Performance gain and electro-mechanical design optimization of microneedles for wearable sensor systems.
Minimally invasive microneedle (MN) is an emerging technology platform for wearable and implantable diagnostics and therapeutics systems. These short MNs offer pain-free insertion and simple operation. Among the MN technologies proposed to enhance interstitial fluid (ISF) extraction, porous and swellable (P-S) hydrogels absorb analyte molecules across the entire lateral surface. Currently, the design, development, and optimization of the MNs rely on empirical, iterative approaches. Based on theory of fluid flow and analyte diffusion through geometrically complex biomimetic systems, here we derive a generalized physics-guided model for P-S MN sensors. The framework (a) quantifies MN extracting efficiency [Formula: see text] in terms of its geometric and physical properties, and (b) suggests strategies to optimize sensor response while satisfying the mechanical constraints related to various skin-types (e.g., mouse, pig, humans, etc.). Our results show that, despite the differences in geometry and composition, P-S MNs obey a universal scaling response, [Formula: see text] with [Formula: see text] being MN length, diffusivity, and radius, respectively, and [Formula: see text], [Formula: see text] and [Formula: see text] are the ratio between approximate vs. exact analytical solutions, the effective biofluid transfer coefficient between dermis and skin, and the exponent for the power-law approximation, respectively. These parameters quantify the biomolecule transfer through the dermis-to-MN interface at different scaling limits. P-S MNs outperform hollow MNs by a 2-6x enhancement factor; however, the buckling-limit of insertion defines the maximized functionality of the sensor. Our model, validated against experimental results and numerical simulations, offers a predictive design framework to significantly reduce the optimization time for P-S MN-based sensor platforms.


A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients.
The purpose of this study was to investigate the effectiveness of zonisamide in the treatment of bipolar depression. Ten patients with DSM-IV bipolar disorder, depressed phase, who had either not tolerated or not responded to previous treatments were given zonisamide in this add-on open-label study. Zonisamide treatment was started at 100 mg/day and increased by 100 mg every 2 weeks to a maximum of 300 mg/day in divided doses (b.i.d. or t.i.d.). Subjects underwent weekly visits at which they were administered the 17-item Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS), and Clinical Global Impressions scale (CGI). Every 2 weeks, subjects also underwent laboratory tests, a urine examination, and a verbal memory test. Outcome measures were analyzed with repeated-measures analysis of variance. Eight subjects completed all 8 weeks of the study. Two subjects completed more than 4 weeks of the study, and their data were analyzed using the last observation carried forward. Bipolar depression subjects had a significant reduction in HAM-D scores (p < .001) and in CGI-Improvement (CGI-I) scores (p < .001). Five of 8 subjects who completed all 8 weeks of the study had more than a 50% decrease in HAM-D scores and were rated much improved on the CGI-I at the end of 8 weeks of treatment. There was no significant drug effect on YMRS scores, weight, or verbal memory. Zonisamide may be a useful drug in the treatment of bipolar depression. Further controlled clinical trials are needed.


A four-compartment model for Ca2+ dynamics: an interpretation of Ca2+ decay after repetitive firing of intact nerve terminals.
In the presynaptic nerve terminals of the bullfrog sympathetic ganglia, repetitive nerve firing evokes [Ca2+] transients that decay monotonically. An algorithm based on an eigenfunction expansion method was used for fitting these [Ca2+] decay records. The data were fitted by a linear combination of two to four exponential functions. A mathematical model with three intraterminal membrane-bound compartments was developed to describe the observed Ca2+ decay. The model predicts that the number of exponential functions, n, contained in the decay data corresponds to n-1 intraterminal Ca2+ stores that release Ca2+ during the decay. Moreover, when a store stops releasing or starts to release Ca2+, the decay data should be fitted by functions that contain one less exponential component for the former and one more for the latter than do the fitting functions for control data. Because of the current lack of a parameter by which quantitative comparisons can be made between two decay processes when at least one of them contained more than one exponential components, we defined a parameter, the overall rate (OR) of decay, as the trace of the coefficient matrix of the differential equation systems of our model. We used the mathematical properties of the model and of the OR to interpret effects of ryanodine and of a mitochondria uncoupler on Ca2+ decay. The results of the analysis were consistent with the ryanodine-sensitive store, mitochondria, and another, yet unidentified store release Ca2+ into the cytosol of the presynaptic nerve terminals during Ca2+ decay. Our model also predicts that mitochondrial Ca2+ buffering accounted for more than 86% of all the flux rates across various membranes combined and that there are type 3 and type 1 and/or type 2 ryanodine receptors in these terminals.


Messenger RNA expression of podocyte-associated molecules in urinary sediment of patients with lupus nephritis.
To examine urinary expression of podocyte-associated molecules in patients with lupus nephritis (LN). We studied 32 patients with active LN (Active group) and 17 patients with inactive lupus (Silent group). Messenger RNA expression of nephrin, podocin, and synaptopodin in urinary sediment was quantified by real-time polymerase chain reaction and compared to other clinical measures. The urinary concentrations of nephrin, podocin, and synaptopodin were significantly higher in the Active than the Silent group (p < 0.05 for all comparisons). There was no relation between urinary gene expression and the histological class of LN, but urinary nephrin expression correlated with proteinuria (r = 0.480, p < 0.01) and the score of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; r = 0.578, p < 0.01). Urinary podocin expression also correlated with SLEDAI score (r = 0.389, p = 0.006). After initiation of immunosuppressive treatment, all patients were followed for an average of 13.7 +/- 2.4 months. The decline of the glomerular filtration rate (GFR) correlated with urinary expression of podocin (r = 0.406, p = 0.005) and synaptopodin (r = 0.337, p = 0.021). In a multiple linear regression model, urinary podocin expression and baseline GFR were independent predictors of GFR decline. The concentration of podocyte-associated molecules in urinary sediment correlated with lupus activity and GFR decline. The clinical utility of quantifying urinary expression of podocyte-associated molecules for risk stratification of patients with LN deserves further study.


Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization.
14-3-3 proteins are abundant and conserved polypeptides that mediate the cellular effects of basophilic protein kinases through their ability to bind specific peptide motifs phosphorylated on serine or threonine. We have used mass spectrometry to analyze proteins that associate with 14-3-3 isoforms in HEK293 cells. This identified 170 unique 14-3-3-associated proteins, which show only modest overlap with previous 14-3-3 binding partners isolated by affinity chromatography. To explore this large set of proteins, we developed a domain-based hierarchical clustering technique that distinguishes structurally and functionally related subsets of 14-3-3 target proteins. This analysis revealed a large group of 14-3-3 binding partners that regulate cytoskeletal architecture. Inhibition of 14-3-3 phosphoprotein recognition in vivo indicates the general importance of such interactions in cellular morphology and membrane dynamics. Using tandem proteomic and biochemical approaches, we identify a phospho-dependent 14-3-3 binding site on the A kinase anchoring protein (AKAP)-Lbc, a guanine nucleotide exchange factor (GEF) for the Rho GTPase. 14-3-3 binding to AKAP-Lbc, induced by PKA, suppresses Rho activation in vivo. 14-3-3 proteins can potentially engage around 0.6% of the human proteome. Domain-based clustering has identified specific subsets of 14-3-3 targets, including numerous proteins involved in the dynamic control of cell architecture. This notion has been validated by the broad inhibition of 14-3-3 phosphorylation-dependent binding in vivo and by the specific analysis of AKAP-Lbc, a RhoGEF that is controlled by its interaction with 14-3-3.


Long-Term Real-World Outcomes of Corneal Changes in Proliferative Diabetic Retinopathy: Panretinal Photocoagulation vs. Intravitreal Conbercept.
To compare long-term real-world outcomes of corneal thickness (CT) alterations in proliferative diabetic retinopathy (PDR) patients treated with panretinal photocoagulation (PRP) and intravitreal conbercept (IVC). This retrospective study included 69 eyes of 69 patients with PDR (42 PRP and 27 IVC). Full corneal thickness (FCT), corneal epithelial thickness (CET) and corneal stromal thickness (CST) measured by anterior segment optical coherence tomography at baseline were compared between groups. These CT changes at last follow-up from baseline were also compared between groups and within each group. During a mean follow-up of more than two years, the IVC group demonstrated a significantly increased corneal thickness from baseline compared to the PRP group in some areas (PRP vs. IVC: FCT 0-2 mm: -0.59 ± 9.31 vs. 5.59 ± 9.23 μm, p = 0.009; CST 0-2 mm: -2.05 ± 8.79 vs. 3.48 ± 7.52 μm, p = 0.015; CST 2-5 mm: -1.78 ± 13.27 vs. 5.68 ± 14.53 μm, p = 0.046). In within-group comparisons, a significantly increased FCT from baseline was found in the 0-2 mm area in the IVC group (p = 0.004), but no significant change was observed in the PRP group (p = 0.691). For CET changes, a significantly increased CT was observed in the 0-2 mm, 2-5 mm and 5-7 mm areas in both groups respectively (all p < 0.05). Regarding CST, an increased CT was found in the 0-2 mm area in the IVC group (p = 0.037), while a decreased trend was observed in 0-2 mm and 2-5 mm areas in the PRP group (all p > 0.05). When using PRP or IVC in the long-term management of PDR, CT changes should be considered. This may provide evidence for corneal protection during PDR treatment.


Aquipuribacter nitratireducens sp. nov., isolated from a soil sample of a mud volcano.
A novel Gram-stain-positive, coccoid, non-motile bacterium, designated strain AMV4T, was isolated from a soil sample collected from a mud volcano located in the Andaman Islands, India. The colony was pale orange. Strain AMV4T was positive for oxidase, aesculinase, lysine decarboxylase and ornithine decarboxylase activities and negative for amylase, catalase, cellulase, protease, urease and lipase activities. 16S rRNA gene sequence analysis indicated that strain AMV4T was a member of the order Actinomycetales and was closely related to Aquipuribacter hungaricus with a sequence similarity of 97.13% (pairwise alignment). Phylogenetic analyses showed that strain AMV4T clustered with Aquipuribacter hungaricus and was distantly related to the other genera of the family Intrasporangiaceae. DNA-DNA hybridization between strains AMV4T and Aquipuribacter hungaricus IV-75T showed a relatedness of 28%. The predominant cellular fatty acids were iso-C15 : 0 (6.9%), anteiso-C15 : 0 (25.3%), C16 : 0 (12.9%), anteiso-C16 : 0 (5.6%), C18 : 1ω9c (19.8%) and C18 : 3ω6,9,12c (9.1%). The diagnostic diamino acid in the cell-wall peptidoglycan of strain AMV4T was meso-diaminopimelic acid. Strain AMV4T contained MK-10(H4) as the predominant respiratory quinone. The polar lipids consisted of phosphatidylglycerol, one unidentified glycolipid, two unidentified phospholipids and five unidentified lipids. The DNA G+C content of strain AMV4T was 74.3 mol%. Based on data from this taxonomic study using a polyphasic approach, it is proposed that strain AMV4T represents a novel species of the genus Aquipuribacter, with the suggested name Aquipuribacter nitratireducens sp. nov. The type strain is AMV4T ( = CCUG 58430T = DSM 22863T = NBRC 107137T).


