New Insights in Thrombin Inhibition Structure-Activity Relationships by Characterization of Octadecasaccharides from Low Molecular Weight Heparin.
Low Molecular Weight Heparins (LMWH) are complex anticoagulant drugs that mainly inhibit the blood coagulation cascade through indirect interaction with antithrombin. While inhibition of the factor Xa is well described, little is known about the polysaccharide structure inhibiting thrombin. In fact, a minimal chain length of 18 saccharides units, including an antithrombin (AT) binding pentasaccharide, is mandatory to form the active ternary complex for LMWH obtained by alkaline β-elimination (e.g., enoxaparin). However, the relationship between structure of octadecasaccharides and their thrombin inhibition has not been yet assessed on natural compounds due to technical hurdles to isolate sufficiently pure material. We report the preparation of five octadecasaccharides by using orthogonal separation methods including size exclusion, AT affinity, ion pairing and strong anion exchange chromatography. Each of these octadecasaccharides possesses two AT binding pentasaccharide sequences located at various positions. After structural elucidation using enzymatic sequencing and NMR, in vitro aFXa and aFIIa were determined. The biological activities reveal the critical role of each pentasaccharide sequence position within the octadecasaccharides and structural requirements to inhibit thrombin. Significant differences in potency, such as the twenty-fold magnitude difference observed between two regioisomers, further highlights the importance of depolymerisation process conditions on LMWH biological activity.


Economic cost analysis of malaria case management at the household level during the malaria elimination phase in The People's Republic of China.
In China, malaria has been posing a significant economic burden on households. To evaluate malaria economic burden in terms of both direct and indirect costs has its meaning in improving the effectiveness of malaria elimination program in China. A number of study sites (eight counties in five provinces) were selected from the malaria endemic area in China, representing the different levels of malaria incidence, risk classification, economic development. A number of households with malaria cases (n = 923) were surveyed during the May to December in 2012 to collect information on malaria economic burden. Descriptive statistics were used to characterize the basic profiles of selected malaria cases in terms of their gender, age group, occupation and malaria type. The malaria economic costs were evaluated by direct and indirect costs. Comparisons were carried out by using the chi-square test (or Z-test) and the Mann-Whitney U test among malaria cases with reference to local/imported malaria patients, hospitalized/out patients, and treatment hospitals. The average cost of malaria per case was 1 691.23 CNY (direct cost was 735.41 CNY and indirect cost was 955.82 CNY), which accounted for 11.1 % of a household's total income. The average costs per case for local and imported malaria were 1 087.58 CNY and 4271.93 CNY, respectively. The average cost of a malaria patient being diagnosed and treated in a hospital at the county level or above (3 975.43 CNY) was 4.23 times higher than that of malaria patient being diagnosed and treated at a village or township hospital (938.80 CNY). This study found that malaria has been posing a significant economic burden on households in terms of direct and indirect costs. There is a need to improve the effectiveness of interventions in order to reduce the impact costs of malaria, especially of imported infections, in order to eliminate the disease in China.


Exploring Biological Predictive Factors of Progression After Surgery in High-Risk Renal Cell Carcinoma: Results From the French Cohort of the Randomized S-TRAC Trial Patients.
Objective: We aimed to explore biological predictive factors of progression after surgery in nonmetastatic renal cell carcinoma (RCC) using the collected tumors in the French cohort of the randomized S-TRAC trial patients. Patients and Methods: We analyzed the tumors of the French cohort of STRAC that included 44 cases of clear cell RCC (ccRCC) that were collected from six centers. The main objective was to explore biological predictive factors of progression (defined as PFS) to sunitinib. Broad-spectrum analysis including immunohistochemistry, fluorescent in situ hybridization (FISH), comparative genomic hybridization (CGH) array, and transcriptomic analyses were performed on the tumors. Results:Analysis of vascular density showed type 1 vascular stroma corresponding to high vascular density was associated with progression (p < 0.034). Loss of poly bromo-1 expression showed a distinct profile: a highly histopathological aggressive tumor with a marked angiogenic profile (vascular endothelial growth factor overexpression and immature vascular stroma type 2), no PD1 or PDL1 expression, and wild-type (WT) status of the VHL gene. There were 27 chromosome regions gained in patients with progression (on chromosomes 7 and 16, and to a lesser extent 8, 12, 17, 17, 19, 20 corresponding to 605 associated genes) and 10 regions lost in these same patients on chromosomes 8 and 9, and to a lesser extent 2 and 21 corresponding to 25 associated genes. Conclusion:We found that an angiogenic phenotype defined by a high vascular density with a vascular type 2 stroma was a predictive factor of sunitinib resistance. Regardless of adjuvant treatment, chromosomal gains and losses and genomic alterations including PBRM1 loss were associated with worse outcomes. Clinical Trial Registration: ClinicalTrials.gov number, NCT00375674.


Real-world assessment of a metered-dose inhaler with integrated dose counter.
Currently available metered dose inhalers (MDIs) do not track the remaining number of doses, indicating the need for a device that accurately monitors medication use. In an open-label study at 37 outpatient centers, patients > or =4 years old with asthma or chronic obstructive pulmonary disease requiring short-acting 32-agonists received two actuations of albuterol hydrofluoroalkane (HFA) [Ventolin HFA: GlaxoSmithKline], 90 microg twice daily, via a novel MDI with an integrated dose counter until all 200 actuations were completed. Concordance between counter readings, diary card-recorded actuations, and canister weights were measured in patients who completed > or =90% of the labeled actuations (n = 224). Adverse events and patient satisfaction were assessed in the intent-to-treat population (n = 268). In 43,865 recorded actuations, 333 counter versus diary discrepancies occurred (discrepancy rate of 0.76%), and 88% of discrepancies were by one to two actuations. Forty-seven percent of patients had no discrepancies. Incidence of the device firing without changes in counter readings was very low (0.09%). Mean expected actuations based on canister weights (184) were slightly lower than mean counter and diary-reported actuations (200 each). At baseline, 62% of patients reported anxiety about not knowing the quantity of medication remaining in their inhaler. On study completion, 92% expressed satisfaction with the dose counter and 92% agreed it would help prevent them from running out of medication. The adverse event profile showed that albuterol HFA was well tolerated. Integrated MDI counters are a useful and reliable tool for tracking a patient's medication supply.


Modulation of porosity in a solid material enabled by bulk photoisomerization of an overcrowded alkene.
The incorporation of photoswitchable molecules into solid-state materials holds promise for the fabrication of responsive materials, the properties of which can be controlled on-demand. However, the possible applications of these materials are limited due to the restrictions imposed by the solid-state environment on the incorporated photoswitches, which render the photoisomerization inefficient. Here we present responsive porous switchable framework materials based on a bistable chiroptical overcrowded alkene incorporated in the backbone of a rigid aromatic framework. As a consequence of the high intrinsic porosity, the resulting framework readily responds to a light stimulus, as demonstrated by solid-state Raman and reflectance spectroscopies. Solid-state 13C NMR spectroscopy highlights an efficient and quantitative bulk photoisomerization of the incorporated light-responsive overcrowded olefins in the solid material. Taking advantage of the quantitative photoisomerization, the porosity of the framework and the consequent gas adsorption can be reversibly modulated in response to light and heat.


[Conners' rating scales in the assessment of attention deficit disorder with hyperactivity (ADHD). A new validation and factor analysis in Spanish children].
The use of Conner's Rating Scales (CRS) is very extended for the assessment of attention deficit disorder with hyperactivity (ADD-H). The main objective of this work is to study the validity of construct of CRS from theoretical basis and data statistical analysis. The study is based on a control group of 633 children and a clinical group of 33 subjects. We used a Spanish version of the Conner's Teacher Rating Scale (CTRS) and Conner's Parents Rating Scale (CPRS) in both groups. From the analysis of scales contents we attribute the items to several behavioral areas and we performed a factorial analysis. Studies of reliability, external validity versus clinical criteria, and analysis of correlations between parents and teachers scales were also performed. Findings from factorial analysis and study of reliability have shown the questions of CTRS to be clustered in three well-defined and reliable factors: hyperactivity, attention deficit, and conduct disorder. The questions dealing with emotional disorders are not sufficiently consistent to constitute a separate factor. CPRS has a lower reliability than CTRS, and its factorial analysis does not allow to consider a factorial distribution. The validity is high in CTRS and no significative in CPRS. Correlation between scales is also low. As a consequence of these results we propose a Spanish experimental revised form of the CTRS, with 20 items. This new form can assess separately: attention deficit; hyperactivity and conduct disorder, according to the current clinical criteria of CIE-10 and DSM-IV.


Understanding global nutrition dynamics as a step towards controlling cancer incidence.
As we look to understand future forces that will affect cancer risk, poor dietary patterns, overweight and obesity are significant concerns. In the past two decades these factors have shifted from issues that face higher-income countries to a global pandemic, and are rapidly becoming less a problem of affluence and more a problem of poverty. Rapid shifts in food systems, food pricing and marketing are the causes that underlie this trend. It is imperative to understand these factors and implement global interventions to slow this pandemic. The alternative is an acceleration of the incidence of the main nutrition-related cancers, primarily in developing countries.


Comparison of primary thyroid lymphoma with anaplastic thyroid carcinoma on computed tomographic imaging.
Primary non-Hodgkin's lymphoma (LY) and anaplastic carcinoma (AC) of the thyroid gland are rare malignant tumors, and the initial symptoms of these diseases are very similar. The aim of our study was to compare the characteristics of the two diseases using computed tomographic (CT) scans in order to make an accurate differential diagnosis. Ten patients with LY and 10 with AC were analyzed. Differences in the CT findings of the two diseases were evaluated before treatment and statistically tested with either Student's t-test or the chi-square test. In the analysis of characteristics of CT imaging, the existence of calcification and necrosis, and heterogeneous tumor were dominant findings in AC, and there was a statistically significant difference in frequency between the two diseases (p < 0.01). Calcification detected in AC was usually multiple and/or gross (mean size: phi8.2 mm). All lymphadenopathies were delineated as having the same homogeneous attenuation as the tumors in the thyroid gland in LY, but were shown as irregular rim enhancement in AC. The CT features of the two diseases are characteristic in terms of calcification, necrosis, and tumor composition. Evaluation by means of CT imaging is useful in distinguishing between LY and AC.


