relationship with microvessel density. However, iNOS positive tumors developed more often distant metastases and the more malignant tumors showed a higher COX-2 expression. There was no correlation with other clinicopathological data. Approximately half of the cases expressed iNOS and COX-2. These two enzymes do not seem to be the key step in angiogenesis or carcinogenesis of pancreatic adenocarcinomas. Due to a low prevalence of COX-2 expression, chemoprevention of pancreatic carcinomas by COX-2 inhibitors can only achieve a limited success.


The promoter of Alzheimer's disease amyloid A4 precursor gene.
The promoter of the gene for the human precursor of Alzheimer's disease A4 amyloid protein (PAD gene) resembles promoters of housekeeping genes. It lacks a typical TATA box and shows a high GC content of 72% in a DNA region that confers promoter activity to a reporter gene in an in vivo assay. Transcription initiates at multiple sites. Sequences homologous to the consensus binding sites of transcription factor AP-1 and the heat shock control element binding protein were found upstream of the RNA start sites. Six copies of a 9-bp-long GC-rich element are located between positions -200 and -100. A protein--DNA interaction could be mapped to this element. The 3.8 kb of the 5' region of the PAD gene include two Alu-type repetitive sequences. These findings suggest that four mechanisms may participate in the regulation of the PAD gene and could be of relevance for the progression of amyloid deposition in Alzheimer's disease.


The proximal bronchoplasty retrieval technique for removal of embedded distal airway foreign bodies.
To describe a novel technique for removal of embedded distal airway foreign bodies with emphasis on procedural steps and management. The proximal bronchoplasty retrieval (PBR) technique is described including indications, rationale, surgical technique, and clinical decision making. Two representative cases are described in detail in order to demonstrate the technique. The PBR technique was successfully used to remove the two described embedded distal airway foreign bodies after other attempts had failed. Airway foreign bodies which have been present for several days or weeks are associated with edema and granulation tissue which often embeds the foreign body and may prevent removal due to proximal airway narrowing. We present a novel technique using endoscopic balloon dilation bronchoplasty to enlarge the airway proximal to the foreign body and enable removal with two example cases presented herein. The PBR technique allowed for removal of otherwise "stuck" distal airway foreign bodies.


Contribution of nuclear BCL10 expression to tumor progression and poor prognosis of advanced and/or metastatic pancreatic ductal adenocarcinoma by activating NF-κB-related signaling.
We previously demonstrated that nuclear BCL10 translocation participates in the instigation of NF-κB in breast cancer and lymphoma cell lines. In this study, we assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC). We analyzed the expression of BCL10-, cell cycle-, and NF-κB- related signaling molecules, and the DNA-binding activity of NF-κB in three PDAC cell lines (mutant KRAS lines: PANC-1 and AsPC-1; wild-type KRAS line: BxPC-3) using BCL10 short hairpin RNA (shBCL10). To assess the anti-tumor effect of BCL10 knockdown in PDAC xenograft model, PANC-1 cells treated with or without shBCL10 transfection were inoculated into the flanks of mice. We assessed the expression patterns of BCL10 and NF-κB in tumor cells in 136 patients with recurrent, advanced, and metastatic PDAC using immunohistochemical staining. We revealed that shBCL10 transfection caused cytoplasmic translocation of BCL10 from the nuclei, inhibited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines. Inhibition of BCL10 differentially blocked cell cycle progression in PDAC cell lines. Arrest at G1 phase was noted in wild-type KRAS cell lines; and arrest at G2/M phase was noted in mutant KRAS cell lines. Furthermore, shBCL10 transfection downregulated the expression of phospho-CDC2, phospho-CDC25C, Cyclin B1 (PANC-1), Cyclins A, D1, and E, CDK2, and CDK4 (BxPC-3), p-IκBα, nuclear expression of BCL10, BCL3, and NF-κB (p65), and attenuated the NF-κB pathway activation and its downstream molecule, c-Myc, while inhibition of BCL10 upregulated expression of p21, and p27 in both PANC-1 and BxPC-3 cells. In a PANC-1-xenograft mouse model, inhibition of BCL10 expression also attenuated the tumor growth of PDAC. In clinical samples, nuclear BCL10 expression was closely associated with nuclear NF-κB expression (p < 0.001), and patients with nuclear BCL10 expression had the worse median overall survival than those without nuclear BCL10 expression (6.90 months versus 9.53 months, p = 0.019). Nuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC.