Natural variants of molybdate transporters contribute to yield traits of soybean by affecting auxin synthesis.
Soybean (Glycine max) is a crop with high demand for molybdenum (Mo) and typically requires Mo fertilization to achieve maximum yield potential. However, the genetic basis underlying the natural variation of Mo concentration in soybean and its impact on soybean agronomic performance is still poorly understood. Here, we performed a genome-wide association study (GWAS) to identify GmMOT1.1 and GmMOT1.2 that drive the natural variation of soybean Mo concentration and confer agronomic traits by affecting auxin synthesis. The soybean population exhibits five haplotypes of the two genes, with the haplotype 5 demonstrating the highest expression of GmMOT1.1 and GmMOT1.2, as well as the highest transport activities of their proteins. Further studies showed that GmMOT1.1 and GmMOT1.2 improve soybean yield, especially when cultivated in acidic or slightly acidic soil. Surprisingly, these two genes contribute to soybean growth by enhancing the activity of indole-3-acetaldehyde (IAAld) aldehyde oxidase (AO), leading to increased indole-3-acetic acid (IAA) synthesis, rather than being involved in symbiotic nitrogen fixation or nitrogen assimilation. Furthermore, the geographical distribution of five haplotypes in China and their correlation with soil pH suggest the potential significance of GmMOT1.1 and GmMOT1.2 in soybean breeding strategies.


Memory: proline induces retrograde amnesia in chicks.
Intracerebral injection of L-proline, 1 minute after one-trial avoidance training of chicks, impaired memory 24 hours later. Chicks injected with proline 1 or 4 hours after training and controls injected with L-isoleucine at intervals after training, showed no impairment of memory 24 hours after training. The retrograde impairment of long-term memory induced by proline occurred without the convulsions or electrographic events usually associated with retrograde amnesic treatments.


Medicare procedural costs in ambulatory surgery centers versus hospital outpatient departments for spine surgeries.
Multiple studies have demonstrated the safety of outpatient spine surgery, with reports of equivalent to improved patient outcomes compared with inpatient procedures. This has resulted in the increased use of outpatient surgery over time. However, there remains a paucity of literature evaluating the difference in costs between ambulatory surgery center (ASC)- and hospital outpatient department (HOPD)-based procedures for Medicare beneficiaries. Publicly available data from Centers for Medicare & Medicaid Services were accessed via the Medicare Procedure Price Lookup tool. Current Procedural Terminology (CPT) codes were used to identify spine-specific procedures approved for the outpatient setting by CMS. Procedures were grouped into decompression (cervical, thoracic, and lumbar), fusion/instrumentation (cervical, lumbar, and sacroiliac), and kyphoplasty/vertebroplasty cohorts, as well as an overall cohort. Data regarding total costs, facility fees, surgeon reimbursement, Medicare payments, and patient copayments were extracted for each procedure. Descriptive statistics were used to calculate means and standard deviations. Differences between ASC- and HOPD-associated costs were analyzed using the Mann-Whitney U-test. Twenty-one individual CPT codes approved by Medicare for the ASC and/or HOPD setting were identified. Decompression procedures were associated with a significantly lower total cost ($4183 ± $411.07 vs $7583.67 ± $410.89, p < 0.001), facility fees ($2998 ± $0 vs $6397 ± $0, p < 0.001), Medicare payments ($3345.75 ± $328.80 vs $6064.75 ± $328.80, p < 0.001), and patient payments ($835.58 ± $82.13 vs $1515.58 ± $82.13, p < 0.001) in ASCs compared with HOPDs. Fusion/instrumentation procedures had significantly lower facility fees ($10,436.6 ± $2347.51 vs $14,161 ± $2147.07, p = 0.044) and Medicare payments ($9501.2 ± $1732.42 vs $13,757 ± $2037.58, p = 0.009) in ASCs, as well as a trend toward lower total costs ($11,876.8 ± $2165.22 vs $15,601.2 ± $2016.06, p = 0.076). Patient payments in the HOPD setting were significantly lower in the fusion/instrumentation cohort ($1843.6 ± $73.42 vs $2374.4 ± $433.48, p = 0.009). In the kyphoplasty/vertebroplasty cohort, there was no statistically significant difference between ASCs and HOPDs, despite lower overall costs in the ASC for all variables. Surgeon fees were the same regardless of setting for all procedures (p > 0.99). When combining decompression, fusion/instrumentation, and kyphoplasty/vertebroplasty CPT codes into a single cohort, ASC setting was associated with significant cost savings in total cost, facility fees, Medicare payments, and patient payments. In general, performing spine surgeries in ASCs is associated with cost savings compared with HOPDs. This was demonstrated for decompression and fusion/instrumentation, and kyphoplasty/vertebroplasty Medicare-approved outpatient procedures.


Outcomes of Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention Receiving an Oral Anticoagulant and Dual Antiplatelet Therapy: A Comparison of Clopidogrel Versus Prasugrel From the TRANSLATE-ACS Study.
The purpose of this study was to determine whether bleeding risk varies depending on which P2Y12 receptor inhibitor agent is used. Prior studies have shown significant bleeding risk among patients treated with triple therapy (i.e., oral anticoagulant, P2Y12 receptor inhibitor, and aspirin). We evaluated patients with acute myocardial infarction (MI) treated with percutaneous coronary intervention (PCI) at 233 hospitals in the United States enrolled in the TRANSLATE-ACS (Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study (April 2010 to October 2012). Using inverse probability-weighted propensity modeling, we compared 6-month adjusted risks of Bleeding Academic Research Consortium (BARC) bleeding, stratifying by whether or not bleeding was associated with rehospitalization among patients discharged on aspirin + anticoagulant + clopidogrel (triple-C), aspirin + anticoagulant + prasugrel (triple-P), aspirin + clopidogrel (dual-C), or aspirin + prasugrel (dual-P). Of 11,756 MI patients, 526 (4.5%) were discharged on triple-C, 91 (0.8%) on triple-P, 7,715 (66%) on dual-C, and 3,424 (29%) on dual-P. Compared with dual-therapy patients, triple-therapy patients had significantly higher any BARC-defined bleeding. Triple-P was associated with a greater risk of any BARC-defined bleeding events compared with triple-C. This finding was driven mostly by an increased risk of bleeding events that were patient-reported only and did not require rehospitalization. There were no significant differences in bleeding requiring rehospitalization between the triple-P and -C groups. Among MI patients, the addition of an oral anticoagulant was associated with a significantly greater risk of any BARC-defined bleeding relative to dual antiplatelet therapy, regardless of which P2Y12 receptor inhibitor was selected. Among patients on triple therapy, prasugrel use was associated with higher patient-reported-only bleeding, but not bleeding requiring rehospitalization, than clopidogrel-treated patients.


Effects of an acidic polysaccharide procuced by Serratia piscatorum on immune responses in mice. I. mitogenicity and stimulation of plaque-forming cells (PFC) in vitro.
An acidic polysaccharide of Serratia piscatorum, consisting of L-rhamnose, D-galactose and D-galacturonic acid, stimulated the primary IgM PFC response of spleen cell cultures against sheep erythrocytes. The polysaccharide (PS) caused dose-dependent stimulation of 3H-thymidine incorporation into DNA of spleen cell cultures and the maximum response was seen after about 48 hr. Nonadherent B (ATXBM) cells were strongly reactive to PS, whereas adherent spleen cells were less reactive. Higher doses of PS suppressed the peak PFC response, but enhanced the earlier PFC responses. Lower doses of PS stimulated the PFC responses significantly throughout the period of PFC production. The optimal dose (0.1 mug/ml) of PS increased the PFC responses in mixed cell cultures containing spleen cells and either B cells, T cells activated with a different antigen, or hydrocortisone-resistant thymus cells of syngeneic origin. However, this dose of PS interfered with the enhanced PFC response of spleen cells due to addition of antigen-primed T cells. Since these characteristic activities of PS were like those of lipopolysaccharides (LPS), this acidic polysaccharide may be useful for further elucidating the modes of LPS action.


Islamic views on organ donation.
As medical technology continues its advance, the use of organ transplantation for the palliation and cure of chronic diseases is rising. However, many barriers to organ donation exist, including religious ones. It has long been known that Muslims in North America tend not to donate organs. In the past this tendency has been attributed to religious prohibitions even though cultural views may also play a strong role. The purpose of this article is to explore and define the Islamic religious opinion on organ donation and transplantation to enhance healthcare professionals' understanding of Islamic views concerning brain death and organ donation. It is hoped that this knowledge and understanding may benefit both patients and caregivers in the North American healthcare setting.


Analysis of filaggrin mutations and expression in corneal specimens from patients with or without atopic dermatitis.
Filaggrin is expressed in the epidermis and is essential for the maintenance of the epidermal barrier. Null mutations within the filaggrin gene (FLG) lead to a disturbed epidermal barrier and are associated with a significantly increased risk of atopic dermatitis (AD). The association of AD with ocular surface disorders prompted us to speculate that common FLG mutations may be particularly prevalent in AD patients with ocular comorbidities. Corneal buttons and biopsies from AD patients with ocular involvement (n = 11) and from non-atopic patients (n = 9) with a histological diagnosis of keratitis were included in the study. DNA samples obtained from paraffin-embedded corneal specimens were genotyped for the two most common FLG mutations (R501X and 2282del4). Filaggrin protein expression was analysed by immunohistochemistry. Normal skin and corneal specimens (n = 6) were positive for filaggrin, which could be detected in the stratum corneum of the skin and in the basal epithelial layer of the cornea. Interestingly, all AD corneal specimens as well as the specimens from keratitis patients without AD were negative for filaggrin expression. Genotyping of the FLG mutations R501X and 2282del4 revealed wild-type alleles in all analysed samples. The lack of filaggrin expression observed in the analysed corneal specimens from AD patients is not due to the two most common FLG mutations (R501X, 2282del4) but is most likely secondary to inflammation, as all keratitis specimens of non-AD patients showed lack of filaggrin expression as well.