A 15-residue bifunctional element in D-AKAP1 is required for both endoplasmic reticulum and mitochondrial targeting.
The cAMP-dependent protein kinase anchoring protein, d-AKAP1, has two N-terminal splice variants. The shorter forms (N0, d-AKAP1a, and -1c) target to mitochondria, and the longer forms (N1, d-AKAP1b, and -1d) with 33 additional residues N-terminal to N0 target to the endoplasmic reticulum (ER) (Huang, L. J., Wang, L., Ma, Y., Durick, K., Perkins, G., Deerinck, T. J., Ellisman, M. H., and Taylor, S. S. (1999) J. Cell Biol. 145, 951-959). In d-AKAP1a, translation may initiate from both Met-34 or Met-49 producing two molecules both targeted to mitochondria. The shorter molecule contains the 15-residue targeting motif, homologous to the N-terminal mitochondrial targeting motif of hexokinase I. Extensive mutagenesis showed that one hydrophobic surface of the 15-residue hexokinase-homologous segment contained the key elements for mitochondrial targeting. The same 15 residues are also part of the ER-targeting signal, but for ER targeting multiple hydrophobic residues are required that encompass both surfaces of the helix. The different involvement of the same helical motif for targeting to the two organelles appears to reflect different modes of interaction with the two organelles. This is the first example of a bifunctional helical element that is required for both ER and mitochondrion targeting.


Oral self-nanoemulsifying drug delivery systems for enhancing bioavailability and anticancer potential of fosfestrol: In vitro and in vivo characterization.
The objective of the current research work was to fabricate a fosfestrol (FST)-loaded self-nanoemulsifying drug delivery system (SNEDDS) to escalate the oral solubility and bioavailability and thereby the effectiveness of FST against prostate cancer. 32 full factorial design was employed, and the effect of lipid and surfactant mixtures on percentage transmittance, time required for self-emulsification, and drug release were studied. The optimized solid FST-loaded SNEDDS (FSTNE) was characterized for in vitro anticancer activity and Caco-2 cell permeability, and in vivo pharmacokinetic parameters. Using different ratios of surfactant and co-surfactant (Km) a pseudo ternary phase diagram was constructed. Thirteen liquid nano emulsion formulations (LNE-1 to LNE-13) were formulated at Km = 3:1. LNE-9 exhibited a higher % transmittance (99.25 ± 1.82 %) and a lower self-emulsification time (24 ± 0.32 s). No incompatibility was observed in FT-IR analysis. Within 20 min the solidified FST loaded LNE-9 (FSTNE) formulation showed almost complete drug release (98.20 ± 1.30 %) when compared to marketed formulation (40.36 ± 2.8 %), and pure FST (32 ± 3.3 %) in 0.1 N HCl. In pH 6.8 phosphate buffer, the release profiles are found moderately higher than in 0.1 N HCl. FSTNE significantly (P < 0.001) inhibited the PC-3 prostate cell proliferation and also caused apoptosis (P < 0.001) compared to FST. The in vitro Caco-2 cell permeability study results revealed 4.68-fold higher cell permeability of FSTNE than FST. Remarkably, 4.5-fold rise in bioavailability was observed after oral administration of FSTNE than plain FST. FSTNE remarkably enhanced the in vitro anticancer activity and Caco-2 cell permeability, and in vivo bioavailability of FST. Thus, FST-SNEDDS could be utilized as a potential carrier for effective oral treatment of prostate cancer.


Induction of phospholipid-binding antibodies in mice and rabbits by immunization with human beta 2 glycoprotein 1 or anticardiolipin antibodies alone.
Anticardiolipin (aCL) antibodies are autoantibodies present in high concentrations in patients with the antiphospholipid syndrome (APS), a disorder of recurrent thrombosis and pregnancy loss. What induces aCL antibodies is uncertain, but a recent report suggested that immunization of mice with beta 2 glycoprotein 1 (beta 2 GP1) in Freund's complete adjuvant (FCA) resulted in aCL antibody production in the recipient mice. Since this observation might explain how autoantibodies might be induced by poor immunogens, such as phospholipids, we decided to explore the question further. In our first series of experiments, we found that aCL antibodies were induced in mice by beta 2GP1 mixed with adjuvants that did not contain lipids (Adju-Prime or aluminium hydroxide). This excluded the possibility that antibody induction occurred because beta 2GP1 formed complexes with lipids in FCA. We also found that aCL antibodies always appeared before anti-beta 2GP1 antibodies, excluding the possibility that aCL antibodies were directed to beta 2GP1 or were induced by formation of anti-idiotypic antibodies (to anti-beta 2GP1). In experiments, we found that immunization of mice with human IgG antibodies from patients with the APS (IgG-APS), also induced aCL antibodies. Immunization with pure bovine serum albumin (BSA) did not induce aCL antibodies. We propose that aCL antibodies are induced by proteins with high avidity for phospholipids. These proteins may be bound to phospholipids when introduced, or may bind circulating phospholipids, so transforming phospholipid molecules into immunogens. Similar mechanisms might explain autoantibody induction to other poor immunogens.


Opioid Use Disorder in Pregnant Patients.
In this issue of Anesthesia & Analgesia, Lim and colleagues offer a scoping review of the available literature encompassing opioid use disorder (OUD) in pregnant patients. As discussed in their review, opioid use and abuse in pregnant patients have increased four-fold in the past decade. As such, these patients can present significant challenges with respect to pain management during labor and delivery. A baseline habituation to opioids can render patients resistant to conventional pain management plans. Those who are additionally prescribed opioid agonist-antagonists or other maintenance medications for OUD such as buprenorphine or methadone have even more complex pharmacologic considerations that make pain management unpredictable. As detailed in their analysis, there is a paucity of literature surrounding optimal management strategies in this population of patients. Reports are increasing over time, however, most publications are of lower tier evidence, with very few randomized trials and systematic reviews to inform practitioners. It becomes plainly evident that this is an area of clinical science that demands greater attention. Specific areas of focus elaborated by the authors include: better characterization of opioid selection and dosing in managing labor analgesia, effectiveness of different regional anesthetic techniques, non-pharmacologic management, and psycho-social support for these patients. The reader is strongly encouraged to review the cited article for an in-depth understanding of the concepts summarized in this infographic.


[Post-cholestatic hypercholeresis in a patient with malignant obstruction of the bile ducts].
Increased choleresis of up to 4950 ml per day was observed after positioning of a PTCD in a patient with complete biliary obstruction due to a malignant tumor. Bile secretion could be temporarily reduced to 15% of the initial flow rate by intravenous administration of somatostatin. Simultaneously, the concentration of bile acids increased from 1.2 to 6.2 mmol/l, whereas the concentrations of electrolytes remained constant. Cholic acid had no influence on bile secretion. To safeguard the patient from excessive loss of fluid and electrolytes, the drained bile was reinfused into the duodenum via a PEG.


End-of-life care education in United States pharmacy schools.
Hospice and palliative care have undergone dramatic changes in the past 30 years. Educational initiatives and certification programs for physicians (American Board of Hospice and Palliative Medicine) and nurses (National Board for Certification of Hospice and Palliative Nurses) have further delineated this area of practice as distinct from geriatrics, neurology, anesthesiology, or oncology. As other professions assess their own practices of hospice and end-of-life (EOL) care education in their respective schools and colleges, the pharmacy profession must also ensure that its future graduates are prepared to adequately participate in this type of care. This was a descriptive study in which all accredited schools and colleges of pharmacy in the US were queried regarding their level of curricular commitment to EOL care. Eighty-three questionnaires were mailed, and 60 schools responded (72 percent). Four primary informational items regarding EOL and palliative care education were targeted, including availability of didactic teaching, specialization of pharmacy faculty, availability and type of clerkships, and method of instruction. Sixty-two percent of respondents indicated EOL care education was provided didactically (3.89 +/- 1.91 lecture hours per year). Fifty-eight percent of respondents indicated that EOL care experiential clerkships were available (4.97 +/- 1.25 weeks in duration). These data indicate that over half of US pharmacy students receive some exposure to EOL care education.


Expression of human gastrin gene in normal and gastrinoma tissues.
The complete sequence of the human gastrin gene is reported here. This gene consists of three exons. Nine Alu family sequences are found within the gene and in the surrounding region. S1 mapping study showed that the transcription of gastrin gene starts at 60, 57, or 55 bp upstream from the 3' end of the first exon. The mechanism of mRNA synthesis in a gastrinoma tissue was studied to clarify the ectopic production of gastrin. It was found that mRNA synthesis starts from the same three transcriptional start points. Southern blotting profiles for normal gastric antrum and gastrinoma DNA were indistinguishable from each other within the 18-kb region containing the gastrin gene, showing that no genomic rearrangements are associated with the gastrinoma formation. Thus, the overproduction of gastrin in this tumor is likely to be due to an aberrant expression control system of the cell, rather than a change in the control region of the gastrin gene.


The role of 99mTc-diphosphonate bone SPECT/CT in the ankle and foot.
The evaluation of the osseous ankle and foot pathology often poses a clinical and diagnostic challenge because of the complex anatomy and structural biomechanics of the region. Further investigation involves a multimodality imaging approach. Although both structural and functional imaging techniques have their strengths, namely, the high specificity of the former and superior sensitivity of the latter, they also have a number of limitations when used in isolation. These include the inability to determine the functional significance of pathological anatomical abnormalities or to further characterize or localize abnormal metabolic activity. The development of integrated single-photon emission computed tomography/computed tomography systems has aimed to overcome the limitations of separate anatomical and functional imaging techniques. This may be of particular value in ankle and foot assessments, in which multiple joints may be affected by different pathologies. This review article aims to highlight the role of both structural and functional imaging techniques, with particular emphasis on the incremental value of single-photon emission computed tomography/computed tomography in evaluation of this complex anatomical region.


Braiding Lateral Morphotropic Grain Boundaries in Homogenetic Oxides.
Interfaces formed by correlated oxides offer a critical avenue for discovering emergent phenomena and quantum states. However, the fabrication of oxide interfaces with variable crystallographic orientations and strain states integrated along a film plane is extremely challenging by conventional layer-by-layer stacking or self-assembling. Here, the creation of morphotropic grain boundaries (GBs) in laterally interconnected cobaltite homostructures is reported. Single-crystalline substrates and suspended ultrathin freestanding membranes provide independent templates for coherent epitaxy and constraint on the growth orientation, resulting in seamless and atomically sharp GBs. Electronic states and magnetic behavior in hybrid structures are laterally modulated and isolated by GBs, enabling artificially engineered functionalities in the planar matrix. This work offers a simple and scalable method for fabricating unprecedented innovative interfaces through controlled synthesis routes as well as providing a platform for exploring potential applications in neuromorphics, solid-state batteries, and catalysis.