Mal de Río Cuarto Virus Infection Triggers the Production of Distinctive Viral-Derived siRNA Profiles in Wheat and Its Planthopper Vector.
Plant reoviruses are able to multiply in gramineae plants and delphacid vectors encountering different defense strategies with unique features. This study aims to comparatively assess alterations of small RNA (sRNA) populations in both hosts upon virus infection. For this purpose, we characterized the sRNA profiles of wheat and planthopper vectors infected by Mal de Río Cuarto virus (MRCV, Fijivirus, Reoviridae) and quantified virus genome segments by quantitative reverse transcription PCR We provide evidence that plant and insect silencing machineries differentially recognize the viral genome, thus giving rise to distinct profiles of virus-derived small interfering RNAs (vsiRNAs). In plants, most of the virus genome segments were targeted preferentially within their upstream sequences and vsiRNAs mapped with higher density to the smaller genome segments than to the medium or larger ones. This tendency, however, was not observed in insects. In both hosts, vsiRNAs were equally derived from sense and antisense RNA strands and the differences in vsiRNAs accumulation did not correlate with mRNAs accumulation. We also established that the piwi-interacting RNA (piRNA) pathway was active in the delphacid vector but, contrary to what is observed in virus-infected mosquitoes, virus-specific piRNAs were not detected. This work contributes to the understanding of the silencing response in insect and plant hosts.


Early diagnosis and treatment of invasive pulmonary aspergillosis in a patient with cystic fibrosis.
Invasive pulmonary aspergillosis is a rare and fatal complication in patients with cystic fibrosis (CF) who lack concomitant risk factors. The few documented cases in children have all resulted in deaths during hospitalisation. We present the case of a 12-year-old boy with CF who was admitted for an exacerbation which was unresponsive to antibiotic therapy. The findings on imaging raised concerns about a possible fungal infection. As a result, voriconazole therapy was started prior to his respiratory deterioration. He was later found to be β-D glucan and Aspergillus Ag galactomannan positive confirming the suspicion for invasive pulmonary aspergillosis. Three months after diagnosis, he was discharged home under stable condition. Voriconazole was continued beyond discharge and resulted in improvement of respiratory symptoms. This underscores the importance of early treatment of pulmonary aspergillosis in patients with CF. Unfortunately, the patient died 6 months after diagnosis from a CF exacerbation.


VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix.
Planar cell polarity (PCP) proteins are implicated in a variety of morphogenetic processes including embryonic cell migration and potentially cancer progression. During zebrafish gastrulation, the transmembrane protein Vang-like 2 (VANGL2) is required for PCP and directed cell migration. These cell behaviors occur in the context of a fibrillar extracellular matrix (ECM). While it is thought that interactions with the ECM regulate cell migration, it is unclear how PCP proteins such as VANGL2 influence these events. Using an in vitro cell culture model system, we previously showed that human VANGL2 negatively regulates membrane type-1 matrix metalloproteinase (MMP14) and activation of secreted matrix metalloproteinase 2 (MMP2). Here, we investigated the functional relationship between VANGL2, integrin αvβ3, and MMP2 activation. We provide evidence that VANGL2 regulates cell surface integrin αvβ3 expression and adhesion to fibronectin, laminin, and vitronectin. Inhibition of MMP14/MMP2 activity suppressed the cell adhesion defect in VANGL2 knockdown cells. Furthermore, our data show that MMP14 and integrin αv are required for increased proteolysis by VANGL2 knockdown cells. Lastly, we have identified integrin αvβ3 as a novel VANGL2 binding partner. Together, these findings begin to dissect the molecular underpinnings of how VANGL2 regulates MMP activity and cell adhesion to the ECM.


A programme for children with nocturnal enuresis.
To describe and evaluate the implementation, effects and outcomes of a nurse-managed nocturnal enuresis treatment programme. The research design comprised three data sources: focus group interviews with six public health nurses providing the nocturnal enuresis treatment programme, case notes of a convenience sample of 30 children who had completed the treatment programme and interviews with seven children who had completed the programme. The study showed a success rate of 87 per cent (n = 26). Success was defined as maintaining nocturnal continence for 14 consecutive nights. Key aspects in the programme's success and delivery included the child taking responsibility for the programme instead of the parent, the nature of the nurse-child interaction and the nurses' flexibility in adapting the programme for each child. The children had experienced low self-esteem as a result of nocturnal enuresis, but success on the programme dramatically improved their self-esteem and ability to socialise with other children. The study affirmed the value of the nurse as the facilitator of this programme. The study has contributed to the knowledge base on the management of nocturnal enuresis in a community-based nurse-managed programme.