Persistent DNA Double-Strand Breaks After Repeated Diagnostic CT Scans in Breast Epithelial Cells and Lymphocytes.
DNA double-strand break (DSB) induction and repair have been widely studied in radiation therapy (RT); however little is known about the impact of very low exposures from repeated computed tomography (CT) scans for the efficiency of repair. In our current study, DSB repair and kinetics were investigated in side-by-side comparison of RT treatment (2 Gy) with repeated diagnostic CT scans (≤20 mGy) in human breast epithelial cell lines and lymphoblastoid cells harboring different mutations in known DNA damage repair proteins. Immunocytochemical analysis of well known DSB markers γH2AX and 53BP1, within 48 h after each treatment, revealed highly correlated numbers of foci and similar appearance/disappearance profiles. The levels of γH2AX and 53BP1 foci after CT scans were up to 30% of those occurring 0.5 h after 2 Gy irradiation. The DNA damage repair after diagnostic CT scans was monitored and quantitatively assessed by both γH2AX and 53BP1 foci in different cell types. Subsequent diagnostic CT scans in 6 and/or 12 weeks intervals resulted in elevated background levels of repair foci, more pronounced in cells that were prone to genomic instability due to mutations in known regulators of DNA damage response (DDR). The levels of persistent foci remained enhanced for up to 6 months. This "memory effect" may reflect a radiation-induced long-term response of cells after low-dose x-ray exposure.


B7 costimulation is required for IL-5 and IL-13 secretion by bronchial biopsy tissue of atopic asthmatic subjects in response to allergen stimulation.
Asthma is a complex disorder characterized by airway hyperreactivity and inflammation. To analyze cellular interactions required for the secretion of cytokines by the bronchial mucosa, we have evaluated the ex vivo response of tissue explants to allergen. Endobronchial mucosal biopsy tissue from mild atopic asthmatic subjects and normal control subjects were maintained in culture for 24 h. To detect reactivity to allergen, the explants were stimulated with dust mite extract Dermatophagoides pteronyssinus (Der p). Our analysis revealed that without any overt stimulation, mRNA transcripts for interleukin (IL)-5 and IL-13 were expressed by asthmatic but not normal bronchial tissue. In contrast, the expression of interferon-gamma was observed in a higher proportion of cultured bronchial biopsies from the normal control subjects than in those from asthmatic subjects. Addition of Der p allergen did not change the cytokine profile of the explants from control volunteers but augmented the expression of IL-5 mRNA and induced secretion of the protein by the asthmatic bronchial tissue. In most cases, allergen also increased the production of IL-13 by bronchial tissue from asthmatic subjects. The allergen-induced secretion of IL-5 and IL-13 was inhibited by the fusion protein CTLA-4Ig, reflecting a requirement for CD80 (B7-1) and/or CD86 (B7-2) costimulation for the expression of the Th2 cytokines. This requirement for B7/CD28 costimulation is consistent with the hypothesis that IL-5 and IL-13 are produced by allergen-specific T cells resident in the asthmatic bronchial mucosa.


Perspectives of value-based policy making in child health care in Japan.
In Japan, epidemiological transition has profoundly influenced the priorities of child healthcare. As pediatric care is shifting from a disease-driven curative approach to an integrated approach, the value of child health care now needs to be redefined with an integrated scope. With the trend to emphasize a rational judgement on the social value in terms of resource allocation and health policy, a value-based approach is necessary for child health care. This study aims to provide an overview and perspective of value-based policy making in child health care, under a context of epidemiological transition, health care system and social changes. The current methodology scheme of CEA and outcome evaluation has limitations, not meeting the urgent need of the application. The outcomes of child health care are no longer limited in clinical and health indicators such as survival rate, cure rate and health related quality of life, but also various aspects other than health, such as education, well-being of children and their primary caregivers, especially when treatment of diseases is no longer the dominant role of health care. Such the evaluation should reflect the impacts of the integrated approach in a long-term scope.


Bilateral posterior cerebral artery infarction.
We report the case of a 70-year-old man who presented with short-term memory impairment and a homonymous left inferior quadrantanopia secondary to simultaneous bilateral posterior cerebral artery (PCA) territory infarction. As in more than a quarter of cases of PCA infarction, no aetiological cause was identified. Unlike the transient nature of symptoms in some cases following unilateral infarction, his deficits persisted on 2-month follow-up.


Vibration modeling of structural fuzzy with continuous boundary.
From experiments it is well known that the vibration response of a main structure with many attached substructures often shows more damping than structural losses in the components can account for. In practice, these substructures, which are not attached in an entirely rigid manner, behave like a multitude of different sprung masses each strongly resisting any motion of the main structure (master) at their base antiresonance. The "theory of structural fuzzy" is intended for modeling such high damping. In the present article the theory of fuzzy structures is briefly outlined and a method of modeling fuzzy substructures examined. This is done by new derivations and physical interpretations are provided. Further, the method is extended and simplified by introducing a simple deterministic approach to determine the boundary impedance of the structural fuzzy. By using this new approach, the damping effect of the fuzzy with spatial memory is demonstrated by numerical simulations of a main beam structure with fuzzy attachments. It is shown that the introduction of spatial memory reduces the damping effect of the fuzzy and in certain cases the damping effect may even be eliminated completely.


Managing heart failure in the long-term care setting: nurses' experiences in Ontario, Canada.
Implementation of heart failure guidelines in long-term care (LTC) settings is challenging. Understanding the conditions of nursing practice can improve management, reduce suffering, and prevent hospital admission of LTC residents living with heart failure. The aim of the study was to understand the experiences of LTC nurses managing care for residents with heart failure. This was a descriptive qualitative study nested in Phase 2 of a three-phase mixed methods project designed to investigate barriers and solutions to implementing the Canadian Cardiovascular Society heart failure guidelines into LTC homes. Five focus groups totaling 33 nurses working in LTC settings in Ontario, Canada, were audiorecorded, then transcribed verbatim, and entered into NVivo9. A complex adaptive systems framework informed this analysis. Thematic content analysis was conducted by the research team. Triangulation, rigorous discussion, and a search for negative cases were conducted. Data were collected between May and July 2010. Nurses characterized their experiences managing heart failure in relation to many influences on their capacity for decision-making in LTC settings: (a) a reactive versus proactive approach to chronic illness; (b) ability to interpret heart failure signs, symptoms, and acuity; (c) compromised information flow; (d) access to resources; and (e) moral distress. Heart failure guideline implementation reflects multiple dynamic influences. Leadership that addresses these factors is required to optimize the conditions of heart failure care and related nursing practice.


Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis.
Peripheral T-cell lymphoma (PTCL) is a biologically diverse lymphoid malignancy. The clinical aggressiveness associated with hemophagocytic syndrome (HS) is a characteristic of PTCL, being more distinctive in CD8(+) PTCL. However, the underlying mechanism of PTCL-associated HS has not yet been fully investigated. We newly established a novel IL-2-dependent CD8(+) PTCL lymphoma cell line (T8ML-1) from a patient with CD8(+) PTCL who suffered recurrent HS accompanying disease flare-up. Focusing on the lymphoma cell T-cell receptor (TCR), we examined the lymphoma cell functions responsible for such clinical manifestations. First, T8ML-1.1 in which endogenous TCR-α/β chains were silenced by siRNAs, and T8ML-1.2 in which endogenous TCR-α/β chains were replaced with HLA-A*24:02-restricted and WT1(235-243)-specific TCR-α/β, were established. T8ML-1 exerted phytohemagglutinin (PHA)-dependent cytotoxicity via granular exocytosis. Additionally, soluble factors produced by PHA-stimulated T8ML-1, which included INF-γ and TNF-α, but not by simple-cultured T8ML-1, caused human monocytes to exhibit erythrophagocytosis and thrombophagocytosis in vitro. PHA binding induced phosphorylation of CD3ζ chain. Furthermore, both cytotoxicity and hemophagocytosis were completely inhibited by T8ML-1.1, but eventually restored by T8ML-1.2. These data suggest that exogenous activation of TCR signaling in PTCL cells might play an important role in the formation of PTCL-associated HS.


Ostomy function after abdominoperineal resection--a clinical and patient evaluation.
Abdominoperineal resection (APR) for rectal cancer results in a permanent colostomy. As a consequence of a recent change in operative technique from standard (S-APR) to extralevator resection (E-APR), the perineal part of the procedure is now performed with the patient in a prone jackknife position. The impact of this change on stoma function is unknown. The aim was to determine stoma-related complications and the individual patient experience of a stoma. Consecutive patients with rectal cancer operated on with APR in one institution in 2004 to 2009 were included. Recurrent cancer, palliative procedures, pre-existing stoma and patients not alive at the start of the study were excluded. Data were collected from hospital records and the national colorectal cancer registry. A questionnaire was sent out to patients. The median follow-up was 44 months (13-84) after primary surgery. Ninety-six patients were alive in February 2011. Seventy seven agreed to participate. Sixty-nine patients (90 %) returned the questionnaire. Stoma necrosis was more common for E-APR, 34 % vs. 10 %, but bandaging problems and low stoma height were more common for S-APR. There were no differences in the patients' experience of stoma function. In all, 35 % of the patients felt dirty and unclean, but 90 % felt that they had a full life and could engage in leisure activities of their choice. This exploratory study indicates no difference in stoma function after 1 year between S-APR and E-APR. Over 90 % of the patients accept their stoma, but our study indicates that more information and support for patients are warranted.


Therapeutic orthosis and electrical stimulation for upper extremity hemiplegia after stroke: a review of effectiveness based on evidence.
Upper extremity hemiplegia after stroke is common and disabling. Apart from conventional physical and occupational therapy, a number of additional approaches that use devices such as orthoses, prostheses, electrical stimulation, and robots have been introduced. The purpose of this review was to assess the clinical efficacy of such devices used for the affected upper extremities of acute, subacute, and chronic stroke patients. Assessments of their effectiveness and recommendations were based on the weight of published scientific evidence. The amount of evidence with respect to hand splints and shoulder slings is limited. Further study with a well-designed randomized controlled trial (RCT) is required to investigate accurately their short- and long-term efficacy. A number of studies suggested that the use of electrical stimulation for reducing shoulder subluxation or improving the function of wrist and finger extensors is effective during or shortly after the daily treatment period. The robotic approach to hemiplegic upper extremities appears to be a novel therapeutic strategy that may help improve hand and arm function. However, the longer term effectiveness after discontinuation as well as the motor recovery mechanism of electrical stimulation or robotic devices remains unclear. More research is needed to determine the evidence-based effectiveness of electrical stimulation or other devices for stroke survivors.