In vitro and in vivo characterizations of tetrandrine on the reversal of P-glycoprotein-mediated drug resistance to paclitaxel.
Multidrug resistance (MDR) is one of the major obstacles limiting the efficacy of cancer chemotherapy. Through screening a series of natural products, we have previously identified six naturally occurring bisbenzylisoquinoline alkaloids (BBIs) that possess potent activity to reverse P-glycoprotein (gp)-mediated drug resistance. In this study, we characterized one of these compounds, termed tetrandrine, and evaluated its reversal activity on P-gp-mediated drug resistance to paclitaxel in vitro and in vivo. Using the human MDR tumor cell line KBv200 and its drug sensitive parental cell line, the reversal activity of tetrandrine on P-gp-mediated resistance to paclitaxel and docetaxel were determined by MTT and other in vitro drug evaluation assays. Further, through establishment of xenograft models bearing the intrinsically resistant KBv200 tumor, we also examined the effect of tetrandrine on potentiating the antitumor activity of paclitaxel in vivo. In vitro studies showed that co-administration of tetrandrine at 2.5 microM, which has little cytotoxicity alone, reversed the sensitivity of KBv200 cells to paclitaxel and docetaxel around 10-fold. In vivo experiments also demonstrated that tetrandrine significantly potentiated the antitumor activity of paclitaxel in xenograft models bearing the intrinsically resistant KBv200 tumors. In addition, accumulation and efflux studies with [3H]-paclitaxel indicated that tetrandrine increases the intracellular accumulation of [3H]-paclitaxel in MDR cells through inhibition of P-gp-mediated drug efflux. The present in vitro and in vivo studies demonstrated that tetrandrine possesses potent and specific activity in reversing P-gp-mediated drug resistance. This naturally occurring compound may be used as a chemosensitizer in the treatment of P-gp-mediated MDR cancers.


A novel technique designed to minimize the morbidity of failure of arteriovenous access in hemodialysis patients.
The failure of dialysis access grafts leads to significant morbidity rates in patients with end-stage renal disease. We describe a novel technique for the insertion of new polytetrafluoroethylene graft segments designed to reduce this morbidity rate. Patients found to have significant intragraft deterioration at thrombectomy undergo insertion of a new nonanastamosed graft parallel to the existing graft. At the next failure of the existing graft, the nonanastamosed segment is anastamosed and used immediately for dialysis, obviating the need for a temporary catheter. Thirty patients have undergone this technique, and 89% of those who returned to surgery have had successful anastamosis of their new segments. Two patients were found to have inadequate incorporation of their new segments into the subcutaneous tissue, and one became frankly infected.


Background echotexture classification in breast ultrasound: inter-observer agreement study.
Background According to the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS), background echotexture in breast ultrasound (US) can be categorized as homogeneous or heterogeneous. Purpose To prospectively evaluate the inter-observer agreement of a four-category classification in background echotexture assessments of breast US and to determine whether background echotexture is related to breast cancer risk factors, including mammography density. Material and Methods Thirty-eight healthy women (age range, 25-72) were recruited. Eleven radiologists performed breast US on all participants and classified each background echotexture into four categories (homogeneous, mild, moderate, and marked heterogeneous). The inter-observer agreement in the assessments was measured using kappa statistics (к). The association between background echotexture and breast cancer risk factors, including mammographic density, menopausal status, and parity, were evaluated using Spearman's correlation coefficient (ρ) and multiple linear regression analysis. Results There was moderate inter-observer agreement between the radiologists for the four categories of background echotexture (average к = 0.45). Heterogeneity of the background echotexture was positively correlated with mammographic density in both pre- and postmenopausal women (premenopausal, ρ = 0.42, P < 0.0001; postmenopausal, ρ = 0.56, P < 0.0001). Multiple linear regression analysis revealed that mammographic density and parity were significantly associated with background echotexture. Conclusion Background echotexture assessment of breast US using a four-category classification showed moderate inter-observer agreement, and more heterogeneous background echotexture was associated with denser breasts and lower parity.


Genome-Edited Coincidence and PMP22-HiBiT Fusion Reporter Cell Lines Enable an Artifact-Suppressive Quantitative High-Throughput Screening Strategy for PMP22 Gene-Dosage Disorder Drug Discovery.
Charcot-Marie-Tooth 1A (CMT1A) is the most common form of hereditary peripheral neuropathies, characterized by genetic duplication of the critical myelin gene Peripheral Myelin Protein 22 (PMP22). PMP22 overexpression results in abnormal Schwann cell differentiation, leading to axonal loss and muscle wasting. Since regulation of PMP22 expression is a major target of therapeutic discovery for CMT1A, we sought to establish unbiased approaches that allow the identification of therapeutic agents for this disease. Using genome editing, we generated a coincidence reporter assay that accurately monitors Pmp22 transcript levels in the S16 rat Schwann cell line, while reducing reporter-based false positives. A quantitative high-throughput screen (qHTS) of 42 577 compounds using this assay revealed diverse novel chemical classes that reduce endogenous Pmp22 transcript levels. Moreover, some of these classes show pharmacological specificity in reducing Pmp22 over another major myelin-associated gene, Mpz (Myelin protein zero). Finally, to investigate whether compound-mediated reduction of Pmp22 transcripts translates to reduced PMP22 protein levels, we edited the S16 genome to generate a reporter assay that expresses a PMP22-HiBiT fusion protein using CRISPR/Cas9. Overall, we present a screening platform that combines genome edited cell lines encoding reporters that monitor transcriptional and post-translational regulation of PMP22 with titration-based screening (e.g., qHTS), which could be efficiently incorporated into drug discovery campaigns for CMT1A.


Prostate Age Gap: An MRI Surrogate Marker of Aging for Prostate Cancer Detection.
Aging is the most important risk factor for prostate cancer (PC). Imaging techniques can be useful to measure age-related changes associated with the transition to diverse pathological states. However, biomarkers of aging from prostate magnetic resonance imaging (MRI) remain to be explored. To develop an aging biomarker from prostate MRI and to examine its relationship with clinically significant PC (csPC, Gleason score ≥7) risk occurrence. Retrospective. Four hundred and sixty-eight (65.97 ± 6.91 years) biopsied males, contributing 7243 prostate MRI slices. A deep learning (DL) model was trained on 3223 MRI slices from 81 low-grade PC (Gleason score ≤6) and 131 negative patients, defined as non-csPC. The model was tested on 90 negative, 52 low-grade (142 non-csPC), and 114 csPC patients. 3-T, axial T2-weighted spin sequence. Chronological age was defined as the age of the participant at the time of the visit. Prostate-specific antigen (PSA), prostate volume, Gleason, and Prostate Imaging-Reporting and Data System (PI-RADS) scores were also obtained. Manually annotated prostate masks were used to crop the MRI slices, and a DL model was trained with those from non-csPC patients to estimate the age of the patients. Following, we obtained the prostate age gap (PAG) on previously unseen csPC and non-csPC cropped MRI exams. PAG was defined as the estimated model age minus the patient's age. Finally, the relationship between PAG and csPC risk occurrence was assessed through an adjusted multivariate logistic regression by PSA levels, age, prostate volume, and PI-RADS ≥ 3 score. T-test, Mann-Whitney U test, permutation test, receiver operating characteristics (ROC), area under the curve (AUC), and odds ratio (OR). A P value <0.05 was considered statistically significant. After adjusting, there was a significant difference in the odds of csPC (OR = 3.78, 95% confidence interval [CI]: 2.32-6.16). Further, PAG showed a significantly larger bootstrapped AUC to discriminate between csPC and non-csPC than that of adjusted PI-RADS ≥ 3 (AUC = 0.981, 95% CI: 0.975-0.987). PAG may be associated with the risk of csPC and could outperform other PC risk factors. 3 TECHNICAL EFFICACY: Stage 3.


A Protective Association between SNAP Participation and Educational Outcomes Among Children of Economically Strained Households.
With the recent cuts to the Supplemental Nutrition Assistance Program (SNAP), more information is needed to assess the impact these policies have on vulnerable children. As such, this study assesses the potential moderating effect of SNAP participation on the association between material deprivation and educational outcomes among children living in poverty (n = 10 971, and n = 14 928). SNAP participation was found to moderate the association between material deprivation and grade retention, indicating that SNAP may be contributing to grade retention among children living in poverty, which can have positive lifelong consequences.


Alteration of the Nonsystemic Behavior of the Pesticide Ferbam on Tea Leaves by Engineered Gold Nanoparticles.
A model system consisting of a nonsystemic pesticide (ferbam), engineered gold nanoparticles (AuNPs) and a plant tissue (tea leaves) was investigated using surface enhanced Raman spectroscopy (SERS). Ferbam has no ability by itself to penetrate into tea leaves. When AuNPs were placed with ferbam onto the surface of tea leaves, however, the SERS signal of the ferbam-AuNPs complex was observed inside of the tea leaves. Within 1 h, the ferbam-AuNPs complex rapidly penetrated into the leaf to a depth of approximately 190 μm, about (1)/3 to (1)/2 of the leaf's thickness. The rate of penetration was dependent on the size of AuNPs, with 30 nm AuNPs-ferbam penetrating more rapidly when compared with complexes made with the 50 and 69 nm AuNPs. These results clearly demonstrated an alteration of the nonsystemic behavior of ferbam in the combined presence with AuNPs. This finding might lead to the development of some new pesticide formulations. Conversely, new toxicity issues may arise as the behaviors and fate of pesticides are altered significantly upon interaction with engineered NPs in the pesticide formulation or environment.


Ultrasound application for the control of decay on apple at different stage of ripening.
Ultrasonic technology is known for many years and is used for several purposes such as sonochemistry, extraction of natural compounds, degassing of solvent, inactivation of enzymes and microorganism. In postharvest ultrasound is applied in not destructive analysis of crop for the determination of the maturation stage. Until now, however, the potential of the sonication as a physical mean for not conventional postharvest treatment of fresh fruit has been little investigated. Here we report on the results obtained with apple fruit (Malus domestica Borkh. cv San Giovanni, from Sardinian germplasm) dipped in a solution of potassium sorbate with or without sonication. Treatment was carried out with an ultrasonic processor (1500 W, 20Khz) connected to a 25 mm phi probe immersed in 10 L of deionized water placed in a steel vessel. Fruit at different ripening stages, inoculated or not inoculated with Penicillium expansum, was sonicated before or after the inoculation. Following the treatment, fruit was left to dry, put into boxes and cold-stored. Results showed that ultrasound alone enhanced the natural resistance of ripe fruit when inoculated after sonication. No effect was observed when the ultrasound application was carried out after inoculation with P. expansum on un-ripe or ripe apples. Potassium sorbate showed to be ineffective in controlling the decay regardless of the ripening stage and the time of inoculation. On the contrary, a significant enhance in decay control was observed when the application of potassium sorbate was performed in the presence of ultrasound.