Contrasting landscape epidemiology of two sympatric rabies virus strains.
Viral strain evolution and disease emergence are influenced by anthropogenic change to the environment. We investigated viral characteristics, host ecology, and landscape features in the rabies-striped skunk disease system of the central Great Plains to determine how these factors interact to influence disease emergence. We amplified portions of the N and G genes of rabies viral RNA from 269 samples extracted from striped skunk brains throughout the distribution of two different rabies strains for which striped skunks were the reservoir. Because the distribution of these two strains overlapped on the landscape and were present in the same host population, we could evaluate how viral properties influenced epidemiological patterns in the area of sympatry. We found that South Central Skunk rabies (SCSK) exhibited intense purifying selection and high infectivity, which are both characteristics of an epizootic virus. Conversely, North Central Skunk rabies (NCSK) exhibited relaxed purifying selection and comparatively lower infectivity, suggesting the presence of an enzootic virus. The host population in the area of sympatry was highly admixed, and skunks among allopatric and sympatric areas had similar effective population sizes. Spatial analysis indicated that landscape features had minimal influence on NCSK movement across the landscape, but those same features were partial barriers to the spread of SCSK. We conclude that NCSK and SCSK have different epidemiological properties that interact differently with both host and landscape features to influence rabies spread in the central Great Plains. We suggest a holistic approach for future studies of emerging infectious diseases that includes studies of viral properties, host characteristics, and spatial features.


DNA engineered copper oxide-based nanocomposites with multiple enzyme-like activities for specific detection of mercury species in environmental and biological samples.
In this paper, we report the synthesis and application of enzyme-like DNA-copper oxide/platinum nanoparticles for the separate quantification of inorganic and organomercury species in various real samples. We synthesized a series of poly(thymine) (T60)-copper oxide/metal nanocomposites (T60-CuxO/M NCs; M = Au, Ag or Pt) that exhibited enzyme-like activities [oxidase (OX), peroxidase (POX), and catalase (CAT)]. The enzyme-like activities are tunable due to the incorporation of various metals into the NCs. Among a series of synthesized CuxO/M NCs, T60-copper oxide-platinum nanocomposites (T60-CuxO/Pt NCs) exhibited the highest OX-like activity via the O2-mediated oxidation of substrates, such as Amplex Red (AR), 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), o-phenylenediamine (OPD), and 3,3',5,5'-tetramethylbenzidine (TMB), to form fluorescent or colored products. Interestingly, inorganic mercury ions (Hg2+) and organomercury species, such as methylmercury (MeHg+), ethylmercury (EtHg+), and phenylmercury (PhHg+), significantly inhibited the OX-like activity of T60-CuxO/Pt NCs. For the selective detection of mercury species, we used ABTS in the T60-CuxO/Pt NCs system, and the ABTS/T60-CuxO/Pt NCs-based assay allowed for the detection of mercury ions at nanomolar concentrations based on the decrease in the catalytic activity caused by the mercury ions. To separately quantify the inorganic and organomercury species in a sample, we employed selenium nanoparticles (Se NPs) as a masking agent, as they preferentially bind with inorganic mercury species. The ABTS/T60-CuxO/Pt NCs-based assay with the masking agent of Se NPs further provided specificity for the detection of organomercury species in environmental water samples (tap water, river water, and seawater) and fish muscle samples (dogfish muscle DORM-II).


A glycolipid antigen associated with Burkitt lymphoma defined by a monoclonal antibody.
The antigen defined by a rat monoclonal antibody directed to a Burkitt lymphoma cell line was identified as globotriaosylceramide [Gal alpha (1 leads to 4)-Gal beta (1 leads to 4)-Glc beta (1 leads to 1)-ceramide]. The antibody demonstrated a strict steric specificity since it did not react with globoisotriaosylceramide [Gal alpha (1 leads to 3)-Gal beta (1 leads to 4)-Glc beta (1 leads to 1)-ceramide], the positional isomer of the antigen associated with the Burkitt lymphoma. Chemical analysis of various Burkitt lymphoma cell lines revealed that the Burkitt lymphoma cells contained more than 100 times as much of the glycolipid antigen as was found in other human lymphoma and leukemia cell lines.


Sequence homology and structural analysis of the clostridial neurotoxins.
The clostridial neurotoxins (CNTs), comprised of tetanus neurotoxin (TeNT) and the seven serotypes of botulinum neurotoxin (BoNT A-G), specifically bind to neuronal cells and disrupt neurotransmitter release by cleaving proteins involved in synaptic vesicle membrane fusion. In this study, multiple CNT sequences were analyzed within the context of the 1277 residue BoNT/A crystal structure to gain insight into the events of binding, pore formation, translocation, and catalysis that are required for toxicity. A comparison of the TeNT-binding domain structure to that of BoNT/A reveals striking differences in their surface properties. Further, the solvent accessibility of a key tryptophan in the C terminus of the BoNT/A-binding domain refines the location of the ganglioside-binding site. Data collected from a single frozen crystal of BoNT/A are included in this study, revealing slight differences in the binding domain orientation as well as density for a previously unobserved translocation domain loop. This loop and the conservation of charged residues with structural proximity to putative pore-forming sequences lend insight into the CNT mechanism of pore formation and translocation. The sequence analysis of the catalytic domain revealed an area near the active-site likely to account for specificity differences between the CNTs. It revealed also a tertiary structure, highly conserved in primary sequence, which seems critical to catalysis but is 30 A from the active-site zinc ion. This observation, along with an analysis of the 54 residue "belt" from the translocation domain are discussed with respect to the mechanism of catalysis.