Interpersonal perception and interpersonal spin.
Interpersonal spin is an indicator of intraindividual variability in social behavior. Spin is positively related to Neuroticism and is maladaptive, with well-documented deleterious effects on social functioning. The perceptual processes associated with spin and how spin emerges are less well-understood. The present research examines the interpersonal perception of individuals with higher spin and tests whether these perceptual processes explain the association of spin with Neuroticism. 267 students participated in a 20-day event contingent recording procedure, reporting on social interactions via mobile application. Participants' perceptions of others' behavior, their own affect, and their own behavior were measured within and across interactions. We examined the affective and behavioral responses of individuals with higher spin to perceptions of others' behaviors. Individuals with higher spin showed greater affective and behavioral reactivity to perceptions of others' communal (agreeable-quarrelsome) behavior. Neuroticism predicted greater affective reactivity (i.e., steeper slopes between event-level perceived communion and negative affect), which in turn predicted higher spin. Individuals with higher spin may have an interpersonal style characterized by greater reactivity to perceptions of others' communal behavior. These individuals' behavioral lability may reflect underlying emotional dysregulation. These processes may ultimately interfere with the formation and maintenance of social bonds.


How Is Telemedicine Being Used In Opioid And Other Substance Use Disorder Treatment?
Only a small proportion of people with a substance use disorder (SUD) receive treatment. The shortage of SUD treatment providers, particularly in rural areas, is an important driver of this treatment gap. Telemedicine could be a means of expanding access to treatment. However, several key regulatory and reimbursement barriers to greater use of telemedicine for SUD (tele-SUD) exist, and both Congress and the states are considering or have recently passed legislation to address them. To inform these efforts, we describe how tele-SUD is being used. Using claims data for 2010-17 from a large commercial insurer, we identified characteristics of tele-SUD users and examined how tele-SUD is being used in conjunction with in-person SUD care. Despite a rapid increase in tele-SUD over the study period, we found low use rates overall, particularly relative to the growth in telemental health. Tele-SUD is primarily used to complement in-person care and is disproportionately used by those with relatively severe SUD. Given the severity of the opioid epidemic, low rates of tele-SUD use represent a missed opportunity. As tele-SUD becomes more available, it will be important to monitor closely which tele-SUD delivery models are being used and their impact on access and outcomes.


Parcellation of the cingulate cortex at rest and during tasks: a meta-analytic clustering and experimental study.
Anatomical, morphological, and histological data have consistently shown that the cingulate cortex can be divided into four main regions. However, less is known about parcellations of the cingulate cortex when involved in active tasks. Here, we aimed at comparing how the pattern of clusterization of the cingulate cortex changes across different levels of task complexity. We parcellated the cingulate cortex using the results of a meta-analytic study and of three experimental studies. The experimental studies, which included two active tasks and a resting state protocol, were used to control the results obtained with the meta-analytic parcellation. We explored the meta-analytic parcellation by applying a meta-analytic clustering (MaC) to papers retrieved from the BrainMap database. The MaC is a meta-analytic connectivity driven parcellation technique recently developed by our group which allowed us to parcellate the cingulate cortex on the basis of its pattern of co-activations during active tasks. The MaC results indicated that the cingulate cortex can be parcellated into three clusters. These clusters covered different percentages of the cingulate parenchyma and had a different density of foci, with the first cluster being more densely connected. The control experiments showed different clusterization results, suggesting that the co-activations of the cingulate cortex are highly dependent on the task that is tested. Our results highlight the importance of the cingulate cortex as a hub, which modifies its pattern of co-activations depending on the task requests and on the level of task complexity. The neurobiological meaning of these results is discussed.


Genetic Polymorphisms of Pesticide-Metabolizing Enzymes and Transporters in Agricultural Workers and Thyroid Hormone Levels.
Chronic exposure to pesticides has been associated with thyroid dysfunction owing to their endocrine disruption ability. Genetic variations in genes encoding phase I and II enzymes and phase III transporters are partly responsible for individual responses to chemical pesticides. This study investigated the association between variations in genes involved in pesticide metabolism and altered thyroid hormone concentrations. We assessed thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) in organic agriculture workers (n = 216) and workers who used chemical pesticides (n = 229). A questionnaire was used to collect sociodemographic, pesticide exposure, and health status data. Blood samples were analyzed for TSH, FT3, and FT4. Genomic DNA was extracted and genotyped using the TaqMan real-time PCR genotyping assay and restriction fragment length polymorphism method for 15 metabolically related genes. Significant differences in the TSH (1.58 vs 1.12 µIU/mL) and FT3 (0.34 vs 0.31 ng/dL) concentrations between the chemical and organic worker groups were observed. The frequencies of all single nucleotide polymorphisms were in Hardy-Weinberg equilibrium and were mostly consistent with Asian populations. The findings showed the association between SNPs of enzymes and transporters and TSH, FT3, and FT4. The odd ratio and adjusted odd ratio (with sex, age, smoking status, alcohol consumption and exposure parameters) for subclinical thyroid disease by the variant alleles CYP1A1 rs1048943, CYP2B6 rs2279343, CYP2C19 rs4244285, NAT2 rs1799931, and PON1 rs662 in the chemical workers compared with the organic workers were found (P values < 0.05). This is the first study to assess gene-environment interactions in Thai agricultural workers by investigating disruptions of the hypothalamic-pituitary-thyroid axis. The investigated SNP profiles revealed several gene-thyroid hormone associations in which even low levels of pesticide exposure could disturb thyroid homeostasis. These findings provide a foundation for planning future studies investigating associations between complex diseases and occupational pesticide exposure.


The supramolecular organisation of fibrillin-rich microfibrils determines the mechanical properties of bovine zonular filaments.
The zonular filaments from the eyes of cows are rich in microfibrils containing fibrillin. Tensile tests, stress-relaxation tests and X-ray diffraction studies were used to study the relationship between the mechanical behaviour of zonular filaments and the molecular packing and structure of the fibrillin-rich microfibrils. Zonular filaments show a non-linear (J-shaped) stress-strain curve and appreciable stress-relaxation. It is proposed that the non-linear properties are due to local variations in waviness in the microfibrils or assemblies of microfibrils, which straighten out and become more regularly aligned with strain. Previous and current X-ray diffraction results consistently show a partial ordering of microfibrils in zonular filaments into staggered aggregates which become more ordered and laterally aligned on stretching. Although the removal and re-addition of Ca(2+) is known to change the molecular structure of fibrillin, no effect was observed on the tensile properties of the zonular filaments. It is hypothesised that strain-induced deformation in the supramolecular aggregate packing may not be Ca(2+)-sensitive but could dominate the mechanical behaviour of microfibrillar arrays in zonular filaments.


Antibiotics for Post-Tonsillectomy Morbidity: Comparative Analysis of a Single Institutional Experience.
We have conducted this study to evaluate the effect of antibiotics, whether oral or intravenous, compared to no antibiotic protocol on post-tonsillectomy morbidity. A total of 270 patients aged 3 - 12 years were included in the study. Patients were assigned into three groups randomly; each group consisted of 90 patients. In the first group (group A), patients were given intravenous injections of ceftriaxone 50 mg/kg/24 hours in divided doses, the second group (group B) received oral co-amoxiclav (dose according to weight) for 5 days post-operatively, and in the third group, patients were not given antibiotics. Patients were evaluated for the incidence of any bleeding, number of days before resuming normal diet, incidence of nausea and vomiting, incidence of abdominal pain, frequency of analgesic use in the first week, and pain. Our study groups were comparable in age, gender, and weight. There were no statistically significant differences between our study groups with regard to the incidence of post-tonsillectomy bleeding, time relapsed to resume normal diet, and pain score scale. Incidence of nausea, vomiting, and abdominal pain was more in the oral antibiotic group, and it was statistically significant. We do not recommend the routine use of antibiotics in post-tonsillectomy period in pediatric age group and oral antibiotics prove to have worse outcome with regard to the incidence of nausea, vomiting, and abdominal pain, and these recommendations need to be evaluated by multicenter evaluation.


TRIM39-RPP21 Variants (∆19InsCCC) Are Not Associated with Juvenile Idiopathic Epilepsy in Egyptian Arabian Horses.
Juvenile idiopathic epilepsy (JIE) is an inherited disease characterized by recurrent seizures during the first year of life in Egyptian Arabian horses. Definitive diagnosis requires an electroencephalogram (EEG) performed by a veterinary specialist. A recent study has suggested that a 19 base-pair deletion, along with a triple-C insertion, in intron five of twelve (∆19InsCCC; chr20:29542397-29542425: GTTCAGGGGACCACATGGCTCTCTATAGA>TATCTTAAGACCC) of the Tripartite Motif-Containing 39-Ribonuclease p/mrp 21kDa Subunit (TRIM39-RPP21) gene is associated with JIE. To confirm this association, a new sample set consisting of nine EEG-phenotyped affected and nine unaffected Egyptian Arabian horses were genotyped using Sanger sequencing. There was no significant genotypic (P = 1.00) or allelic (P = 0.31) association with the ∆19InsCCC variant and JIE status. The previously reported markers in TRIM39-RPPB1 are therefore not associated with JIE in well-phenotyped samples. The ∆19InsCCC variant is a common variant that happens to be positioned in a highly polymorphic region in the Arabian breed.


Management of polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS), also known as Stein-Leventhal Syndrome, is a condition that afflicts many women during their childbearing years. It is one of the leading causes of female infertility. Symptoms of PCOS are related to androgen excess and are not associated with estrogen deficiency. Classic symptoms include amenorrhea, hirsutism, acne, and obesity. Management of PCOS is directed by the client's concerns regarding symptoms, desire for pregnancy, and degree of morbidity related to androgen excess. First-line management of PCOS includes diet modification, weight loss, and stress management. First-line treatment for androgen excess is estrogen therapy, the combination of estrogen and progesterone being the drugs of choice. Uncomplicated amenorrhea in PCOS is managed with monthly or bimonthly administration of medroxyprogesterone. The antiestrogen clomiphene citrate has been the drug of choice for inducing ovulation. The success of any treatment plan will depend largely on the client's ability to reduce body weight.