Adapting the Rivermead Behavioural Memory Test for use with children aged 5 to 10 years.
We describe modifications made to the Rivermead Behavioural Memory Test (RBMT) to make it appropriate for use with children. Results of a sample of 335 children aged 5 to 10 years, attending mainstream schools, are reported. Each child was given two of the four versions of the modified test for children together with a number of tests of memory and achievement from the Wechsler Intelligence Test for Children (Revised WISC-R), and the British Ability Scales (BAS). The children's version of the behavioural memory test (RBMTC) has good interrater and parallel from reliability. The validity of the RBMTC was established in two ways. First, with other tests of memory from the WISC and BAS. Second, a small (n = 36) group of children with severe epilepsy and memory difficulties, attending a residential school, were tested. The houseparents of these children were asked to complete rating scales on everyday memory performance. There was significant agreement between houseparents' observations and scores on the RBMTC (Spearman rank correlation = .71, p < .001), indicating that the test is indeed assessing everyday memory.


A reinterpretation of transparency perception in terms of gamut relativity.
Classical approaches to transparency perception assume that transparency constitutes a perceptual dimension corresponding to the physical dimension of transmittance. Here I present an alternative theory, termed gamut relativity, that naturally explains key aspects of transparency perception. Rather than being computed as values along a perceptual dimension corresponding to transmittance, gamut relativity postulates that transparency is built directly into the fabric of the visual system's representation of surface color. The theory, originally developed to explain properties of brightness and lightness perception, proposes how the relativity of the achromatic color gamut in a perceptual blackness-whiteness space underlies the representation of foreground and background surface layers. Whereas brightness and lightness perception were previously reanalyzed in terms of the relativity of the achromatic color gamut with respect to illumination level, transparency perception is here reinterpreted in terms of relativity with respect to physical transmittance. The relativity of the achromatic color gamut thus emerges as a fundamental computational principle underlying surface perception. A duality theorem relates the definition of transparency provided in gamut relativity with the classical definition underlying the physical blending models of computer graphics.


Unique solutions in pediatric critical care.
This pediatric intensive care unit (PICU) functions as a part of a multidisciplinary adult ICU and has evolved into a unique health care setting. The Special Care Unit (SCU), which is the name for our ICU, serves a population of adult and pediatric patients, including trauma, open-heart surgery, medicine, surgery, and neurosurgery. All staff are expected to provide care for adults and children without regard to admitting diagnosis. In addition to meeting the critical care needs of this diverse pediatric population in the SCU, we provide a pediatric critical care ground transport program for critically ill children from outlying hospitals. Competency-based orientation tools were developed and are used to guide the orientation process. The tools identify the required knowledge base necessary for a staff member to adequately care for the adult and pediatric populations and track each staff member's progress through orientation. The model used to deliver care to adults and children in this setting is innovative. This model represents one solution to providing critical care to both the adult and pediatric population in today's era of health care redesign.


Cytotoxic activity against breast cancer cells of two species of marine sponges from shallows of Yucatan peninsula.
This study aimed to evaluate the in vitro activity of extracts of two marine sponge species, occurring in the shallows of the Yucatan peninsula coast, on two cancer and one normal mammalian cell lines. Hexane, dichloromethane, ethyl acetate and methanol extracts of Halichondria magniconulosa and Halichondria melanadocia were screened for their cytotoxic activity against hormone-dependent breast cancer (MCF-7) and human cervix cancer (SiHa) cell lines. The ethyl acetate extract of H. magniconulosa exhibited significant cytotoxicity against MCF-7 cells to a CC50 of 0.8 µg/mL, as well as high selectivity (SI = 24.5). On the other hand, SiHa cells were moderately sensitive to the dichloromethane and ethyl acetate extracts of the same species. (CC50 = 34.9 and 31.5 µg/mL, respectively). None of the extracts of H. melanadocia were considered active due their CC50's were ranged from 59.0 to 94.5 µg/mL.


Celiac Crisis: an unusual presentation of gluten-sensitive enteropathy.
Celiac disease (CD)-also known as gluten-sensitive enteropathy-is a chronic, genetically predisposing and autoimmune entity with a wide range of clinical manifestations triggered by gluten ingestion, which affects 1% of the general population. Currently, up to 60% of the diagnosis of CD is in adults due to the atypical course of the disease. The severe acute onset of CD-also called celiac crisis-is very uncommon and is still not well documented in adults. We report the case of a 58-year-old man who presented a 45-day history of subtle-onset diarrhea followed by malabsorption syndrome with progressive weight loss, anasarca, and electrolyte disturbances. The diagnostic work-up included an upper digestive endoscopy, which showed scalloping of the duodenal mucosa with pathological features confirmed on biopsies. Specific antibodies were positive, and a satisfactory clinical response was obtained once a gluten-free diet was started. Celiac crisis is a rare initial presentation of CD characterized by severe diarrhea, dehydration, weight loss, hypoproteinemia, and metabolic and electrolyte disturbances. Although rare, it should be considered in patients with apparently unexplained chronic diarrhea.


[Refusal of psychiatric de-hospitalization: a qualitative study].
This study is justified based on the large number of individuals currently institutionalized in psychiatric hospitals in Brazil, despite the current proposal for de-hospitalization. The study focused on factors involved in the refusal of de-hospitalization, based on reports by patients in a psychiatric hospital with a diagnosis of schizophrenia and preserved verbal capacity. Based on a random selection, six patients answered a semi-structured interview. The interviews were later submitted to thematic content analysis. After reading the transcriptions, the following key thematic contents were extracted: a feeling of freedom even while hospitalized, the material and subjective protection provided by the hospital, and the way institutionalized hospital life is incorporated by patients. The findings can contribute to the drafting of public policies in mental health and to the understanding of this population's subjective dynamics.


Plant Toxin-Based Immunotoxins for Cancer Therapy: A Short Overview.
Immunotoxins are chimeric proteins obtained by linking a toxin to either an intact antibody or an antibody fragment. Conjugation can be obtained by chemical or genetic engineering, where the latter yields recombinant conjugates. An essential requirement is that the target molecule recognized by the antibody is confined to the cell population to be deleted, or at least that it is not present on stem cells or other cell types essential for the organism's survival. Hundreds of different studies have demonstrated the potential for applying immunotoxins to many models in pre-clinical studies and in clinical trials. Immunotoxins can be theoretically used to eliminate any unwanted cell responsible for a pathological condition. The best results have been obtained in cancer therapy, especially in hematological malignancies. Among plant toxins, the most frequently employed to generate immunotoxins are ribosome-inactivating proteins, the most common being ricin. This review summarizes the various approaches and results obtained in the last four decades by researchers in the field of plant toxin-based immunotoxins for cancer therapy.


Sensitivity and specificity of first screen mammography in 15 NBSS centres.
We report the sensitivity and specificity of first screen mammography in a 15-centre randomized screening trial. Of 44,718 women who received mammography and physical examination at first screening, 238 were diagnosed with breast cancer at first screen, 34 in the 12-month interval after the first screen, and 98 at the second screen. Seventeen of the interval cases and 47 of the second-year cancers were defined as potentially detectable at first screening. Interpretations of first screen mammograms by radiologists at the screening centres were matched to known histological outcomes. Simultaneous blind review of 2908 cases, which included all cancers detected at first and second screenings as well as interval cancers, was done by a single reference radiologist. The sensitivity of the technique as carried out at all NBSS centres was 0.75, the specificity 0.94, the positive predictive value 0.07, and the negative predictive value 0.998.


Paediatric cardiac rapid response systems: a survey of multicentre practices.
While the efficacy and guidelines for implementation of rapid response systems are well established, limited information exists about rapid response paradigms for paediatric cardiac patients despite their unique pathophysiology. With endorsement from the Paediatric Cardiac Intensive Care Society, we designed and implemented a web-based survey of paediatric cardiac and multidisciplinary ICU medical directors in the United States of America and Canada to better understand paediatric cardiac rapid response practices. Sixty-five (52%) of 125 centres responded. Seventy-one per cent of centres had ∼300 non-ICU beds and 71% had dedicated cardiac ICUs. To respond to cardiac patients, dedicated cardiac rapid response teams were utilised in 29% of all centres (39% and 5% in centres with and without dedicated cardiac ICUs, respectively) [p = 0.006]. Early warning scores were utilised in 62% of centres. Only 31% reported that rapid response teams received specialised training. Transfers to ICU were higher for cardiac (73%) compared to generalised rapid response events (54%). The monitoring and reassessment of patients not transferred to ICU after the rapid response was variable. Cardiac and respiratory arrests outside the ICU were infrequent. Only 29% of centres formally appraise critical deterioration events (need for ventilation and/or inotropes post-rapid response) and 34% perform post-event debriefs. Paediatric cardiac rapid response practices are variable and dedicated paediatric cardiac rapid response systems are infrequent in the United States of America and Canada. Opportunity exists to delineate best practices for paediatric cardiac rapid response and standardise practices for activation, training, patient monitoring post-rapid response events, and outcomes evaluation.


Czech dysplasia metatarsal type.
We report three further patients of the recently described new bone dysplasia-dominantly inherited pseudorheumatoid arthritis. The patients of this report have a similar clinical history, the same distinctive phenotype and almost identical radiographic findings. The only major difference is absence of weather dependent articular pain which characterized the family of the previous study. This report expands the clinical data of this bone dysplasia. All patients are Caucasians and originate from different parts of the Czech Republic. It seems that this disorder is quite a common constitutional bone disorder in this country. We propose the name of Czech Dysplasia Metatarsal Type for this unique disease.