Adult necrotising enterocolitis: a rare entity.
A case of Adult Necrotising Enterocolitis in an adult female whom diagnosed with intestinal obstruction was reported. On exploratory laparotomy, the mechanical caused was not found although major part of small bowel, caecum and proximal ascending colon were gangrenous along with intervening normal parts. Resection of affected bowel was performed followed by jejunostomy and transverse colostomy. Unfortunately, the patient not survive in the postoperative periods. Adult Necrotising Enterocolitis may mimic intestinal obstruction clinically or radiologically and prompt medical and surgical intervention is indicated in doubtful cases although it carries a poor prognosis.


Circulating cell-free-DNA concentration is a good biomarker for diagnosis of colorectal cancer in Mexican patients.
Colorectal cancer (CRC) is the third most common cancer in the world. Overall survival is related to clinical stage: more advanced stages show lower survival rates; therefore, they need to be monitored regularly with new, less invasive and more specific biomarkers. The concentration and integrity index of circulating cell-free DNA (ccfDNA) have been proposed as potential diagnostic and prognostic biomarkers for CRC, however, inconsistent results are still observed in different reports. Here we analyze these potential CRC biomarkers in a Mexican population. In this study, 124 patients with sporadic CRC and 37 healthy individuals were examined as a reference group. The ccfDNA was isolated from plasma samples of all included subjects. The ccfDNA concentration was determined by fluorometry and the integrity index (ALU247/ALU115 ratio) by quantitative PCR amplification (qPCR) of ALU sequences. The results show that ccfDNA concentration was higher in CRC patients than in the reference group (P=0.001). The integrity index showed no significant differences between these groups (P=0.258), except for histological type (P=0.012). A higher ccfDNA concentration was also associated with patients younger than 50 years (P=0.030). The ccfDNA concentration showed significant discriminatory power (AUC: 0.854, C.I.: 0.78-0.92, P=0.001) between patients and the reference group and between tumor-node-metastasis (TNM) stages. In conclusion, ccfDNA concentration proves to be a good diagnostic biomarker for CRC patients, whereas the integrity index did not show diagnostic utility.


Dasatinib + Gefitinib, a non platinum-based combination with enhanced growth inhibitory, anti-migratory and anti-invasive potency against human ovarian cancer cells.
Ovarian cancer is the leading cause of death for gynecological cancers and the 6th cause of women cancer death in developed countries. The late stage detection, the peritoneal dissemination and the acquisition of resistance against carboplatin are the main reasons to explain this poor prognosis and strengthen the need of alternative treatments to improve the management of ovarian cancer and/or to sensitize tumors to platinum salts. Epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (Met) and cellular Src kinase (c-Src) are crucial kinases implied in ovarian tumor growth, survival, invasion and resistance to carboplatin. Their expression is increased in advanced ovarian cancers and is correlated with poor prognosis. Despite a clear potential in inhibiting these proteins in ovarian cancer, as a single agent or in combination with a carboplatin treatment, we need to target kinases in tandem because of their capacity to trigger compensatory pathways that synergize to promote drug resistance. Here we target EGFR, c-Src and Met individually or in combination with carboplatin, using Gefitinib, Dasatinib and Crizotinib respectively, in a panel of carboplatin-sensitive (OVCAR-3, IGROV-1 and A2780) and carboplatin-resistant cells (SKOV-3 and EFO-21). We studied the ability of the most potent combination to induce apoptosis, regulate migration, invasion and to modulate the activation of proliferation and survival proteins. Crizotinib, Dasatinib and Gefitinib, alone or in combination with carboplatin, showed a cell-specific cytotoxic synergy in ovarian cancer cells. The Dasatinib plus Gefitinib combination was synergistic in OVCAR-3, SKOV-3 and, in IGROV-1 cells (high concentrations). This combination was unable to induce apoptosis but suppressed cell migration, invasion and the activation of EGFR, Erk, c-Src and Akt compared to single treatments. Combining carboplatin with kinase inhibitors lead to synergistic interactions in a cell-specific manner. Unlike platinum-based combinations, mixing Dasatinib with Gefitinib led to cytotoxic activity, inhibition of cell migration and invasion. Thus, the Dasatinib + Gefitinib combination presents anti-tumour properties that are superior to those of platinum-based combinations, indicating that it may well represent a promising new treatment modality to be tested in the clinic.