Chosen Name Use Is Linked to Reduced Depressive Symptoms, Suicidal Ideation, and Suicidal Behavior Among Transgender Youth.
This study aimed to examine the relation between chosen name use, as a proxy for youths' gender affirmation in various contexts, and mental health among transgender youth. Data come from a community cohort sample of 129 transgender and gender nonconforming youth from three U.S. cities. We assessed chosen name use across multiple contexts and examined its association with depression, suicidal ideation, and suicidal behavior. After adjusting for personal characteristics and social support, chosen name use in more contexts was associated with lower depression, suicidal ideation, and suicidal behavior. Depression, suicidal ideation, and suicidal behavior were lowest when chosen names could be used in all four contexts. For transgender youth who choose a name different from the one given at birth, use of their chosen name in multiple contexts affirms their gender identity and reduces mental health risks known to be high in this group.


Chemoselective N-H functionalization of indole derivatives via the Reissert-type reaction catalyzed by a chiral phosphoric acid.
An asymmetric N-alkylation of indole derivatives via the Reissert-type reaction was realized in the presence of a catalytic amount of chiral phosphoric acid. Various enantioenriched indoles with N-1 substituted by 1,2-dihydroisoquinoline could be obtained under mild conditions in good yields and enantioselectivities at room temperature (up to 98% yield, 94% ee). The current method is compatible with gram-scale reaction and the products can undergo versatile chemical transformations.


Chemical profiling and anti-psoriatic activity of marine sponge (Dysidea avara) in induced imiquimod-psoriasis-skin model.
Since Marine sponge Dysidea avara is regarded as a source of anti-inflammatory compounds, we decided to evaluate its potential anti-psoriatic activity in a psoriasis Imiquimod-induced in the mouse model. Psoriatic mice were treated with three different methanolic extracts of Dysidea avara compared with betamethasone-treated mice in in- vivo studies. Clinical skin severity was assessed with the psoriasis area index (PASI), whilst ELISA detected the expression of TNF-α, IL-17A, and IL-22. Dysidea avara activity was studied by employing GC-MS (to distinguish compounds), HPTLC (for skin permeation and accumulation), and SEA DOCK to predict single compound potential anti-inflammatory activity. After 7 days of treatment, mice treated with Dysidea avara displayed a dose-dependent, statistically significant improvement compared to controls (p< 0.001). In line with the clinical results, ELISA revealed a statistically significant decrease in IL-22, IL-17A, and TNF-α after treatment; the same SEA DOCK analysis suggests a possible anti-psoriatic activity of the extracts.


Development of software and modification of Q-FISH protocol for estimation of individual telomere length in immunopathology.
Telomere length is an important indicator of proliferative cell history and potential. Decreasing telomere length in the cells of an immune system can indicate immune aging in immune-mediated and chronic inflammatory diseases. Quantitative fluorescent in situ hybridization (Q-FISH) of a labeled (C3TA[Formula: see text] peptide nucleic acid probe onto fixed metaphase cells followed by digital image microscopy allows the evaluation of telomere length in the arms of individual chromosomes. Computer-assisted analysis of microscopic images can provide quantitative information on the number of telomeric repeats in individual telomeres. We developed new software to estimate telomere length. The MeTeLen software contains new options that can be used to solve some Q-FISH and microscopy problems, including correction of irregular light effects and elimination of background fluorescence. The identification and description of chromosomes and chromosome regions are essential to the Q-FISH technique. To improve the quality of cytogenetic analysis after Q-FISH, we optimized the temperature and time of DNA-denaturation to get better DAPI-banding of metaphase chromosomes. MeTeLen was tested by comparing telomere length estimations for sister chromatids, background fluorescence estimations, and correction of nonuniform light effects. The application of the developed software for analysis of telomere length in patients with rheumatoid arthritis was demonstrated.


Pathological findings on peripheral nerves, lymph nodes, and visceral organs of leprosy.
Pathological findings in a) 103 autopsies, b) biopsy material of peripheral nerve tissue from 210 tuberculoid patients, and c) inguinal lymph nodes from 106 leprosy cases are presented. Overall, lesions in peripheral nerves were most common in the ulnar (85.7% in the TT type, 98.3% in LL), peroneal (77.8% in TT, 97.9% in LL), median (80% in TT, 90.2% in LL), radial (66.6% in TT, 82% in LL), and the great auricular, tibial and supraorbital nerves. The ratio of bilateral nerve involvement in the same nerve was higher than unilateral involvement (approximately 5:1). Lesions of the peripheral nerve ganglion were seen in the LL type (22 cases, 61.1%) and the TT type (8 cases, 53.3%). These have seldom been mentioned in past literature. Superficial lymph nodes were most commonly affected in all types of leprosy. Lymph nodes in the hepatic and splenic portal areas were sometimes involved in lepromatous or borderline cases. Between the two polar types of leprosy, the lesions in the lymph nodes showed gradual transitions in a spectrum-like pattern which were similar to the changes in the lesions in the skin. In lepromatous leprosy, lesions could be found in 85.3% of the cases in the liver, 41.1% in the spleen, 86.7% in the testes, approximately 50% in the upper respiratory tract (including 36.4% in the nasopharynx), and 34.4% in the adrenal gland. Three cases had ophthalmologic lesions. In borderline leprosy, biphasic lesions of leprosy were found in various internal organs.(ABSTRACT TRUNCATED AT 250 WORDS)


Developmental consequences of prenatal tobacco exposure.
This paper reviews results from published, in press, and conference proceedings from 2007 and 2008 that link in-utero tobacco exposure to neurodevelopmental outcomes in exposed offspring. Prenatal tobacco exposure (PTE) affected speech processing, levels of irritability and hypertonicity, attention levels, ability to self-regulate, need to be handled, and response to novelty preference in infants. In early childhood, PTE effects were mostly behavioral outcomes including activity and inattention and externalizing behaviors, including conduct disorder and antisocial behavior. In adolescents, PTE predicted increased attention deficit hyperactivity disorder, modulation of the cerebral cortex and white matter structure, and nicotine addiction. Several studies found moderating effects with PTE and genetic susceptibilities including dopamine transporter, serotonergic synaptic function, and monomine oxidase pathways. Other studies suggested that environmental and genetic factors might be more important than the direct teratological effects of PTE. The majority of studies reviewed were prospective and tobacco exposure was quantified biologically. Most demonstrated a direct association between PTE and neurodevelopmental outcomes. More work is needed to examine multifactorial influences. Effects of PTE on the offspring appear to be moderated by genetic variability, neurobehavioral disinhibition, and sex.


Anti-Xa effect of a low molecular weight heparin (dalteparin) does not accumulate in extended duration therapy for venous thromboembolism in cancer patients.
Many patients with venous thromboembolism are being treated with low molecular weight heparin for extended periods of time. It is not certain if it is necessary to assess anti-Xa levels for extended treatment periods. This study is a prospective assessment of anti-Xa levels in patients on long-term therapy for acute venous thromboembolism who have active cancer. Consecutive consenting patients from one center in a multicenter trial that compared 6 months of low molecular weight heparin with oral anticoagulant therapy were treated with therapeutic doses of dalteparin (200 IU per kilogram) subcutaneously daily. Anti-Xa levels were assessed at the end of weeks 1 and 4,4-6 hours after injection of dalteparin. Patients were followed for bleeding and recurrent venous thromboembolism. There were 24 patients who had anti-Xa levels measured at weeks 1 and 4. Two other patients had week 1 measurements performed but died before the week 4 sample was collected due to their underlying cancer. The mean anti-Xa levels at weeks 1 and 4 were 1.11 and 1.03 anti-Xa units/ml respectively (P=0.13). These results suggest that for patients with active cancer receiving extended duration therapy with low molecular weight heparin (dalteparin) there is no accumulation of anti-Xa effect over the first month of therapy. Monitoring of anti-Xa levels in this situation is usually not required.


Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort.
Approximately 1% of lung adenocarcinomas are driven by oncogenic ROS1 rearrangement. Crizotinib is a potent inhibitor of both ROS1 and ALK kinase domains. In the absence of a prospective clinical trial in Europe, we conducted a retrospective study in centers that tested for ROS1 rearrangement. Eligible patients had stage IV lung adenocarcinoma, had ROS1 rearrangement according to fluorescent in situ hybridization, and had received crizotinib therapy through an individual off-label use. Best response was assessed locally using RECIST (version 1.1). All other data were analyzed centrally. We identified 32 eligible patients. One patient was excluded because next-generation sequencing was negative for ROS1 fusion. Median age was 50.5 years, 64.5% of patients were women, and 67.7% were never-smokers. Thirty patients were evaluable for progression-free survival (PFS), and 29 patients were evaluable for best response. We observed four patients with disease progression, two patients with stable disease, and objective response in 24 patients, including five complete responses (overall response rate, 80%; disease control rate, 86.7%). Median PFS was 9.1 months, and the PFS rate at 12 months was 44%. No unexpected adverse effects were observed. Twenty-six patients received pemetrexed (either alone or in combination with platinum and either before or after crizotinib) and had a response rate of 57.7% and a median PFS of 7.2 months. Crizotinib was highly active at treating lung cancer in patients with a ROS1 rearrangement, suggesting that patients with lung adenocarcinomas should be tested for ROS1. Prospective clinical trials with crizotinib and other ROS1 inhibitors are ongoing or planned.


How prenatal head ultrasound reference ranges affect evaluation of possible fetal microcephaly.
Different fetal ultrasound (US) nomograms of the head circumference (HC) have been established; however, comparisons between the detection rates of microcephaly among US nomograms are few and inconsistent. We aimed to compare the prenatal diagnostic rate of fetal microcephaly (FM) among four widely used US nomograms of the fetal HC, when applied to the same group of fetuses. We retrospectively identified singleton pregnancies complicated by fetal HC < 5th percentile for gestational age (GA) by US, without other risk factors for FM and with normal fetal brain MRI. Raw values of HC by US were converted to z-scores using four nomograms (Chervenak = A, Hadlock = B, Gelber = C, Papageorghiou = D). Z-scores value of the HC were classified as normal, possible normal, or microcephaly if values were >-2, ≤ -2 and >-3, or ≤ -3, respectively and compared among the four nomograms. Fifty one fetuses at a mean (±SD) GA of 28 (±4) weeks were included. The four nomograms resulted in different z-score values of the fetal HC for the same subject (p < .001) and none of them showed 100% agreement. Reference C and D showed the highest agreement in classifying subjects as normal, possible normal, or with microcephaly (simple Kappa = 0.8915, % agreement = 94.1%), while A and B had the lowest agreement (simple Kappa = 0.0977, % agreement = 51.0%). Despite the use of similar prenatal cutoff z-score values of the fetal HC, the four nomograms led to different diagnostic rates of FM. More consistent diagnostic criteria are therefore needed to define FM, especially in the absence of other risk factors for FM and normal fetal brain MRI, since the prenatal diagnosis can affect pregnancy management.