EVOLUTION OF HAPLODIPLOIDY IN DERMANYSSINE MITES (ACARI: MESOSTIGMATA).
Haplodiploidy, a widespread phenomenon in which males are haploid and females are diploid, can be caused by a number of different underlying genetic systems. In the most common of these, arrhenotoky, males arise from unfertilized eggs, whereas females arise from fertilized eggs. In another system, pseudoarrhenotoky, males arise from fertilized eggs, but they eliminate the paternal genome at some point prior to spermatogenesis, with the consequence that they do not pass this genome to their offspring. In 1931 Schrader and Hughes-Schrader suggested that arrhenotoky arises through a series of stages involving pseudoarrhenotokous systems such as those found in many scale insects (Homoptera: Coccoidea), however, their hypothesis has been largely ignored. We have used a phylogenetic analysis of 751 base pairs of 28S rDNA from a group of mites (Mesostigmata: Dermanyssina) that contains arrhenotokous, pseudoarrhenotokous, and ancestrally diplodiploid members to test this hypothesis. Neighbor-joining, maximum-parsimony, and maximum-likelihood methods all indicate that the arrhenotokous members of this group form a clade that arose from a pseudoarrhenotokous ancestor, rather than directly from a diplodiploid one. This provides unequivocal support for the hypothesis of Schrader and Hughes-Schrader. The wider implications of this result for the evolution of uniparental genetic systems are discussed.


Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma.
Clinical studies have suggested that bisphosphonates may prolong the survival of sub-sets of myeloma patients. Newer nitrogen containing bisphosphonates such as zoledronate act, at least in part, by inhibiting farnesyl diphosphate synthase and subsequent protein prenylation, furthermore, limited data suggests that zoledronate exerts a direct anti-tumour effect against human myeloma cell lines. We therefore investigated the anti-myeloma potential of zoledronate in comparison to, and in combination with, two other inhibitors of the mevalonate pathway: the HMGCoA reductase inhibitor fluvastatin and the farnesyl transferase inhibitor SCH66336. We found that fluvastatin was able to inhibit the proliferation of myeloma cells more effectively than zoledronate or SCH66336 and that combinations of zoledronate and fluvastatin, but not zoledronate and SCH66336 acted synergistically. Our data indicated that the anti-proliferative effect of mevalonate pathway inhibitors is mediated principally via prevention of geranylgeranylation and is the result of both cell cycle arrest and apoptosis induction. Microarray and quantitative real-time PCR analyses further demonstrated that genes related to apoptosis, cell cycle control, and the mevalonate pathway were particularly affected by zoledronate and fluvastatin, and that some of these genetic effects were synergistic. We conclude that the mechanisms of geranylgeranylation inhibition mediated anti-myeloma effects warrant further evaluation and may provide novel targets for future therapeutic development.


Dynamics and stability: epigenetic conversions in position effect variegation.
Position effect variegation (PEV) refers to quasi-stable patterns of gene expression that are observed at specific loci throughout the genomes of eukaryotes. The genes subjected to PEV can be completely silenced or fully active. Stochastic conversions between these 2 states are responsible for the variegated phenotypes. Positional variegation is used by human pathogens (Trypanosoma, Plasmodium, and Candida) to evade the immune system or adapt to the host environment. In the yeasts Saccharomyces cerevisiae and Saccharomyces pombe, telomeric PEV aids the adaptation to a changing environment. In metazoans, similar epigenetic conversions are likely to accompany cell differentiation and the setting of tissue-specific gene expression programs. Surprisingly, we know very little about the mechanisms of epigenetic conversions. In this article, earlier models on the nature of PEV are revisited and recent advances on the dynamic nature of chromatin are reviewed. The normal dynamic histone turnover during transcription and DNA replication and its perturbation at transcription and replication pause sites are discussed. It is proposed that such perturbations play key roles in epigenetic conversions and in PEV.


Radiolabeling of methanol extracts of yarrow (Achillea millefolium l) in rats.
Current study is focused on extraction with methanol, purification, labeling with (131)I using iodogen method of the yarrow plant and investigating in vivo biological activity using biodistribution and imaging studies on healthy animal models. The aim of the study is to contribute plant extracts to discover new drugs in the diagnosis and treatment of several diseases. Nine female and nine male healthy Wistar albino rats, which were approximately 100-150 g in weight, were used for biodistribution studies. For imaging studies four healthy male Balb-C mice were used. Quality control studies were done utilizing thin layer radio chromatography (TLRC) and high performance liquid chromatography (HPLC) methods. For biodistribution studies, (131)I radiolabeled Peak 7 ((131)I-Peak 7) was sterilized and injected into the tail veil of rats and imaging studies were obtained using Kodak FX PRO in vivo Imaging System. The radiolabeling yield of each purified the bioactive extracts of the yarrow plant, seven peaks was between 79 and 92%. The highest radiolabeling yield was calculated for (131)I radiolabeled seventh peak ((131)I-Peak 7) (92.78 ± 5.04, n=5). For this reason the biodistribution and imaging studies were done for (131)I-Peak 7. That's why; these studies with Peak 7 were carried out. Peak 7 was radiolabeled with (131)I in high yield for using imaging and therapeutic studies in nuclear medical applications.


Optimal Blood Pressure Thresholds for Minimal Coronary Artery Disease Risk in Type 1 Diabetes.
We aimed to determine optimal blood pressure (BP) thresholds for minimizing coronary artery disease (CAD) risk in people with childhood-onset type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study participants without known CAD at baseline (n = 605) were included and followed for 25 years. The associations of time-weighted BP measures (systolic BP [SBP], diastolic BP [DBP], and mean arterial pressure) with incident CAD were examined by using Cox models. Areas under the receiver operating characteristic curve (AUC) were summarized by different cut points of time-weighted BPs. Risk stratification analyses were then performed on the basis of BP (<120/80 vs. ≥120/80 mmHg) and HbA1c (<8% vs. ≥8%). Baseline mean age was 27 years. Half of the cohort were women and 98% were white. A dose-gradient association was observed for categorized time-weighted BPs and CAD. According to AUC, the optimal cut point for SBP was 120 mmHg and for DBP was 80 mmHg. BP ≥120/80 mmHg was associated with a 1.9 times (95% CI 1.4, 2.6) greater risk of developing CAD than that for BP <120/80 mmHg. Participants with good control of both BP and HbA1c had BP <120/80 mmHg and HbA1c <8%. Those with only high BP (hazard ratio [HR] 2.0 [95% CI 1.1, 3.9]) carried a similar risk of developing CAD as those with only high HbA1c (HR 1.6 [95% CI 0.97, 2.8]). The optimal BP threshold associated with minimal CAD risk is 120/80 mmHg in young adults with childhood-onset type 1 diabetes.


Rumen succinate production may ameliorate the effects of cobalt-vitamin B-12 deficiency on methylmalonyl CoA mutase in sheep.
When lambs were fed a cobalt-deficient whole barley diet there was a rapid and massive increase in rumen succinate concentrations. Within 2 d of feeding the Co-deficient diet, the rumen succinate concentrations rose 200-fold and peaked at a level 1000-fold higher than that in Co-sufficient controls. Rumen propionate concentrations decreased, suggesting that an alteration in the balance between succinate- and propionate-producing microorganisms had occurred. The rumen succinate can be absorbed and thus may lead to elevated plasma succinate concentrations in Co-deficient animals, whether fed barley or grass. Thus, the absorbed succinate can at least partially overcome the effect on gluconeogenesis of a decreased activity of methylmalonyl CoA mutase induced by Co-deficiency. These findings suggest that impaired propionate metabolism may not be the primary metabolic defect in ovine Co-deficiency.


A 16-year retrospective study of dacryocystitis in adult patients in the Moldavia Region, Romania.
Chronic dacryocystitis (CD) is an inflammation of the lacrimal sac and nasolacrimal duct with a long-standing evolution. The aims of this study were to analyze the epidemiology and to evaluate the histopathological features and the chronic inflammation score (CIS) system of chronic dacryocystitis in the region of Moldavia, Romania, over a period of 16 years. We conducted a retrospective descriptive analysis of all pathological reports of chronic dacryocystitis from the Department of Pathology, "Prof. Dr. Nicolae Oblu" Emergency Clinical Hospital, Iasi, Romania, between January 1, 1999 and December 31, 2015, with the final application of CIS. We also recorded the demographic information of patients and lesion localizations. Eighteen cases of CD were identified, with a female:male ratio of 8:1. Patient median age was 66.27 years (range 33-83 years), 55.55% being in their eighth and ninth decade of life. A non-systemized growth trend starting with 2002 could be identified. Microscopically, several histopathological features were identified, some of them being associated: epithelial lining hyperplasia with pseudopapillary folds (77.77% of the cases), epithelial invaginations in the submucosa (11.11%), squamous metaplasia (16.66%) or partial denudation (33.33%). The sac wall revealed chronic diffusion (88.88%) or nodular lymphocytic inflammation (11.11%). 5.55% of cases presented fibrosis in the lacrimal sac wall with few lymphocytes. Applying CIS system, the majority of cases (13 patients, 72.22%) were identified with moderate chronic inflammation, only one case (5.55%) pointed out a mild degree of inflammation with a CIS<3, but four (22.22%) cases showed severe inflammatory changes with a CIS>6. In our region, CD is more frequent in senior women, probably due to their deficient immune system. Histological specimens of CD are not commonly found in practice of pathologists, but when the histological sections are analyzed they reflect a multitude of aspects that need to be known in order to guide ophthalmologists in their practice. In our region, CD is more frequent in senior women, probably due to their deficient immune system and to the specific anatomy of their nasolacrimal duct. The histological appearances varied from patient to patient and even in the same patient varied from one area to another. There were histopathological changes indicating adaptive changes, which could lead to the development of malignant tumors at this level. Therefore, there is a need for patient education with CD both in terms of ophthalmic hygiene and in what regards possible complications in the absence of a regular presentation to the ophthalmologist.


Double-blind trial RU 41740 vs. placebo: immunological and clinical effects in a group of patients with chronic bronchitis.
A double-blind trail was performed to investigate the effects of RU 41740, a glycoprotein extract from Klebsiella pneumoniae, on host defenses and its efficacy in reducing the number of exacerbation in 29 evaluable patients with chronic bronchitis, out of 36 patients who entered the study. The drug enhanced the phagocytosis indexes of both polymorphonuclear and mononuclear phagocytes. Increased candidacidal activity of monocytes was also observed. These effects, already detectable after one course of therapy and during the entire period of treatment, were no longer detectable when tested 6 months after the end of treatment. A significantly (p less than 0.05) larger number of patients in the treated group than in the placebo group had no exacerbations during drug administration (0-3 months). Moreover, patients treated with RU 41740 had significantly fewer and shorter episodes of acute exacerbation. The positive decreases in these two parameters persisted throughout the follow-up.


