Electron density of KNiF3: analysis of the atomic interactions
The topological analysis of the electron density in the perovskite KNiF3, potassium nickel trifluoride, based on the accurate X-ray diffraction data, has been performed. The topological picture of the atomic interactions differs from that resulting from the classic crystal chemistry consideration. The shapes of atoms in KNiF3 defined by zero-flux surfaces in the electron density are, in general, far from spherical. At the same time, their asphericity in the close-packed layer is very small. The topological coordination numbers of K and Ni are the same as the geometrical ones, whereas topological coordination for the F atom (6) differs from the geometrical value. The latter results from a specific shape of the Ni-atom basin preventing the bond-path formation between F atoms in the same atomic close-packed layer, in spite of the fact that the closest F-F distance is the same as K-F. Judging by the electron density value and curvature at the bond critical points, the K-F interaction in KNiF3 can be considered ionic, while the Ni-F bond belongs to the polar covalent type. No correlation of the topological ionic radii with crystal or ionic radii was found in KNiF3. Critical points in the electrostatic potential have also been studied.


Exploring QSAR, pharmacophore mapping and docking studies and virtual library generation for cycloguanil derivatives as PfDHFR-TS inhibitors.
Resistance of available antimalarial drugs against Plasmodium species is one of the major problems of malaria control in the developing world. In the present study, we have performed QSAR, pharmacophore mapping and molecular docking studies of cycloguanil derivatives as Plasmodium falciparum dihydrofolate reductase thymidylate synthase (PfDHFR-TS) inhibitors to explore essential features required for the antimalarial activity and important interaction patterns between the enzyme and ligands for the design of new potent PfDHFR-TS inhibitors. The QSAR studies have been carried out using topological parameters along with thermodynamic and structural descriptors. Acceptable values of internal and external validation parameters for the developed QSAR models confirm acceptability of the models. Pharmacophore mapping revealed that two hydrogen bond donor (HBD) features and a hydrophobic feature (HYD) are important parameters for PfDHFR-TS inhibitory activity. The docking studies suggest that the PfDHFR-TS inhibitors interact with Asp54, Ile14, Ile164, ser108, Ser111, Tyr170, Met55, Ala16, Thr185, Leu46, Cys15, Phe58, Ile112, Trp48, Tyr57 and Leu119 amino acid residues. The QSAR, pharmacophore and docking studies inferred that i) branching of the substituents at R1 and R2 positions should be less (small alkyl chain substituents are favored); ii) the electronegativity of the molecules should be high but within some limit; iii) the size and volume of the molecules should be high; iv) molecules should be flexible enough; v) R configuration at C6 position of the triazine ring favors the inhibitory binding affinity; vi) the substituents of the phenyl ring at 3, 4 and 5 position of the phenyl ring should be small hydrophobic groups. Based on these studies, we have designed a library of cycloguanil derivatives with good in silico predicted PfDHFR-TS inhibitory activity.


Expression of histamine H4 receptor in synovial cells from rheumatoid arthritic patients.
The last of four histamine receptors (HRs), H4 receptor (H4R), was identified in the year 2000. Since that time, the H4R has been implicated in cellular mechanisms related to immune systems, inflammatory processes, and allergic reactions. We have previously reported the expression of H4R mRNA in rheumatoid arthritic (RA) synovial cell cultures by means of the RT-PCR method. The present study demonstrates the expression of H4R at the protein level in RA synovial cell cultures. We also identified that the receptor was expressed in two specific types of cell populations, fibroblast-like and macrophage-like cells from RA synovial tissues. In the culture system, the fifth generation of fibroblast-like synoviocytes showed as strong expression of H4R as in the primary culture. The results provide pragmatic evidence for H4R as a novel target in the development of pharmacotherapeutic agents for RA treatment. Furthermore, the culture system used here will be useful for future studies concerning basic molecular mechanisms underlying the pharmacology of H4R.


[Process of institutional child guidance counseling reflected by the Central Continuing Education of the Federal Conference for Child Guidance Counseling].
The Bundeskonferenz für Erziehungsberatung (bke) is the federation for child guidance and family-counseling in Germany. Members are the working groups for child guidance and family-counseling of the Länder, where the employees of the child guidance are organized. The federation was founded in 1962. It is sponsored by the Federal Ministry for Family, Seniors, Women and Youth. Further education for professional youth workers is central mission of bke. The constitution of the federation lais down these contents. Every autumn the bke publishes the program for further education for the following year in a brochure called Zentrale Weiterbildung--the program for child guidance, family counseling and youth counseling. A special Kommission Zentrale Weiterbildung acquires the contents of the program for further education und selects the referents. Since 1968 the Zentrale Weiterbildung of Bundeskonferenz für Erziehungsberatung offers events for professional youth workers in child guidance, family counseling. The program for further education contributes the quality of the institution of child guidance. After a time with above average use of the program for further education with therapeutical focal point, the orientation of the program changes to child and youth services. A constant number of counselors use the program. Beside the change of contents there was a change to effectiveness of contents and a reduction of participants.