Distinct subsets of retroviruses encode dUTPase.
The nonprimate lentiviruses feline immunodeficiency virus, equine infectious anemia virus, visna virus, and caprine encephalitis virus contain a gene segment in the polymerase gene that is lacking in the primate lentiviruses. A related sequence has been noted in other retroviruses, most notably the type D retroviruses. Computer searches have indicated a relatedness between this unique gene segment, termed proteaselike element and elements of both the aspartate proteinase and the dUTPase enzyme families. In this report, we show that members of both nonprimate lentiviruses and type D retroviruses possess dUTPase activity and present a formal demonstration that in feline immunodeficiency virus, the activity is encoded by the proteaselike element.


Efficient generation of vesicular stomatitis virus (VSV)-pseudotypes bearing morbilliviral glycoproteins and their use in quantifying virus neutralising antibodies.
Morbillivirus neutralising antibodies are traditionally measured using either plaque reduction neutralisation tests (PRNTs) or live virus microneutralisation tests (micro-NTs). While both test formats provide a reliable assessment of the strength and specificity of the humoral response, they are restricted by the limited number of viral strains that can be studied and often present significant biological safety concerns to the operator. In this study, we describe the adaptation of a replication-defective vesicular stomatitis virus (VSVΔG) based pseudotyping system for the measurement of morbillivirus neutralising antibodies. By expressing the haemagglutinin (H) and fusion (F) proteins of canine distemper virus (CDV) on VSVΔG pseudotypes bearing a luciferase marker gene, neutralising antibody titres could be measured rapidly and with high sensitivity. Further, by exchanging the glycoprotein expression construct, responses against distinct viral strains or species may be measured. Using this technique, we demonstrate cross neutralisation between CDV and peste des petits ruminants virus (PPRV). As an example of the value of the technique, we demonstrate that UK dogs vary in the breadth of immunity induced by CDV vaccination; in some dogs the neutralising response is CDV-specific while, in others, the neutralising response extends to the ruminant morbillivirus PPRV. This technique will facilitate a comprehensive comparison of cross-neutralisation to be conducted across the morbilliviruses.


Expression of human glucocerebrosidase in long-term reconstituted mice following retroviral-mediated gene transfer into hematopoietic stem cells.
A retroviral vector (GTN) in which the glucocerebrosidase (GCase) cDNA is driven by the Moloney murine leukemia virus (Mo-MuLV) long terminal repeat (LTR) was tested for transfer efficiency and expression of the GCase gene in long-term reconstituted mice. Eleven W/Wv mice were transplanted with unselected GTN-infected bone marrow cells and 10 of these mice were analyzed 3 months later. Seven of these 10 mice (70%) contained the intact proviral genome in bone marrow, spleen, and thymus. Of these 7,3 mice contained a high-copy number of the provirus in all the hematopoietic tissues tested. The mice contained anywhere from one to four proviral integration sites that were the same in all three tissues, indicating that these mice have been repopulated by one or more transduced multipotential hematopoietic stem cells. Five months after transplantation, bone marrow from the eleventh mouse was transplanted into secondary recipient animals. The secondary recipients contained the intact proviral genome in the bone marrow, spleen, thymus, and macrophages 4 months after the secondary transplantation. This further supports the conclusion that hematopoietic stem cells have indeed been targeted. Human GCase RNA was detected in all 7 mice containing the proviral DNA. These results demonstrate expression of the human GCase gene in the progeny of repopulating hematopoietic stem cells of mice following gene transfer.


Pseudarcicella hirudinis gen. nov., sp. nov., isolated from the skin of the medical leech Hirudo medicinalis.
A pinkish-pigmented, Gram-stain-negative, rod-shaped, non-spore-forming bacterium, strain E92(T), was isolated from the skin of the medical leech Hirudo medicinalis, on R2A agar. 16S rRNA gene sequence analysis of strain E92(T) showed a relatively low 16S rRNA gene sequence similarity (93.0-93.5 %) to representatives of the genus Arcicella and 91.5-92.0 % to members of the genus Flectobacillus. The polar lipid profile was composed of the major compounds phosphatidylethanolamine, an unidentified aminophospholipid, an unidentified aminolipid and an unidentified polar lipid; glycolipids were not detected. The major quinone was menquinone MK-7, and the major compound in the polyamine pattern was spermidine. The predominant fatty acids were C(16 : 1)ω5c and C(16 : 1)ω7c and/or iso-C(15 : 0) 2-OH (detected as summed feature 3). The isolate did not contain C(14 : 0) or the hydroxyl fatty acid iso-C(17 : 0) 3-OH found in all representatives of the genera Arcicella and Flectobacillus, but did produce C(18 : 1)ω7c and 11-methyl C(18 : 1)ω7c which are not found in these two genera. The DNA G+C content of strain E92(T) was 64.4 mol%. The unique 16S rRNA gene sequence, and specific chemotaxonomic and physiological data revealed that strain E92(T) represents a new genus in the family Cytophagaceae for which we propose the name Pseudarcicella hirudinis gen. nov., sp. nov., with the type strain of the type species as E92(T) (= LMG 26720(T) = CCM 7988(T)).


The mental health of young people in Australia: key findings from the child and adolescent component of the national survey of mental health and well-being.
To identify the prevalence of three mental disorders (Depressive Disorder, Conduct Disorder and Attention-Deficit/Hyperactivity Disorder), the prevalence of mental health problems, the health-related quality of life of those with problems, and patterns of service utilisation of those with and without mental health problems, among 4-17-year-olds in Australia. To identify rates of health-risk behaviours among adolescents with mental health problems. The mental disorders were assessed using the parent-version of the Diagnostic Interview Schedule for Children Version IV. Parents completed the Child Behaviour Checklist to identify mental health problems and standard questionnaires to assess health-related quality of life and service use. The Youth Risk Behaviour Questionnaire completed by adolescents was employed to identify health-risk behaviours. Fourteen percent of children and adolescents were identified as having mental health problems. Many of those with mental health problems had problems in other areas of their lives and were at increased risk for suicidal behaviour. Only 25% of those with mental health problems had attended a professional service during the six months prior to the survey. Child and adolescent mental health problems are an important public health problem in Australia. The appropriate balance between funding provided for clinical interventions focusing on individual children and families and funding for interventions that focus on populations, requires careful study. The latter are an essential component of any strategy to reduce mental health problems as the high prevalence of problems makes it unlikely that individual care will ever be available for all those needing help. Clinical and population health interventions must take into account the comorbid problems experienced by children with mental disorders.


Regulation of polycystin expression, maturation and trafficking.
The major autosomal dominant polycystic kidney disease (ADPKD) genes, PKD1 and PKD2, are wildly expressed at the organ and tissue level. PKD1 encodes polycystin 1 (PC1), a large membrane associated receptor-like protein that can complex with the PKD2 product, PC2. Various cellular locations have been described for both PC1, including the plasma membrane and extracellular vesicles, and PC2, especially the endoplasmic reticulum (ER), but compelling evidence indicates that the primary cilium, a sensory organelle, is the key site for the polycystin complex to prevent PKD. As with other membrane proteins, the ER biogenesis pathway is key to appropriately folding, performing quality control, and exporting fully folded PC1 to the Golgi apparatus. There is a requirement for binding with PC2 and cleavage of PC1 at the GPS for this folding and export to occur. Six different monogenic defects in this pathway lead to cystic disease development, with PC1 apparently particularly sensitive to defects in this general protein processing pathway. Trafficking of membrane proteins, and the polycystins in particular, through the Golgi to the primary cilium have been analyzed in detail, but at this time, there is no clear consensus on a ciliary targeting sequence required to export proteins to the cilium. After transitioning though the trans-Golgi network, polycystin-bearing vesicles are likely sorted to early or recycling endosomes and then transported to the ciliary base, possibly via docking to transition fibers (TF). The membrane-bound polycystin complex then undergoes facilitated trafficking through the transition zone, the diffusion barrier at the base of the cilium, before entering the cilium. Intraflagellar transport (IFT) may be involved in moving the polycystins along the cilia, but data also indicates other mechanisms. The ciliary polycystin complex can be ubiquitinated and removed from cilia by internalization at the ciliary base and may be sent back to the plasma membrane for recycling or to lysosomes for degradation. Monogenic defects in processes regulating the protein composition of cilia are associated with syndromic disorders involving many organ systems, reflecting the pleotropic role of cilia during development and for tissue maintenance. Many of these ciliopathies have renal involvement, likely because of faulty polycystin signaling from cilia. Understanding the expression, maturation and trafficking of the polycystins helps understand PKD pathogenesis and suggests opportunities for therapeutic intervention.


HIV-1 Tat induces DNMT over-expression through microRNA dysregulation in HIV-related non Hodgkin lymphomas.
A close association between HIV infection and the development of cancer exists. Although the advent of highly active antiretroviral therapy has changed the epidemiology of AIDS-associated malignancies, a better understanding on how HIV can induce malignant transformation will help the development of novel therapeutic agents. HIV has been reported to induce the expression of DNMT1 in vitro, but still no information is available about the mechanisms regulating DNMT expression in HIV-related B-cell lymphomas. In this paper, we investigated the expression of DNMT family members (DNMT1, DNMT3a/b) in primary cases of aggressive B-cell lymphomas of HIV-positive subjects. Our results confirmed the activation of DNMT1 by HIV in vivo, and reported for the first time a marked up-regulation of DNMT3a and DNMT3b in HIV-positive aggressive B-cell lymphomas. DNMT up-regulation in HIV-positive tumors correlated with down-regulation of specific microRNAs, as the miR29 family, the miR148-152 cluster, known to regulate their expression. Literature reports the activation of DNMTs by the human polyomavirus BKV large T-antigen and adenovirus E1a, through the pRb/E2F pathway. We have previously demonstrated that the HIV Tat protein is able to bind to the pocket proteins and to inactivate their oncosuppressive properties, resulting in uncontrolled cell proliferation. Therefore, we focused on the role of Tat, due to its capability to be released from infected cells and to dysregulate uninfected ones, using an in vitro model in which Tat was ectopically expressed in B-cells. Our findings demonstrated that the ectopic expression of Tat was per se sufficient to determine DNMT up-regulation, based on microRNA down-regulation, and that this results in aberrant hypermethylation of target genes and microRNAs. These results point at a direct role for Tat in participating in uninfected B-cell lymphomagenesis, through dysregulation of the epigenetical control of gene expression.