'In general, how do you feel today?'--self-rated health in the context of aging in India.
This thesis is centered on self-rated health (SRH) as an outcome measure, as a predictor, and as a marker. The thesis uses primary data from the WHO Study on global AGEing and adult health (SAGE) implemented in India in 2007. The structural equation modeling approach is employed to understand the pathways through which the social environment, disability, disease, and sociodemographic characteristics influence SRH among older adults aged 50 years and above. Cox proportional hazard model is used to explore the role of SRH as a predictor for mortality and the role of disability in modifying this effect. The hierarchical ordered probit modeling approach, which combines information from anchoring vignettes with SRH, was used to address the long overlooked methodological concern of interpersonal incomparability. Finally, multilevel model-based small area estimation techniques were used to demonstrate the use of large national surveys and census information to derive precise SRH prevalence estimates at the district and sub-district level. The thesis advocates the use of such a simple measure to identify vulnerable communities for targeted health interventions, to plan and prioritize resource allocation, and to evaluate health interventions in resource-scarce settings. The thesis provides the basis and impetus to generate and integrate similar and harmonized adult health and aging data platforms within demographic surveillance systems in different regions of India and elsewhere.


The status of the species Bacillus aerius. Request for an Opinion.
During a recent study assessing the diversity of the species Bacillus licheniformis, it became apparent that the type strain of Bacillus aerius was not available from any established culture collection or from the authors who originally described it. Other authors have reported similar findings when trying to obtain the strain (Lai et al., 2014), therefore, this species cannot currently be included in any further scientific studies. It is proposed that, if suitable replacements for type strains are not found or neotype strains are not proposed within two years following the publication of this Request for an Opinion, the Judicial Commission of the International Committee of Systematics of Prokaryotes place the name B. aerius on the list of rejected names.


Are anticapsular antibodies the primary mechanism of protection against invasive pneumococcal disease?
Antibody to capsular polysaccharide has been the basis of several vaccines that offer protection against invasive disease from Streptococcus pneumoniae. The success of such vaccines has led to the inference that natural protection against invasive pneumococcal disease is largely conferred by anticapsular antibody. If this is so, one would expect that the decline in disease from different serotypes would vary significantly, and that the appearance of substantial concentrations of anticapsular antibodies would coincide temporally with the decline in age-specific incidence. Using incidence data from the United States, we show that, on the contrary, the decline in incidence with age is quite similar for the seven most important serogroups, despite large differences in exposure in the population. Moreover, only modest increases in antibody concentration occur over the second and third years of life, a period in which serotype-specific incidence declines to less than 25% of its peak. We also present detailed data on the distribution of antibody concentrations in Israeli toddlers, which are consistent with the United States findings. The same conclusion is supported by new data on age-specific incidence in Finland, which is compared with published data on antibody acquisition in Finnish toddlers. We suggest some additional studies of the mechanisms of protection that could distinguish among potential alternative mechanisms, including acquired immunity to noncapsular antigens, maturation of nonspecific immune responses, or changes in anatomy or exposure.


Microtia: a microform of hemifacial microsomia.
An analysis of associated deformities in 74 patients with isolated microtia is reported. Microtia should be considered a microform of hemifacial microsomia because of similar (1) asymmetrical nature of the defects, (2) incidence and pattern of seventh nerve paresis, (3) correlation of the degree of seventh nerve weakness with grade of auricular deformity and not with the severity of mandibular hypoplasia, (4) right-sided preponderance, (5) incidence of associated cleft lip and palate, (6) male predilection, and (7) equivocal mode of inheritance. These clinical observations confirm the concept that microtia and hemifacial microsomia have the same etiopathogenesis which is not shared by mandibulofacial dysostosis.


Silibinin Promotes Cell Proliferation Through Facilitating G1/S Transitions by Activating Drp1-Mediated Mitochondrial Fission in Cells.
Heart, liver, and kidney, which are known as the essential organs for metabolism, possess the unique ability to regulate the proliferation function of the body against injury. Silibinin (SB), a natural polyphenolic flavonoid extracted from traditional herb Silybum marianum L., has been used to protect hepatocytes. Whether SB can regulate mitochondrial fission in normal cells and the underlying mechanisms remain unclear. Here, we showed that SB markedly promoted cell proliferation by facilitating G1/S transition via activating dynamin-related protein 1 (Drp1), which in turn mediated mitochondrial fission in these normal cells. SB dose-dependently increased the mitochondrial mass, mtDNA copy number, cellular adenosine triphosphate production, mitochondrial membrane potential, and reactive oxygen species in normal cells. Furthermore, SB dose-dependently increased the expression of Drp1. Blocking Drp1 abolished SB-induced mitochondrial fission. In conclusion, we demonstrate that SB promotes cell proliferation through facilitating G1/S transition by activating Drp1-mediated mitochondrial fission. This study suggests that SB is a potentially useful herbal derivative for the daily prevention of various diseases caused by impaired mitochondrial fission.