[Development of Takotsubo Cardiomyopathy during Recovery from General Anesthesia: A Case Report].
Takotsubo cardiomyopathy is a cardiac syndrome characterized by transient left ventricular dysfunction. A 61-year-old woman underwent laparoscopic cholecystectomy under general anesthesia. During recovery from general anesthesia, several arrhythmias occurred without cardiac collapse following desflurane discontinuation and sugammadex sodium administration. She had a chest pain after extubation, with ST segment elevation in leads aV(L) and V2-4. Emergency left ventricular angiogram revealed no significant coronary stenosis, and excessive contraction of the base and severe hypokinesis of the apex suggested Takotsubo cardiomyopathy. Sympathetic hyperactivity during acute recovery from anesthesia with desflurane discontinuation and muscle relaxant reversal with sugammadex sodium was considered the likely cause of Takotsubo cardiomyopathy.


Using Activity Monitors to Measure Sit-to-Stand Transitions in Overweight/Obese Youth.
Reducing sedentary behavior has emerged as an important health intervention strategy. Although hip-worn, and more recently wrist-worn, accelerometers are commonly used for measuring physical activity and sedentary behavior, they may not provide accurate measures of postural changes. The current study examined the validity of commonly used hip- and wrist-worn accelerometer cut points and the thigh-worn activPAL activity monitor for measuring sit-to-stand transitions as compared with direct observation in youth with overweight and obesity. Nine children wore three activity monitors while being directly observed. The monitors included a hip- and wrist-worn ActiGraph and thigh-worn activPAL. The hip-worn ActiGraph was processed with the normal- and low-frequency filters and the inclinometer function. Cut points of ≤25 counts per 15-s epoch for the hip and ≤105 counts per 15-s epoch for the wrist were applied to the vertical axis to identify sit-to-stand transitions. Epoch-level absolute agreement, Bland-Altman plots, mixed-effects linear regression, and intraclass correlation coefficients (ICC) were investigated. The hip and wrist accelerometer cut points and the hip inclinometer function overestimated the number of hourly sit-to-stand transitions by approximately triple as compared with direct observation. ICC values between the ActiGraph methods and the direct observation were all <0.12. Sit-to-stand transitions assessed from activPAL were within 17% of direct observation; ICC was 0.26. Despite the common use of the 100-count hip-worn accelerometer cut point for assessing sedentary time, these processing decisions should be used with caution for assessing sit-to-stand transitions. Future research should investigate other processing methods for ActiGraph data, and studies investigating postural changes should consider including devices such as activPAL.


Epidemiology of basal and squamous cell carcinoma in Belgium: the need for a uniform and compulsory registration.
Non-melanoma skin cancer (NMSC) is the most common type of cancer among Caucasians, however, few data exist on its incidence. Because of a sheer volume of these tumours, NMSC is often not systematically registered. To describe and analyse the incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in Belgium. Incidence data of BCC and SCC, including multiple primary skin tumours in the same patient, were extracted from the Belgian Cancer Registry from 2004 to 2012 (predominantly coming from pathology notifications). Belgian legislation makes cancer registration compulsory for oncological care programmes and for all pathological anatomy laboratories. Between 2004 and 2012, 113 254 BCC and 33 153 SCC cases were reported in Belgium. A total of 130 339 patients had 146 407 tumours. Approximately, 10% of the patients (12 759 patients) had multiple tumours. The world age-standardised incidence rate (WSR) for BCC increased from 36.9 in 2004 to 98.4 per 100 000 person years in 2012 for males and from 34.2 in 2004 to 102.0 in 2012 for females. For SCC, the WSR increased from 14.9 in 2004 to 24.7 in 2012 for males and from 6.8 in 2004 to 13.5 in 2012 for females. From 2004 to 2012, the incidence of BCC and SCC markedly rose in Belgium, as also seen worldwide. Known causes are increased sun exposure caused by changed sunlight-related behaviour (increased outdoor activities and holidays, use of tanning beds and changes in clothing style), ageing and improved registration. Because of their high and increasing incidence, these cancers will have major implications on healthcare planning and preventive measures. Therefore, we recommend compulsory registration, whenever is possible, of BCC and SCC, although it is an ambitious objective, especially in countries with a high burden of these tumours and in countries where registration is currently unavailable.


Intensity of Nematode Infection in Children Aged 3 to 5 Years Living in Mukuru Kwa Njenga Slum Settlement, Nairobi, Kenya.
The burden of nematode infections is high mostly in children below 5 years old, with clinical manifestations ranging from mild to painful symptoms due to severe infections that end up suppressing the immune system of the infected children. The occurrence of these infections is highest in areas of extreme poverty. This study evaluated the intensity of nematode infections and assessed the status of deworming in children aged 3 to 5 years living in Mukuru slum settlement, Nairobi County, Kenya. Methodology. A total of 172 children aged between 3 and 5 years were sampled across the 5 major villages of Mukuru Slum settlement: Kwa Njenga, Vietnum, Wapewape, Kwa Reuben, and Motomoto. Community health workers administered questionnaires on the deworming history of children. Stool samples were collected, macroscopically examined, and microscopically analysed using Kato-Katz technique to assess the intensity of infection. The intensities of nematode infections were expressed as eggs per gram (epg) of faeces. The point prevalence of nematode infection among the 98 children in the 1st sampling was 25.5% with a mean infection intensity of 5424 epg, whereas among the 74 children sampled in 2nd sampling, 47.3% had nematode infection with a mean infection intensity of 12384 epg. The average nematode infection for the 172 participants was 34.9% with a mean intensity of 17808 epg. The highest number of children infected with nematodes was in the village of Wapewape where 34 participants were examined and 36.3% were infected with a mean intensity of 3216 epg. Kwa Reuben and Vietnum villages had the same prevalence values of 32.4% where 34 participants in each village had a mean intensity of 3624 epg and 4512 epg, respectively. In both samplings, more than 80% of children had been dewormed more than 6 months prior to the study. Ascaris lumbricoides was the only species of intestinal nematodes identified to be present in the stool samples of children in this study, whereas Trichuris trichiura and hookworm infections were found to be absent. The intensity of infection was not dependent on age or gender.


One perturbation of the mother cell gene regulatory network suppresses the effects of another during sporulation of Bacillus subtilis.
In the mother cell of sporulating Bacillus subtilis, a regulatory network functions to control gene expression. Four transcription factors act sequentially in the order sigma(E), SpoIIID, sigma(K), GerE. sigma(E) and sigma(K) direct RNA polymerase to transcribe different regulons. SpoIIID and GerE are DNA-binding proteins that activate or repress transcription of many genes. Several negative regulatory loops add complexity to the network. First, transcriptionally active sigma(K) RNA polymerase inhibits early sporulation gene expression, resulting in reduced accumulation of sigma(E) and SpoIIID late during sporulation. Second, GerE represses sigK transcription, reducing sigma(K) accumulation about twofold. Third, SpoIIID represses cotC, which encodes a spore coat protein, delaying its transcription by sigma(K) RNA polymerase. Partially circumventing the first feedback loop, by engineering cells to maintain the SpoIIID level late during sporulation, causes spore defects. Here, the effects of circumventing the second feedback loop, by mutating the GerE binding sites in the sigK promoter region, are reported. Accumulation of pro-sigma(K) and sigma(K) was increased, but no spore defects were detected. Expression of sigma(K)-dependent reporter fusions was altered, increasing the expression of gerE-lacZ and cotC-lacZ and decreasing the expression of cotD-lacZ. Because these effects on gene expression were opposite those observed when the SpoIIID level was maintained late during sporulation, cells were engineered to both maintain the SpoIIID level and have elevated sigK expression late during sporulation. This restored the expression of sigma(K)-dependent reporters to wild-type levels, and no spore defects were observed. Hence, circumventing the second feedback loop suppressed the effects of perturbing the first feedback loop. By feeding information back into the network, these two loops appear to optimize target gene expression and increase network robustness. Circumventing the third regulatory loop, by engineering cells to express cotC about 2 h earlier than normal, did not cause a detectable spore defect.


Sensitive Detection of RNase A Activity and Collaborative Drug Screening Based on rGO and Fluorescence Probe.
In addition to being an important object in theoretical and experimental studies in enzymology, RNase A also plays an important role in the development of many kinds of diseases by regulating various physiological or pathological processes, including cell growth, proliferation, differentiation, and invasion. Thus, it can be used as a useful biomarker for disease theranostics. Here, a simple, sensitive, and low-cost assay for RNase A was constructed by combining a fluorogenic substrate with reduced graphene oxide (rGO). The method with detection limit of 0.05 ng/mL was first applied for RNase A targeted drug screening, and 14 natural compounds were identified as activators of this enzyme. Then, it was applied to detect the effect of drug treatment and Hepatitis B virus (HBV) infection on RNase A activity. The results indicated that RNase A level in tumor cells was upregulated by G-10 and Chikusetsusaponin V in a concentration-dependent manner, while the average level of RNase A in the HBV infection group was significantly inhibited compared with that in the control group. Furthermore, the concentration-dependent inhibitory effect of heavy metal ions on RNase A was observed using the method and the results indicated that Ba2+, Co2+, Pb2+, As3+, and Cu2+ inhibited RNase A activity with IC50 values of 93.7 μM (Ba2+), 90.9 μM (Co2+), 110.6 μM (Pb2+), 171.5 μM (As3+), and 165.1 μM (Cu2+), respectively. In summary, considering the benefits of rapidity and high sensitivity, the method is practicable for RNase A assay in biosamples and natural compounds screening in vitro and in vivo.


The Missing Piece in Biosynthesis of Amphidinols: First Evidence of Glycolate as a Starter Unit in New Polyketides from Amphidinium carterae.
Two new members of the amphidinol family, amphidinol A (1) and its 7-sulfate derivative amphidinol B (2), were isolated from a strain of Amphidinium carterae of Lake Fusaro, near Naples (Italy), and chemically identified by spectroscopic and spectrometric methods. Amphidinol A showed antifungal activity against Candida albicans (MIC = 19 µg/mL). Biosynthetic experiments with stable isotope-labelled acetate allowed defining the elongation process in 1. For the first time the use of glycolate as a starter unit in the polyketide biosynthesis of amphidinol metabolites was unambiguously demonstrated.