The Science Underlying COVID-19: Implications for the Cardiovascular System.
The coronavirus disease 2019 (COVID-19) pandemic has affected health and economy worldwide on an unprecedented scale. Patients have diverse clinical outcomes, but those with preexisting cardiovascular disease, hypertension, and related conditions incur disproportionately worse outcome. The high infectivity of severe acute respiratory syndrome coronavirus 2 is in part related to new mutations in the receptor binding domain, and acquisition of a furin cleavage site in the S-spike protein. The continued viral shedding in the asymptomatic and presymptomatic individuals enhances its community transmission. The virus uses the angiotensin converting enzyme 2 receptor for internalization, aided by transmembrane protease serine 2 protease. The tissue localization of the receptors correlates with COVID-19 presenting symptoms and organ dysfunction. Virus-induced angiotensin converting enzyme 2 downregulation may attenuate its function, diminish its anti-inflammatory role, and heighten angiotensin II effects in the predisposed patients. Lymphopenia occurs early and is prognostic, potentially associated with reduction of the CD4+ and some CD8+ T cells. This leads to imbalance of the innate/acquired immune response, delayed viral clearance, and hyperstimulated macrophages and neutrophils. Appropriate type I interferon pathway activation is critical for virus attenuation and balanced immune response. Persistent immune activation in predisposed patients, such as elderly adults and those with cardiovascular risk, can lead to hemophagocytosis-like syndrome, with uncontrolled amplification of cytokine production, leading to multiorgan failure and death. In addition to the airways and lungs, the cardiovascular system is often involved in COVID-19 early, reflected in the release of highly sensitive troponin and natriuretic peptides, which are all extremely prognostic, in particular, in those showing continued rise, along with cytokines such as interleukin-6. Inflammation in the vascular system can result in diffuse microangiopathy with thrombosis. Inflammation in the myocardium can result in myocarditis, heart failure, cardiac arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. Aggressive support based on early prognostic indicators with expectant management can potentially improve recovery. Appropriate treatment for heart failure, arrhythmias, acute coronary syndrome, and thrombosis remain important. Specific evidence-based treatment strategies for COVID-19 will emerge with ongoing global collaboration on multiple approaches being evaluated. To protect the wider population, antibody testing and effective vaccine will be needed to make COVID-19 history.


Pathology of intracranial neoplasms.
This article discusses the gross and microscopic pathology of intracranial neoplasms. Primary intracranial neoplasms include tumors of the brain parenchyma; meninges; and rest of mesenchymal, epithelial, and germ cell derivation. The concept of tumor malignancy for primary central nervous system (CNS) neoplasms is somewhat different from that for systemic tumors. Although the capacity to metastasize is a defining feature of systemic malignancies and metastasis to the brain is a relatively common occurrence, primary CNS neoplasms rarely metastasize outside the CNS.


Robotic automation of cyclosporine analysis in whole blood.
Cyclosporin A (CsA) is currently the most selective immunosuppressant used clinically to prevent organ rejection after transplantation. We used a reprogrammable robot, the Benchmate (Zymark Inc., Hopkinton, MA), to automate much of the sample preparation involved in solid-phase extraction of CsA. Lysed whole-blood specimens containing previously added internal standard were placed on the Benchmate in the specimen-holding area, and a C18 Bond-Elut column was placed in the top of the sample tube. Specimen extraction from this point was handled automatically by the Benchmate, after which we manually injected the sample into the HPLC system for quantification. Analytical recovery of CsA in two concentrations of calibrator was similar for the manual and Benchmate methods. Analytical imprecision for the Benchmate was less than for manual extraction: within-run imprecision (CV) was less than 8% at either concentration. Between-run imprecision, determined by having the Benchmate extract CsA from two specimens each day for 20 days, was less than 9%. Patients' specimens were extracted manually (x) or by using the Benchmate robot (y); the results, compared by linear regression, agreed well: (y = 0.99 (SD 0.02)x + 2.6 (SD 2.8) micrograms/L (Sy[x = 7.59 micrograms/L, n = 27). We conclude that the Benchmate usefully reduces the manual steps necessary to extract specimens before HPLC analysis for CsA.


Cell density-dependent modulation of the Vibrio fischeri luminescence system in the absence of autoinducer and LuxR protein.
Expression of the Vibrio fischeri luminescence genes (luxR and luxICDABEG) in Escherichia coli requires autoinducer (N-3-oxohexanoyl homoserine lactone) and LuxR protein, which activate transcription of luxICDABEG (genes for autoinducer synthase and the luminescence enzymes), and cyclic AMP (cAMP) and cAMP receptor protein (CRP), which activate transcription of the divergently expressed luxR gene. In E. coli and in V. fischeri, the autoinducer-LuxR protein-dependent induction of luxICDABEG transcription (called autoinduction) is delayed by glucose, whereas it is promoted by iron restriction, but the mechanisms for these effects are not clear. To examine in V. fischeri control of lux gene expression by autoinducer, cAMP, glucose, and iron, lux::Mu dI(lacZ) and lux deletion mutants of V. fischeri were constructed by conjugation and gene replacement procedures. beta-Galactosidase synthesis in a luxC::lacZ mutant exhibited autoinduction. In a luxR::lacZ mutant, complementation by the luxR gene was necessary for luminescence, and addition of cAMP increased beta-galactosidase activity four- to sixfold. Furthermore, a luxI::lacZ mutant produced no detectable autoinducer but responded to its addition with induced synthesis of beta-galactosidase. These results confirm in V. fischeri key features of lux gene regulation derived from studies with E. coli. However, beta-galactosidase specific activity in the luxI::lacZ mutant, without added autoinducer, exhibited an eight- to tenfold decrease and rise back during growth, as did beta-galactosidase and luciferase specific activities in the luxR::lacZ mutant and luciferase specific activity in a delta(luxR luxICD) mutant. The presence of glucose delayed the rise back in beta-galactosidase and luciferase specific activities in these strains, whereas iron restriction promoted it. Thus, in addition to transcriptional control by autoinducer and LuxR protein, the V. fischeri lux system exhibits a cell density-dependent modulation of expression that does not require autoinducer, LuxR protein, or known lux regulatory sites. The response of autoinducer-LuxR protein-independent modulation to glucose and iron may account for how these environmental factors control lux gene expressions.


Family treatment of childhood anxiety: a controlled trial.
A family-based treatment for childhood anxiety was evaluated. Children (n = 79) aged 7 to 14 who fulfilled diagnostic criteria for separation anxiety, overanxious disorder, or social phobia were randomly allocated to 3 treatment conditions: cognitive-behavioral therapy (CBT), CBT plus family management (CBT + FAM), and waiting list. The effectiveness of the interventions was evaluated at posttreatment and at 6 and 12 months follow-up. The results indicated that across treatment conditions, 69.8% of the children no longer fulfilled diagnostic criteria for an anxiety disorder, compared with 26% of the waiting-list children. At the 12-month follow-up, 70.3% of the children in the CBT group and 95.6% of the children in the CBT + FAM group did not meet criteria. Comparisons of children receiving CBT with those receiving CBT + FAM on self-report measures and clinician ratings indicated added benefits from CBT + FAM treatment. Age and gender interacted with treatment condition, with younger children and female participants responding better to the CBT + FAM condition.


Phase IV postmarketing surveillance study shows continued efficacy and safety of Stempeucel in patients with critical limb ischemia due to Buerger's disease.
Buerger's disease or thromboangiitis obliterans is a type of obstructive vascular diseases categorized as vasculitis and usually present in 95% of young smoker men. The main pathogenetic mechanism is interplay between immune system and inflammation. Earlier our phase II study has shown that Stempeucel is safe when injected at 2 million cells/kg body weight by virtue of its anti-inflammatory, immunomodulatory, and angiogenetic properties. The present study was conducted to further assess the safety and efficacy of Stempeucel in critical limb ischemia due to Buerger's disease after obtaining approval from Indian FDA based on the data generated in the phase II study. This is an open label, multicenteric phase IV PMS study conducted across India with experienced vascular surgeons. Fifty patients of critical limb ischemia due to Buerger's disease with Rutherford III-5 or III-6 were included in the study and each individual received a dose of 2 million cells/kg body weight of Stempeucel in the calf muscles and around the ulcer. These patients were evaluated over 12 months from drug administration. The present study showed the continued long term efficacy over a period of 12 months follow up in these patients corroborating the result obtained in the previous phase II studies. There was significant improvement in rest pain, ankle systolic pressure, and ankle brachial pressure index with accelerated ulcer healing. In conclusion, the present study shows that the intramuscular administration of Stempeucel continues to be safe, tolerable, and effective alternative treatment in patients with Buerger's disease.


Allyl isothiocyanate inhibits cell metastasis through suppression of the MAPK pathways in epidermal growth factor‑stimulated HT29 human colorectal adenocarcinoma cells.
Allyl isothiocyanate (AITC) has been found to present sources from consumed cruciferous vegetables. AITC is known to possess pharmacological and anticancer activities. The present study was designed to test the hypothesis that AITC suppressed the invasion and migration of epidermal growth factor (EGF)-stimulated HT29 cells and to elucidate the mechanisms for the antimetastatic abilities in vitro. The invasion and migration of EGF-stimulated HT29 cells were determined individually by Transwell cell invasion and wound-healing assays. Our results showed that AITC effectively inhibited both the invasive and migratory ability of HT29 cells. Furthermore, AITC downregulated the protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and mitogen-activated protein kinases (MAPKs) (p-JNK, p-ERK and p-p38) by western blot analysis in HT29 cells following EGF induction. Thus, the metastatic responses in AITC-treated HT29 cells after EGF stimulation were mediated by the MMP-2/-9 and MAPK signaling pathways. We also used gene expression microarrays to investigate the gene levels related to cell growth, G-protein coupled receptor, angiogenesis, cell adhesion, cell cycle and mitosis, cell migration, cytoskeleton organization, DNA damage and repair, transcription and translation, EGFR and PKB/mTOR signals. In summary, it is possible that AITC suppresses the invasion and migration of EGF-induced HT29 cells, resulting from MMP-2/-9 and MAPKs. Hence, AITC may be beneficial in the treatment of human colorectal adenocarcinoma in the future.