Rhythms of Core Clock Genes and Spontaneous Locomotor Activity in Post-Status Epilepticus Model of Mesial Temporal Lobe Epilepsy.
The interaction of Mesial Temporal Lobe Epilepsy (mTLE) with the circadian system control is apparent from an oscillatory pattern of limbic seizures, daytime's effect on seizure onset and the efficacy of antiepileptic drugs. Moreover, seizures per se can interfere with the biological rhythm output, including circadian oscillation of body temperature, locomotor activity, EEG pattern as well as the transcriptome. However, the molecular mechanisms underlying this cross-talk remain unclear. In this study, we systematically evaluated the temporal expression of seven core circadian transcripts (Bmal1, Clock, Cry1, Cry2, Per1, Per2, and Per3) and the spontaneous locomotor activity (SLA) in post-status epilepticus (SE) model of mTLE. Twenty-four hour oscillating SLA remained intact in post-SE groups although the circadian phase and the amount and intensity of activity were changed in early post-SE and epileptic phases. The acrophase of the SLA rhythm was delayed during epileptogenesis, a fragmented 24 h rhythmicity and extended active phase length appeared in the epileptic phase. The temporal expression of circadian transcripts Bmal1, Cry1, Cry2, Per1, Per2, and Per3 was also substantially altered. The oscillatory expression of Bmal1 was maintained in rats imperiled to SE, but with lower amplitude (A = 0.2) and an advanced acrophase in the epileptic phase. The diurnal rhythm of Cry1 and Cry2 was absent in the early post-SE but was recovered in the epileptic phase. Per1 and Per2 rhythmic expression were disrupted in post-SE groups while Per3 presented an arrhythmic profile in the epileptic phase, only. The expression of Clock did not display rhythmic pattern in any condition. These oscillating patterns of core clock genes may contribute to hippocampal 24 h cycling and, consequently to seizure periodicity. Furthermore, by using a pool of samples collected at 6 different Zeitgeber Times (ZT), we found that all clock transcripts were significantly dysregulated after SE induction, except Per3 and Per2. Collectively, altered SLA rhythm in early post-SE and epileptic phases implies a possible role for seizure as a nonphotic cue, which is likely linked to activation of hippocampal-accumbens pathway. On the other hand, altered temporal expression of the clock genes after SE suggests their involvement in the MTLE.


A novel 6D-approach to radically transform undergraduate medical education: preliminary reflections from MBRU.
Designers of undergraduate medical education (UME) need to address the exponentially expanding volume and variability of scientific knowledge, where by didactic teaching techniques need to be augmented by innovative student-centric pedagogical strategies and implementation of milieus, where information, communication and technology-enabled tools are seamlessly integrated, and lifelong information gathering, assimilation, integration and implementation is the ultimate goal. In UME, the basic sciences provide a solid scaffold allowing students to develop their personal critical decisional framework as well as define the understanding of normal human physiology, pivotal for the identification, categorization and management of pathophysiology. However, most medical schools confine themselves to "stagnant curricula", with the implementation of traditional "teacher centered" pedagogical techniques in the dissemination of the courses pertaining to basic sciences in UME. To tackle the above paucity, we present a novel "6D-Approach" for the dissemination of concepts in basic sciences through mentored journal-clubs. The approach is informed by a teaching principle derived from Constructivism. The technique in which the 6D-approach can be implemented in UME, is shown using an example from a first-year course of Molecular Biology and Principles of Genetics at our medical school. A reflection on the impact of 6D-Approach for students as well as instructors is also presented. The 6D-approach was positively received by the students and the formal feedback for the course: Molecular Biology and Principles of Genetics, where the approach was repeatedly employed, indicated that students expressed satisfaction with the teaching strategies employed in the course, with ~ 89% of the students in the cohort strongly agreeing with the highest grading score "extremely satisfied". Further, the approach through the use of mentored journal clubs encourages retention of knowledge, critical thinking, metacognition, collaboration and leadership skills in addition to self-evaluation and peer feedback. Hence, through the 6D-Approach, our attempt is to initiate, advance and facilitate critical thinking, problem-solving and self-learning in UME, demonstrated by graduating accomplished, competent and safe medical practitioners.