Pathological conformations involving the amino terminus of tau occur early in Alzheimer's disease and are differentially detected by monoclonal antibodies.
Conformational changes involving the amino terminus of the tau protein are among the earliest alterations associated with tau pathology in Alzheimer's disease and other tauopathies. This region of tau contains a phosphatase-activating domain (PAD) that is aberrantly exposed in pathological forms of the protein, an event that is associated with disruptions in anterograde fast axonal transport. We utilized four antibodies that recognize the amino terminus of tau, TNT1, TNT2 (a novel antibody), Tau12, and Tau13, to further study this important region. Using scanning alanine mutations in recombinant tau proteins, we refined the epitopes of each antibody. We examined the antibodies' relative abilities to specifically label pathological tau in non-denaturing and denaturing assays to gain insight into some of the mechanistic details of PAD exposure. We then determined the pattern of tau pathology labeled by each antibody in human hippocampal sections at various disease stages in order to characterize PAD exposure in the context of disease progression. The characteristics of reactivity for the antibodies fell into two groups. TNT1 and TNT2 recognized epitopes within amino acids 7-12 and specifically identified recombinant tau aggregates and pathological tau from Alzheimer's disease brains in a conformation-dependent manner. These antibodies labeled early pre-tangle pathology from neurons in early Braak stages and colocalized with thiazine red, a marker of fibrillar pathology, in classic neurofibrillary tangles. However, late tangles were negative for TNT1 and TNT2 indicating a loss of the epitope in later stages of tangle evolution. In contrast, Tau12 and Tau13 both identified discontinuous epitopes in the amino terminus and were unable to differentiate between normal and pathological tau in biochemical and tissue immunohistological assays. Despite the close proximity of these epitopes, the antibodies demonstrated remarkably different abilities to identify pathological changes in tau indicating that detection of conformational alterations involving PAD exposure is not achieved by all N-terminal tau antibodies and that a relatively discrete region of the N-terminus (i.e., amino acids 7-12, the TNT1 and TNT2 epitope) is central to the differences between normal and pathological tau. The appearance of PAD in early tau pathology and its disappearance in late-stage tangles suggest that toxic forms of tau are associated with the earliest forms of tau deposits. Collectively, these findings demonstrate that the TNT antibodies are useful markers for early conformational display of PAD and provide information regarding conformational changes that have potential implications in the toxic mechanisms of tau pathology.


Platelet antibody: review of detection methods.
The driving force behind development of in vitro methods for platelet antibodies is identification of plasma factors causing platelet destruction. Early methods relied on measurement of platelet activation. Current methods are more specific and use a purified antibody against immunoglobulin or complement, which is usually labeled with 125I or tagged with an enzyme or fluorescein. Comparisons of quantitation of platelet-associated IgG show wide variability between different methods. The disparate results can be related both to differences in binding of secondary antibodies to immunoglobulin in solution compared to immunoglobulins attached to platelets and to the improper assumption that the binding ratio between the secondary detecting and primary antiplatelet antibody is one. Most assays can 1) identify neonatal isoimmune thrombocytopenia and posttransfusion purpura, 2) help to differentiate between immune and nonimmune thrombocytopenias, 3) help to sort out the offending drug when drug-induced thrombocytopenia is suspected, and 4) identify platelet alloantibodies and potential platelet donors via a cross match assay for refractory patients. However, the advantages of quantitative assays over qualitative methods with respect to predictions of patients clinical course and response to different treatments remain to be investigated.


Teamwork in microtubule motors.
Diverse cellular processes are driven by the collective force from multiple motor proteins. Disease-causing mutations cause aberrant function of motors, but the impact is observed at a cellular level and beyond, therefore necessitating an understanding of cell mechanics at the level of motor molecules. One way to do this is by measuring the force generated by ensembles of motors in vivo at single-motor resolution. This has been possible for microtubule motor teams that transport intracellular organelles, revealing unexpected differences between collective and single-molecule function. Here we review how the biophysical properties of single motors, and differences therein, may translate into collective motor function during organelle transport and perhaps in other processes outside transport.


Robust, Self-Healing, and Multistimuli-Responsive Supergelator for the Visual Recognition and Separation of Short-Chain Cycloalkanes and Alkanes.
In this study, we show that a novel kind of cholesterol-based gelator NPS containing pyridyl and naphthalimide units can visually discriminate cyclohexane/cyclopentane from hexane/pentane on the basis of distinct optical differences in the gel platform, which is not observed in solution. The effect of congeneric solvents on the gel properties, such as morphology, rheology, and stimuli-responsive properties, is also studied. Intriguingly, NPS can form self-supporting, self-healing, fluorescent, and highly visible transmittance gels in cyclohexane that can selectively and visually respond to picric acid. It is deduced that NPS adopted H-type aggregation mode in cyclohexane, and the gel exhibits a strong green emission, whereas, in hexane, J-type aggregates of NPS molecules are observed with yellow emission. Correlations between the gelation properties and Hansen solubility parameters indicate that the dispersion interactions are the main factor for the selective gelation of NPS toward short-chain alkanes. A comparison of Hansen solvent parameters indicated that a similar energetic weight of the hydrogen-bonding units is the major contribution for the strong and specific interaction between NPS and cyclohexane. Furthermore, we demonstrated that the NPS xerogel can selectively solidify cyclohexane in the single-phase liquid of solvent mixtures, exhibiting fast gelation, high separation efficiency (>92%), and easy recycling of gelator and liquids. To the best of our knowledge, herein, we report the first paradigm that molecular gel formation is developed to visually discriminate and separate organic analogues of solvents with similar polarity.


Use of negative pressure wound therapy with reticulated open cell foam for lower extremity trauma.
The use of negative pressure wound therapy with reticulated open cell foam (NPWT/ROCF) as delivered by V.A.C.(R) Therapy (KCI, San Antonio, TX) has been a valuable adjunct in the treatment of complex lower-extremity injuries. The use of NPWT/ROCF for lower extremity traumatic wounds is based on mechanical effects on the surrounding tissues, biological effects at the cellular level, and simplification of wound care for nursing personnel. For patients with compartment syndrome, risk of secondary infection and need for skin grafting to achieve soft-tissue coverage may theoretically be reduced. For traumatic wounds, dressing care may be simplified and healing encouraged. For surgical incisions, risk of secondary wound dehiscence and infection may be lowered.


Grapevine VpPR10.1 functions in resistance to Plasmopara viticola through triggering a cell death-like defence response by interacting with VpVDAC3.
As one of the most serious diseases in grape, downy mildew caused by Plasmopara viticola is a worldwide grape disease. Much effort has been focused on improving susceptible grapevine resistance, and wild resistant grapevine species are important for germplasm improvement of commercial cultivars. Using yeast two-hybrid screen followed by a series of immunoprecipitation experiments, we identified voltage-dependent anion channel 3 (VDAC3) protein from Vitis piasezkii 'Liuba-8' as an interacting partner of VpPR10.1 cloned from Vitis pseudoreticulata 'Baihe-35-1', which is an important germplasm for its resistance to a range of pathogens. Co-expression of VpPR10.1/VpVDAC3 induced cell death in Nicotiana benthamiana, which accompanied by ROS accumulation. VpPR10.1 transgenic grapevine line showed resistance to P. viticola. We conclude that the VpPR10.1/VpVDAC3 complex is responsible for cell death-mediated defence response to P. viticola in grapevine.


Animal models for human metapneumovirus (HMPV) infections.
Since its detection in 2001 the human Metapneumovirus (HMPV), a member of the Paramyxoviridae family, was observed to be a serious pathogen in human respiratory infections during childhood. Meanwhile, several animal models have been established to study the virus-host interactions and pathogenic effects. Mainly, small laboratory animals like mice and cotton rats have been used, although the usage of these two species for HMPV research is controversially discussed and contradictious results were obtained by different groups. Further trials with ferrets, hamsters and non human primates were performed revealing different success in their individual usage. In this review we present the different animal models, summarize their advantages and disadvantages, and discuss the controversial results from different studies.


Hyoid bone fractures.
Surgeons who manage patients with craniofacial trauma should be comfortable with evaluating and treating fractures throughout the head and neck. This includes the hyoid bone, which may cause significant airway concerns if fractured. The authors report the case of a patient who sustained a fracture of the hyoid bone. The hospital records from a busy, level I trauma center were reviewed to document similar injuries over a seven-year period. To supplement the scant literature concerning hyoid fractures, a review of the anatomy, diagnosis, and management of such injuries is provided.


Minimal prevalence of Huntington's disease in the South of Brazil and instability of the expanded CAG tract during intergenerational transmissions.
Huntington's disease (HD) is due to dominant expansions of the CAG repeat of the HTT gene. Meiotic instability of the (CAG)n might impact the disorder frequency. We report on HD minimal prevalence in Rio Grande do Sul (RS) state, Brazil, and on intergenerational instability of the (CAG)n in HD families. Symptomatic and at-risk subjects from 179 HD families were ascertained between 2013 and 2016. Clinical, molecular and family history data were obtained. Expanded (CAG)n length differences between parent and child (delta-expanded-(CAG)n) were calculated. Effect of parental age on the (CAG)n instability upon transmission was inferred by correlating delta-expanded-(CAG)n between siblings to their age differences. HD minimal prevalence in RS state was estimated as 1.85:100,000 inhabitants. Alleles with (CAG)27-35 were found on 21/384 non-disease associated chromosomes (5.5%); among 253 expanded alleles, four (1.6%) were within reduced penetrance range with (CAG)36-39. In 32 direct transmissions, mean instability was larger among paternal than maternal transmissions. In direct transmissions and in 51 sibling pairs, parental age at the time of child birth were not correlated with delta-expanded-(CAG)n. Briefly, HD prevalence in RS state was lower than those reported for European populations. Expanded (CAG)n transmissions were unstable and not associated to parental age.


Serotonin receptor inhibitor is associated with falls independent of frailty in older adults.
To evaluate whether fall risk in older adults is associated with the use of selective serotonin receptor inhibitor (SSRI) monotherapy among geriatric outpatients, and whether this association is moderated by the presence of depressive disorder and/or frailty. Prospective cohort study with a 12-month follow-up and including 811 community-dwelling adults aged 60 or older from a university-based Geriatric Outpatient Unit. Major depressive disorder (MDD) was diagnosed according to DSM-5 criteria; subsyndromal depression as not meeting MDD criteria, but a Geriatric Depression Scale 15-item score ≥ 6 points. Frailty was evaluated with the FRAIL questionnaire. The association between SSRI use, depression, or both as well as the association between SSRI use, frailty, or both with falls were estimated through a generalized estimating equation (GEE) adjusted for relevant confounders. At baseline, 297 patients (36.6%) used a SSRI (82 without remitted depression) and 306 (37.7%) were classified as physically frail. Frailty was more prevalent among SSRI users (44.8% versus 33.7%, p =.004). After 12 months, 179 participants had at least one fall (22.1%). SSRI use, depression as well as frailty were all independently associated with falls during follow-up. Nonetheless, patients with concurrent of SSRI usage and non-remitted depression had no higher risk compared to either remitted SSRI users or depressed patients without SSRIs. In contrast, concurrence of SSRI use and frailty increases the risk of falling substantially above those by SSRI usage or frailty alone. SSRI usage was independently associated with falls. Especially in frail-depressed patients, treatment strategies for depression other than SSRIs should be considered.