Downregulation of miR-1266-5P, miR-185-5P and miR-30c-2 in prostatic cancer tissue and cell lines.
Over the latest decade, the role of microRNAs (miRNAs/miRs) has received more attention. miRNAs are small non-coding RNAs that may serve a role as oncogenes or tumor suppressor genes. Certain miRNAs regulate the apoptosis pathway by influencing pro- or anti-apoptotic genes. We hypothesized that increases in the expression of B cell lymphoma 2 (BCL2) and BCL2-like 1 (BCL2L1) genes, which have been reported in various types of cancer tissues, may be due to the downregulation of certain miRNAs. The present study aimed to identify miRNAs that target BCL2 and BCL2L1 anti-apoptotic genes in prostate cancer (PCa) clinical tissue samples. Certain candidate miRNAs were selected bioinformatically and their expression in PCa samples was analyzed and compared with that in benign prostatic hyperplasia (BPH) tissue samples. The candidate miRNAs that targeted BCL2 and BCL2L1 genes were searched in online databases (miRWalk, microRNA.org, miRDB and TargetScan). A total of 12 miRNAs that target the 3'-untranslated region of the aforementioned genes and/or for which downregulation of their expression has previously been reported in cancer tissues. A total of 30 tumor tissue samples from patients with PCa and 30 samples tissues from patients with BPH were obtained and were subjected to reverse transcription-quantitative polymerase chain reaction for expression analysis of 12 candidate miRNAs, and the BCL2 and BCL2L1 genes. Additionally, expression of 3 finally selected miRNAs and genes was evaluated in prostate cancer PC3 and DU145 cell lines and human umbilical vein endothelial cells. Among 12 miRNA candidates, the expression of miR-1266, miR-185 and miR-30c-2 was markedly downregulated in PCa tumor tissues and cell lines. Furthermore, downregulation of these miRNAs was associated with upregulation of the BCL2 and BCL2L1 genes. An inverse association between three miRNAs (miR-1266, miR-185 and miR-30c-2) and two anti-apoptotic genes (BCL2 and BCL2L1) may be considered for interventional miRNA therapy of PCa.


Haplo2Ped: a tool using haplotypes as markers for linkage analysis.
Generally, SNPs are abundant in the genome; however, they display low power in linkage analysis because of their limited heterozygosity. Haplotype markers, on the other hand, which are composed of many SNPs, greatly increase heterozygosity and have superiority in linkage statistics. Here we developed Haplo2Ped to automatically transform SNP data into haplotype markers and then to compute the logarithm (base 10) of odds (LOD) scores of regional haplotypes that are homozygous within the disease co-segregation haploid group. The results are reported as a hypertext file and a 3D figure to help users to obtain the candidate linkage regions. The hypertext file contains parameters of the disease linked regions, candidate genes, and their links to public databases. The 3D figure clearly displays the linkage signals in each chromosome. We tested Haplo2Ped in a simulated SNP dataset and also applied it to data from a real study. It successfully and accurately located the causative genomic regions. Comparison of Haplo2Ped with other existing software for linkage analysis further indicated the high effectiveness of this software. Haplo2Ped uses haplotype fragments as mapping markers in whole genome linkage analysis. The advantages of Haplo2Ped over other existing software include straightforward output files, increased accuracy and superior ability to deal with pedigrees showing incomplete penetrance. Haplo2Ped is freely available at: http://bighapmap.big.ac.cn/software.html.


Impact of antiphospholipid syndrome iBook on medical students' improvement of knowledge: An international randomized controlled study.
iBook on Antiphospholipid Syndrome (APS) did not exist before our work, and hence the utility of an Apple iBook as a teaching method in APS for medical students has never been assessed. Our objective was to evaluate medical students' improvement of knowledge and satisfaction with an interactive APS iBook, in comparison with conventional teaching methods. An iBook designer with the guidance of a medical team developed the APS iBook in both French and English. Second-year medical students, naïve of APS knowledge, were enrolled from two institutions. For the "teaching intervention", participants were randomly assigned to three groups: a) APS iBook with interactive capability; b) printed copy of the APS iBook material; and c) classroom lecture presentation of the APS iBook material by a physician-scientist experienced in APS. The participants filled a standardized medical questionnaire about APS before and after teaching interventions to determine the relative change of knowledge. Participants were asked to fill out a standardized satisfaction survey. After 20 weeks of the intervention, recall capability of students was tested. A total of 233 second-year medical students were enrolled (iBook group: 73; print group: 79, and lecture group: 81). Relative change of knowledge was not different between the iBook group and the printed material group; additionally, it was significantly higher in the lecture group than the two other methods. Satisfaction was significantly higher in both the lecture and the iBook groups than the print group, on several dimensions including overall quantitative satisfaction, subjective enhanced knowledge, interactivity, quality of content, comprehensibility, and pleasure of learning. Recall capability of students (n=109, 47%) was not significantly different among groups. The APS iBook is as effective as printed material in improving medical student's knowledge, although a classroom lecture was the most effective method when compared to self-learning methods. Among self-learning methods, medical students are more satisfied with the APS iBook, whereas the recall capability was not different among groups. These results suggest that the APS iBook will help medical students in their curriculum and increase the awareness of APS among the community.