Update on course and outcome in eating disorders.
To review recent studies describing eating disorder course and outcome. Electronic and manual searches were conducted to identify relevant articles published since 2004. Twenty-six articles were identified. For anorexia nervosa (AN), most patients ascertained through outpatient settings achieved remission by 5-year follow-up. Inpatient treatment predicted poor prognosis as inpatient samples demonstrated lower remission rates. Outcome differed between bulimia nervosa (BN) and eating disorders not otherwise specified (EDNOS), including binge eating disorder (BED), for shorter follow-up durations; however, outcomes appeared similar between BN and related EDNOS by 5-year follow-up. Greater psychiatric comorbidity emerged as a significant predictor of poor prognosis in BN, whereas few prognostic indicators were identified for BED or other EDNOS. Results support optimism for most patients with eating disorders. However, more effective treatments are needed for adult AN inpatients and approximately 30% of patients with BN and related EDNOS who remain ill 10-20 years following presentation.


Adherence to Antiretroviral Therapy Among Iranian HIV/AIDS Patients
Treatment adherence of 95% or higher is recommended for appropriate therapeutic response and improving the function of immune system in HIV positive patients. To the best of our knowledge, there was report of adherence to HAART regimen from Iran. In the present study, we have reported the HAART adherence rate of Iranian HIV positive patients. In a twelve-month period, all patients older than 18 years old who referred to HIV clinic were on HAART regimen enrolled in the study. Beside demographic and clinical characteristics of Iranian HIV positive patients, Adherence to HAART was assessed by self-report and pill count methods at during the three consecutive months of the patients' visits. The mean of patients' adherence to HAART regimen based on the self-report method was 69.4%, 64.6% and 62.8% in the first, second and third month of follow up, respectively. The mean of adherence rates in three months followup assessed by self-report (65.5%) and pill count (60.4%) methods were correlated significantly (r=0.93 and p<0.001). Living with family members, changing the HAART regimen and stage of disease had a significant relationship with adherence rates. Although the adherence level of Iranian HIV infected patients is acceptable compared to other countries, the available antiretroviral medications are limited in our country, therefore, encouraging patients to have higher levels of adherence is more important.


[Concomitant use of intravenous ozone therapy and small doses of direct current in the integrated treatment of patient with sterile pancreatonecrosis].
To estimate effectiveness of concomitant use of direct current in a small doses and intravenous ozone therapy in the integrated treatment of patients with sterile pancreatonecrosis. 89 (39 women and 50 men, average age 48,2 +/- 3,6 years) Patient medical records, received a treatment for sterile pancreatonecrosis in surgery departments of Aktobe oblast were analyzed. In the period of 1997-2013, diagnosis of sterile pancreatonecrosis and its complication was found out on the basis of historical study, physical examination, clinical laboratory findings, ultrasound investigation and computerized tomography. All patients passed through complex basic conservative therapy and main group received also intravenous ozone therapy and small doses (20-25mkA) of direct current. Usage of small doses of direct current and intravenous ozone therapy in the integrated treatment of patients with sterile pancreatonecrosis helped on more rapid general well-being mend of patients. registered drop of transition frequency of sterile pancreatonecrosis into infected forms in 3 times, reduction of patients period of stay at hospital in 1,6 times and mortality rates--in 1,3 times.


Strand scission in DNA induced by curcumin in the presence of Cu(II).
Curcumin, a naturally occurring phytochemical responsible for the colour of turmeric, has shown a wide range of pharmacological properties including anti-inflammatory, anti-tumour promoter and anti-oxidant effects. In this paper we show that in the presence of Cu(II), curcumin caused breakage of calf thymus and supercoiled plasmid pBR322 DNA. The products were relaxed circles with no detectable linear forms. Other metal ions tested (Mg(II), Ca(II), Fe(II) and Ni(II)) were ineffective or less effective in the DNA breakage reaction. Cu(I) was shown to be an essential intermediate by using the Cu(I)-specific sequestering reagent neocuproine. The involvement of active oxygen species, such as H2O2 and (1)O2 was established by the inhibition of DNA breakage by catalase and azide. Curcumin is also able to directly produce O2- and H2O2 and in the presence of Cu(II), OH is generated. Absorption spectra of curcumin in the presence of DNA indicated that a complex is formed between the two. The results are discussed in relation to the established pro-oxidant activities of other known anti-oxidants.


Adoption of risk-related factors through early adolescence: associations with weight status and implications for causal mechanisms.
To examine cross-sectional and longitudinal associations between weight status and measures of risk and protective factors in youth. Participants included 3010 students (72.1% white, 27.9% nonwhite), with a baseline mean age of 12.7 years from the Teens Eating for Energy and Nutrition at School (TEENS) study. Surveys were administered in grades 7 and 8. Cross-sectional and longitudinal mixed-effects regression analyses were conducted to determine the association between body mass index z-score percentiles (BMI) and risk and protective factors (including substance use, depression, fighting, optimism, and spirituality). Only depression was associated with BMI at the beginning of grade 7. However, by the end of grade 8, binge drinking, alcohol, tobacco, and other drug (ATOD) use, fighting, and depression were all cross-sectionally associated with BMI. Longitudinally, BMI in grade 7 did not predict risk and protective factors in grade 8. However, ATOD use, fighting, depression, and optimism in grade 7 predicted BMI in grade 8. This study suggests there is a notable co-occurrence of unhealthy factors (including weight status, ATOD use, depression) which appears to develop during the critical transition period through early adolescence. Specifically, earlier ATOD use, depression, increased fighting, and decreased optimism may lead to unhealthy increases in weight status, whereas early indicators of increased weight status do not appear to predict increases in these factors. This work yields important insights into the causal mechanisms underlying adolescent behavior patterning and the progression with which these unhealthy risk factor profiles are adopted during this critical age.