Syntactic priming in spoken production: linguistic and temporal interference.
Current evidence about the persistence of syntactic priming effects (Bock, 1986) is equivocal: Using spoken picture description, Bock and Griffin (2000) found that it persisted over as many as 10 trials; using written sentence completion, Branigan, Pickering, and Cleland (1999) found that it dissipated if even a single sentence intervened between prime and target. This paper asks what causes it to be long lasting. On one account, the rapid decay evidenced by Branigan et al. occurs because the task emphasizes conceptual planning; on another account, it is due to the written nature of their task. If conceptual planning is the cause, this might relate to planning the prime sentence or planning an intervening sentence. Hence we conducted an experiment with spoken sentence completion, contrasting no delay, an intervening sentence, and a pure temporal delay. The results indicated that strong and similar priming occurred in all three cases, therefore lending support to the claim that spoken priming is long lasting.


'Scuola sicura': a school screening testing programme to prevent the spread of COVID-19 in students in Piedmont.
'Scuola sicura' (SS) programme aims to monitor the rate of COVID-19 and to contain its spread within the school population through early case isolation. to describe the initial process and outcome evaluation results. descriptive study of an experimental screening testing programme in children in Piedmont Region (Northern Italy) in the period January-March 2021. The data used came from the COVID-19 platform and the Local Health Units, the archives of birth certificates (CedAP), and hospital discharge files (SDO). the screening programme targeted second and third grade students in first level secondary schools. Participants were subdivided into four groups; one group each week underwent screening, yielding one test per student per month. it was calculated: 1. number of positive cases detected vs total number of students tested in the SS programme; 2. number of positive cases detected outside the SS program vs. total number of students in the target population. The number of quarantines due to SS and no-SS case identification were detected. To investigate the spread of COVID-19 in households, the mother-child pairs were identified through record linkage between the CedAP and SDO archives, and positive mothers were identified. sixty-nine percent of schools and 19.5% of the students participated in the programme. SS detected 114 positives cases for SARS-CoV-2. On 08.03.2021, the target classes started distance learning: 69 of the 114 positive students were identified before that date, leading to the activation of 67 quarantine measures. Only for 61 out of 69 of those students (88%) was possible to identify the mother; 46 mothers had performed a swab test after the positivity of their child with a positive result in 11 cases. Asymptomatic cases identified at screening during in-class learning period accounted for 26.5% of the total number of cases occurred in the participating classes. this is one of the few studies (and the first in Italy) to describe the functioning and predictive capacity of school screening testing for SARS-CoV-2 in a real-world situation. The findings provide data-driven suggestions for government agencies when planning large-scale school screening testing programmes.


[Benign metastasizing leiomyoma of the lung. Report of a case].
Benign metastasizing leiomyoma (BML) is the term used to describe multiple benign pulmonary leiomyomatous lesions occurring in patients with a previous history of uterine leiomyoma. On the other hand, pulmonary fibroleiomyomatous hamartoma (FLH) is also multiple nodules and the discrimination of the nodules between BML and FLH is not determined. We report the case of 36-year-old woman who had a previous history of uterine leiomyoma. The woman was referred to our hospital for evaluation of asymptomatic bilateral nodules in chest roentgenogram examination. A chest X-ray showed multiple nodules in bilateral lung. Chest computed tomography (CT) scan showed round nodules well-defined margins in bilateral lung. Thoracoscopic partial resection of the lung was performed. Pathological examination revealed that the tumor composed of spindle-shaped smooth muscle cells and its characteristics were remarkably similar to those of the previously resected uterine leiomyoma. Therefore, these lung tumors could be considered to be lung metastases from a uterine leiomyoma (benign metastasizing leiomyoma).


Association between the Stin2 VNTR polymorphism of the serotonin transporter gene and treatment outcome in alcohol-dependent patients.
The aim of this study was to investigate the potential association between functional polymorphisms of dopaminergic [dopamine receptor D2 (DRD2), dopamine receptor D3 (DRD3) and dopamine transporter (SLC6A3)] and serotonergic [serotonin 2A receptor (HTR2A) and serotonin transporter (SLC6A4)] genes and treatment outcome in alcohol-dependent patients. A total of 90 Spanish Caucasian alcohol-dependent outpatients (ICD-10 criteria) were enrolled in the study. The association between genotypes and drinking outcomes was measured over 6 months of treatment. Biomarkers of alcohol consumption, as well as alcohol consumption and its consequences, craving, disability and quality of life, were assessed. Based on those measures, we created a composite secondary measure to globally assess treatment outcome in alcoholism. No association was found between DRD2, DRD3, SLC6A3 or HTR2A gene variants and treatment outcome. However, SLC6A4 STin2 12/12 carriers showed poor 6-month time point treatment outcome [32.8% in the good outcome group versus 64.0% in the poor outcome group, chi(2) (df) = 7.20 (1), corrected P = 0.042, OR (95% CI) = 0.27 (0.10-0.72)]. Nevertheless, independent analysis of each treatment group reveals that the excess of 12/12 carriers in the poor outcome group was only found in the naltrexone-treated group [24.1% versus 64.7% chi(2) (df) = 7.41 (1), corrected P = 0.042, OR (95% CI) = 0.17 (0.05-0.64)]. In the whole sample, the L-10 repeats haplotype (5-HTTLPR-STin2 VNTR) is associated with good outcome (LRT = 3.88, df = 1, P = 0.049). Our findings suggest that functional polymorphism of the SLC6A4 gene may have an influence on treatment outcome in alcohol-dependent patients.


Structure-efficiency relationships of cyclodextrin scavengers in the hydrolytic degradation of organophosphorus compounds.
New derivatives of cyclodextrins were prepared in order to determine the relative importance of the structural key elements involved in the degradation of organophosphorus nerve agents. To avoid a competitive inclusion between the organophosphorus substrate and the iodosobenzoate group, responsible for its degradation, the latter group had to be covalently bound to the cyclodextrin scaffold. Although the presence of the α nucleophile iodosobenzoate was a determinant in the hydrolysis process, an imidazole group was added to get a synergistic effect towards the degradation of the agents. The degradation efficiency was found to be dependent on the relative position of the heterocycle towards the reactive group as well as on the nature of the organophosphorus derivative.


Emerging Role of G-quadruplex DNA as Target in Anticancer Therapy.
DNA has represented the most exploited target for the development of anticancer agents. It is now established that DNA may assume a variety of non-B conformations. This evidence has generated a total novel wave of interest in DNA as a cancer-associated target, since its distinct non-B structures may be regarded as sites for selective therapeutic intervention. G-quadruplexes are peculiar non-B DNA conformations that may form within guaninerich nucleic acid sequences. They are generated by a core of two or more vertically stacked G-quartets (i.e., the square planar arrangement of four guanine residues) held together by intervening loops of variable length. The evidence that G-quadruplexes are highly polymorphic and overrepresented within human genome points out at such non-B DNA conformations as druggable sites amenable of targeting by small molecules. In the present paper we will provide a concise overview on the emerging role of G-quadruplex structures forming within telomeres, gene promoters and mitochondrial DNA as a promising therapeutic target in cancer. In this context, a variety of small molecules has been documented to have excellent G-quadruplex binding/stabilizing properties and to exert good antiproliferative and antitumor activity in several in vitro and in vivo models of human cancers. Pieces of evidence indicate that targeting G-quadruplexes may represent an innovative and fascinating approach for the therapeutic management of the neoplastic disease. However, several issues still need to be addressed both at chemical and biological level before G-quadruplex-interacting molecules will turn out into effective therapeutic agents. Nevertheless, this has been an exciting, though sometime subdued, field of research over the last century. The continued improvements in methodologies and the development of specific tools will contribute not only to achieve the design and development of potentially novel anticancer approaches but also to deepen our knowledge of G-quadruplex biology and, consequently, of cancer at molecular level.


Three-dimensional heterogeneous assembly of coded microgels using an untethered mobile microgripper.
Three-dimensional (3D) heterogeneous assembly of coded microgels in enclosed aquatic environments is demonstrated using a remotely actuated and controlled magnetic microgripper by a customized electromagnetic coil system. The microgripper uses different 'stick-slip' and 'rolling' locomotion in 2D and also levitation in 3D by magnetic gradient-based pulling force. This enables the microrobot to precisely manipulate each microgel by controlling its position and orientation in all x-y-z directions. Our microrobotic assembly method broke the barrier of limitation on the number of assembled microgel layers, because it enabled precise 3D levitation of the microgripper. We used the gripper to assemble microgels that had been coded with different colours and shapes onto prefabricated polymeric microposts. This eliminates the need for extra secondary cross-linking to fix the final construct. We demonstrated assembly of microgels on a single micropost up to ten layers. By increasing the number and changing the distribution of the posts, complex heterogeneous microsystems were possible to construct in 3D.


Diversification through multitrait evolution in a coevolving interaction.
Mutualisms between species are interactions in which reciprocal exploitation results in outcomes that are mutually beneficial. This reciprocal exploitation is evident in the more than a thousand plant species that are pollinated exclusively by insects specialized to lay their eggs in the flowers they pollinate. By pollinating each flower in which she lays eggs, an insect guarantees that her larval offspring have developing seeds on which to feed, whereas the plant gains a specialized pollinator at the cost of some seeds. These mutualisms are often reciprocally obligate, potentially driving not only ongoing coadaptation but also diversification. The lack of known intermediate stages in most of these mutualisms, however, makes it difficult to understand whether these interactions could have begun to diversify even before they became reciprocally obligate. Experimental studies of the incompletely obligate interactions between woodland star (Lithophragma; Saxifragaceae) plants and their pollinating floral parasites in the moth genus Greya (Prodoxidae) show that, as these lineages have diversified, the moths and plants have evolved in ways that maintain effective oviposition and pollination. Experimental assessment of pollination in divergent species and quantitative evaluation of time-lapse photographic sequences of pollination viewed on surgically manipulated flowers show that various combinations of traits are possible for maintaining the mutualism. The results suggest that at least some forms of mutualism can persist and even diversify when the interaction is not reciprocally obligate.