Identification of the biosynthetic gene clusters for the lipopeptides fusaristatin A and W493 B in Fusarium graminearum and F. pseudograminearum.
The closely related species Fusarium graminearum and Fusarium pseudograminearum differ in that each contains a gene cluster with a polyketide synthase (PKS) and a nonribosomal peptide synthetase (NRPS) that is not present in the other species. To identify their products, we deleted PKS6 and NRPS7 in F. graminearum and NRPS32 in F. pseudograminearum. By comparing the secondary metabolite profiles of the strains we identified the resulting product in F. graminearum as fusaristatin A, and as W493 A and B in F. pseudograminearum. These lipopeptides have previously been isolated from unidentified Fusarium species. On the basis of genes in the putative gene clusters we propose a model for biosynthesis where the polyketide product is shuttled to the NPRS via a CoA ligase and a thioesterase in F. pseudograminearum. In F. graminearum the polyketide is proposed to be directly assimilated by the NRPS.


Perinatal group B streptococcal disease prevention, Minnesota.
In 2002, revised guidelines for preventing perinatal group B streptococcal disease were published. In 2002, all Minnesota providers surveyed reported using a prevention policy. Most screen vaginal and rectal specimens at 34-37 weeks of gestation. The use of screening-based methods has increased dramatically since 1998.


Critical Angiographic and Sonographic Analysis of Intra Aneurysmal and Downstream Hemodynamic Changes After Flow Diversion.
Successful treatment of intracranial aneurysms after flow diversion (FD) is dependent on the flow modulating effect of the device. We aimed to investigate the intra-aneurysmal and parent vessel hemodynamic changes, as well as the incidence of silent emboli following treatment with various FD devices. We evaluated the appearance of the eclipse sign in nine distinct phases of cerebral angiography before and immediately after FD placement in correlation with aneurysm occlusion. Angiographic and clinical data of consecutive procedures were analyzed retrospectively. Patients who had successful FD procedure without adjunctive coiling, visible eclipse sign on post embolization angiography, and reliable follow-up angiographic data were included in the analysis. Detailed analysis of hemodynamic data from transcranial doppler after FD was performed in selected patients, such as monitoring for silent emboli. Among all patients (N = 65) who met inclusion criteria, complete aneurysm occlusion at 12 months was achieved in 89% (58/65). Eclipse sign prior to FD was observed in 42% (27/65) with unchanged appearance in 4.6% (3/65) of the treated patients. None of these three patients achieved complete aneurysm occlusion. Among all analyzed variables, such as aneurysm size, device type used, age, and appearance of the eclipse sign pre- and post-FD, the most reliable predictor of permanent aneurysm occlusion at 12 months was earlier, prolonged, and sustained eclipse sign visibility in more than three angiographic phases in comparison to the baseline (p < 0.001). Elevation in flow velocities within the ipsilateral vascular territory was noted in 70% (9/13), and bilaterally in 54% (7/13) of the treated patients. None of the patients had silent emboli. Intra-aneurysmal and parent vessel hemodynamic changes after FD can be reliably assessed by the cerebral angiography and transcranial doppler with important implications for the prediction of successful treatment.


[Cytokines in experimental acute pancreatitis].
The authors induced acute necrotizing pancreatitis in Wistar rat by intraductal injection of taurocholic acid (150 microliters or 200 microliters 6%). Plasma values of amylase, TNF, IL-6 levels and wet pancreas weight/body weight ratio have been determined. Histologic analysis of pancreas proved severe acute necrotizing pancreatitis with microabscess formation and beginning respiratory distress syndrome was observed in the lungs, TNF and IL-6 levels increased significantly after administration of 200 microliters 6% taurocholic acid. The authors emphasise the importance of cytokines in the development of acute necrotizing pancreatitis.


Reduction of speckle noise in holographic images using spatial jittering in numerical reconstructions.
This Letter presents an easy, fast, and efficient single-shot method to reduce speckle noise in digital Fresnel holography. In this method, several images from a single hologram are reconstructed by introducing spatial displacements in the Fresnel kernel. Spatial jitters produce images with different speckle positions. Averaging the set of numerically produced images leads to a strong reduction of speckle noise in both amplitude and phase difference images. The experimental results show the suitability of the proposed approach and confirm its applicability to digital holographic interferometry.


Lactic dehydrogenase isoenzyme electrophoretic patterns in the diagnosis of pleural effusion.
The relative value of each lactic dehydrogenase isoenzyme (iso LDH) was measured by electrophoretic separation in the serum and the pleural fluid of 100 patients. In each case, the cause of the pleural effusion was known. Two types of LDH isoenzyme pattern were found in the serum: a normal type with a low value of LDH 5 and an abnormal type with a high value of LDH 5. This high LDH-5 level is due to an impaired liver function. In the pleural fluid, the electrophoretic patterns of five LDH isoenzymes were found by computerized processing. During congestive heart failure (28 cases) the electrophoretic pattern of the LDH isoenzymes was always similar in the serum and in the pleural fluid (transudative pleural effusion). During thoracic empyema, the relative values of the isoenzymes in the pleural fluid were regularly increasing from LDH 1 to LDH 5. In this situation, the evaluation of LDH 5 appeared to emanate from the increased granulocytes in the pleural fluid. In 22 inflammatory pleural effusions, the relative values of the five isoenzymes were equal. During malignant effusions (35 cases) a high level of LDH 5 was found in 21 patients. LDH 5 is known to be secreted by malignant tissue, and the authors confirmed it by finding a high level of LDH 5 in biopsy specimens of patients with mesothelioma or epidermoid lung cancer (7 cases). Conversely, the level of LDH 5 was low in biopsy specimens from normal lung tissue or benign inflammatory pleuritis (6 cases). Among the 14 patients with low levels of LDH 5 in the pleural fluid during malignant pleural effusion, the authors found the malignant lymphomas (three cases) and the small cell lung carcinoma (five cases). In these cases, the low level of LDH 5 was in agreement with the result of a low level of LDH 5 found in the biopsy of a metastatic liver localization of a small cell lung carcinoma. So the electrophoretic determination of LDH isoenzymes pattern in pleural fluid is a sensitive tool for the management of pleural effusion.


Terahertz and infrared spectroscopy of gated large-area graphene.
We have fabricated a centimeter-size single-layer graphene device with a gate electrode, which can modulate the transmission of terahertz and infrared waves. Using time-domain terahertz spectroscopy and Fourier-transform infrared spectroscopy in a wide frequency range (10-10 000 cm(-1)), we measured the dynamic conductivity change induced by electrical gating and thermal annealing. Both methods were able to effectively tune the Fermi energy, E(F), which in turn modified the Drude-like intraband absorption in the terahertz as well as the "2E(F) onset" for interband absorption in the mid-infrared. These results not only provide fundamental insight into the electromagnetic response of Dirac fermions in graphene but also demonstrate the key functionalities of large-area graphene devices that are desired for components in terahertz and infrared optoelectronics.


The response of polycyclic aromatic hydrocarbon degradation in coking wastewater treatment after bioaugmentation with biosurfactant-producing bacteria Pseudomonas aeruginosa S5.
The polycyclic aromatic hydrocarbons (PAHs) that accumulate during the coking wastewater treatment process are hazardous for the surrounding environment. High molecular weight (HMW) PAHs account for more than 85% of the total PAHs in coking wastewater and sludge, respectively. The degradation of total PAHs increased by 18.97% due to the increased bioavailability of PAHs, after the biosurfactant-producing bacteria Pseudomonas aeruginosa S5 was added. The toxicity of total PAHs to humans was reduced by 26.66% after inoculation with S5. The results suggest biosurfactant-producing bacteria Pseudomonas aeruginosa S5 not only increase the biodegradation of PAHs significantly, but also have a better effect on reducing the human toxicity of PAHs. Kinetic analyses show that PAHs biodegradation fits to first-order kinetics. The degradation rate constant (k) value decreases as the number of PAH rings increases, indicating that HMW PAHs are more difficult to be biodegraded than low molecular weight (LMW) PAHs. The results indicate the bioaugmentation with the biosurfactant-producing strain has significant potential and utility in remediation of PAHs-polluted sites.


Phase behavior of n-alkanes in supercritical solution: a Monte Carlo study.
We present a coarse-grained model for n-alkanes in a supercritical solution, which is exemplified by a mixture of hexadecane and CO2. For pure hexadecane, the Monte Carlo simulations of the coarse-grained model reproduce the experimental phase diagram and the interfacial tension with good accuracy. For the mixture, the phase behavior sensitively depends on the compatibility of the polymer with the solvent. We present a global phase diagram with critical lines, which is in semiquantitative agreement with experiments. In this context we developed two computational schemes: The first adopts Wang-Landau sampling to the off-lattice grand canonical ensemble, the second combines umbrella sampling with an extrapolation scheme to determine the weight function. Additionally, we use Wertheim's theory (TPT1) to obtain the equation of state for our coarse-grained model of supercritical mixtures and discuss the behavior for longer alkanes.


Comparison of the taste mechanisms of umami and bitter peptides from fermented mandarin fish (Chouguiyu) based on molecular docking and electronic tongue technology.
Unclear taste mechanisms of peptides limit rapid screening of taste peptides with high intensity. In this study, the taste mechanisms of umami and bitter peptides from Chouguiyu were compared. After molecular docking of core umami (NWDDMEK, WFKDEEF, EEEKPKF, DFDDIQK, and DGEKVDF) and bitter (VQDVLKL, VELLKLE, LVVDGVK, VVDLTVR, and VVDGVKL) peptides with T1R1/T1R3 and TASR14, respectively, salt bridges and conventional hydrogen bonds were the main interactions in all taste peptides, in which acidic amino acid residues contributed to the interaction with their receptors. The taste intensity of peptides after solid-phase synthesis was further verified using electronic tongue technology. Spearman correlation analysis showed that docking energy was an important factor for the intensity of taste peptides, while interaction energy and the distance between the binding unit (BU) and the stimulating unit (SU) were also responsible for the bitter intensity. This study provides a theoretical basis to screen novel taste peptides with high taste intensity in fermented foods.