Visualizing signalling by phosphoinositide 3-kinase pathway lipids.
Cells signal through lipids produced by phospholipid and phosphoinositide metabolism that involves three enzymic processes: (i) ester and phosphodiester hydrolysis by phospholipases; (ii) monophosphate hydrolysis by phosphatases; and (iii) phosphorylation of hydroxy groups by kinases. Unregulated enzyme activity correlates with specific pathologies, which are specific targets for therapeutic intervention. Three categories of reagents developed at the University of Utah and at Echelon Biosciences permit monitoring of in vitro enzyme activity and spatiotemporal changes in intracellular lipid concentrations, and identification of lipid-protein interactions.


Multimorbidity and healthcare resource utilization in Switzerland: a multicentre cohort study.
Multimorbidity is associated with higher healthcare resource utilization, but we lack data on the association of specific combinations of comorbidities with healthcare resource utilization. We aimed to identify the combinations of comorbidities associated with high healthcare resource utilization among multimorbid medical inpatients. We performed a multicentre retrospective cohort study including 33,871 multimorbid (≥2 chronic diseases) medical inpatients discharged from three Swiss hospitals in 2010-2011. Healthcare resource utilization was measured as 30-day potentially avoidable readmission (PAR), prolonged length of stay (LOS) and difference in median LOS. We identified the combinations of chronic comorbidities associated with the highest healthcare resource utilization and quantified this association using regression techniques. Three-fourths of the combinations with the strongest association with PAR included chronic kidney disease. Acute and unspecified renal failure combined with solid malignancy was most strongly associated with PAR (OR 2.64, 95%CI 1.79;3.90). Miscellaneous mental health disorders combined with mood disorders was the most strongly associated with LOS (difference in median LOS: 17 days) and prolonged LOS (OR 10.77, 95%CI 8.38;13.84). The number of chronic diseases was strongly associated with prolonged LOS (OR 9.07, 95%CI 8.04;10.24 for ≥10 chronic diseases), and to a lesser extent with PAR (OR 2.16, 95%CI 1.75;2.65 for ≥10 chronic diseases). Multimorbidity appears to have a higher impact on LOS than on PAR. Combinations of comorbidities most strongly associated with healthcare utilization included kidney disorders for PAR, and mental health disorders for LOS.


Quantitative trait loci analysis of nitrate storage in Arabidopsis leading to an investigation of the contribution of the anion channel gene, AtCLC-c, to variation in nitrate levels.
Storage of excess nitrate in the vacuole and its subsequent remobilization is an important aspect of a plant's nitrogen economy, but the genes controlling the underlying processes have not all been identified and characterized. Cape Verdi Island (Cvi)/Landsberg erecta (Ler) and Columbia (Col)/Landsberg erecta recombinant inbred line (RIL) populations of Arabidopsis thaliana were used to identify quantitative trait loci (QTL) controlling natural variation in nitrate concentrations. One major and two minor QTLs were found for the Cvi/Ler population and one minor QTL for the Col/Ler RIL. These were designated NA1 to NA4. The major Cvi/Ler QTL (NA3) was located at the bottom of chromosome 5. No interaction among the QTLs was found by two-way ANOVA. By comparing in silico the locations of the QTLs with a physical map of the Arabidopsis genome, candidate genes for each QTL were identified. Several of these were anion channels of the AtCLC family. One of these, AtCLC-c, coincided with NA3 and its role was investigated using a mutant with a transposon insertion in AtCLC-c. Mutant plants homozygous for the insertion (designated clcc-1) had less than 5% of AtCLC-c mRNA compared with wild-type (WT) shoots. They also had significantly lower nitrate concentrations when grown at a range of external nitrate concentrations. The concentrations of chloride, malate, and citrate were also affected in the mutant. In wild-type plants, expression of AtCLC-c was down-regulated in the presence of nitrate, but ammonium had a much smaller effect while chloride and sulphate did not affect expression. These and published results suggest that multiple genes affect nitrate concentrations in plants and that AtCLC-c and other members of the AtCLC gene family play some role in this.