A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages.
Conditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood-brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood-brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system.


Distribution of trace elements in the Houston environment: relationship to mortality from arteriosclerotic heart disease.
The relationship of trace elements to arteriosclerotic heart disease (AHD) was assessed. Samples of water supplies in the Houston area were analyzed periodically for cadmium, lithium, iron and zinc. Mortality data for each of the sampling areas, delineated according to boundary of water service, were used to compute average annual age-adjusted death rates for white males aged 35 to 64 during the years 1969 to 1971. Linear regression analyses were performed on the chemical constituents for the age-adjusted death rates due to AHD. Positive correlation coefficients for lithium and zinc were found to be statistically significant at the 0.05 probability level.


Merging the best of two worlds: artificial metalloenzymes for enantioselective catalysis.
Artificial metalloenzymes result from combining a catalytically active organometallic moiety with a macromolecular host. The resulting hybrid catalysts combine attractive features of both homogeneous and enzymatic systems. Herein we summarize the recent progress in this emerging field and outline the challenges ahead.


Ability of regional hospitals to meet projected avian flu pandemic surge capacity requirements.
Hospital surge capacity is a crucial part of community disaster preparedness planning, which focuses on the requirements for additional beds, equipment, personnel, and special capabilities. The scope and urgency of these requirements must be balanced with a practical approach addressing cost and space concerns. Renewed concerns for infectious disease threats, particularly from a potential avian flu pandemic perspective, have emphasized the need to be prepared for a prolonged surge that could last six to eight weeks. The surge capacity that realistically would be generated by the cumulative Greater Dayton Area Hospital Association (GDAHA) plan is sufficient to meet the demands of an avian influenza pandemic as predicted by the [US] Centers for Disease Control and Prevention (CDC) models. Using a standardized data form, surge response plans for each hospital in the GDAHA were assessed. The cumulative results were compared to the demand projected for an avian influenza pandemic using the CDC's FluAid and FluSurge models. The cumulative GDAHA capacity is sufficient to meet the projected demand for bed space, intensive care unit beds, ventilators, morgue space, and initial personal protective equipment (PPE) use. There is a shortage of negative pressure rooms, some basic equipment, and neuraminidase inhibitors. Many facilities lack a complete set of written surge policies, including screening plans to segregate contaminated patients and staff prior to entering the hospital. Few hospitals have agreements with nursing homes or home healthcare agencies to provide care for patients discharged in order to clear surge beds. If some of the assumptions in the CDC's models are changed to match the morbidity and mortality rates reported from the 1918 pandemic, the surge capacity of GDAHA facilities would not meet the projected demand. The GDAHA hospitals should test their regional distributors' ability to resupply PPE for multiple facilities simultaneously. Facilities should retrofit current air exchange systems to increase the number of potential negative pressure rooms and include such designs in all future construction. Neuraminidase inhibitor supplies should be increased to provide treatment for healthcare workers exposed in the course of their duties. Each hospital should have a complete set of policies to address the special considerations for a prolonged surge. Additional capacity is required to meet the predicted demands of a threat similar to the 1918 pandemic.


Duration of the effect of aspirin on the synthesis of thromboxane by density subpopulations of rabbit platelets stimulated with thrombin.
The controversy concerning the relationship between platelet buoyant density and platelet age is unresolved. Our earlier results with rabbit platelets indicate that the most-dense subpopulations are enriched in young platelets and that some platelets become less dense as they age. Other investigators have concluded that platelets either do not change in density upon aging or become more dense. In the present experiments, rabbit platelets were separated on discontinuous gradients of Stractan. Most-dense platelets synthesized significantly more thromboxane B2 (TXB2) (1.27 ng per 10(6) platelets) in response to thrombin (0.75 U/mL) than did least-dense platelets (0.70 ng per 10(6) platelets), indicating that the arachidonate pathway in most-dense platelets is more active than in least-dense platelets. After aspirin administration to rabbits, most-dense platelets recovered their ability to synthesize thromboxane B2 significantly more quickly than did least-dense platelets. Because the platelet cyclooxygenase that is responsible for TXB2 formation is permanently inhibited by aspirin, it is only the new platelets entering the circulation that will be able to form TXB2. These results indicate that, at least in rabbits, the most-dense platelets are enriched in young platelets, and that platelets decrease in density as they age in the circulation.


Is Procalcitonin Biomarker-Guided Antibiotic Therapy a Cost-Effective Approach to Reduce Antibiotic Resistant and Clostridium difficile Infections in Hospitalized Patients?
Antibiotics (AB) can reduce morbidity and mortality in the treatment of patients with sepsis and chronic obstructive pulmonary disease (COPD) exacerbations. Yet, AB overuse or misuse increases antibiotic resistance (ABR) and Clostridium difficile infections (CDI). This study projected the expected impact of a procalcitonin (PCT) biomarker testing strategy on incremental ABR cases and CDI, and costs of care in a population of patients hospitalized with suspected sepsis or a COPD exacerbation, in three European countries: the United Kingdom, Germany, and the Netherlands. Based on a systematic literature search and a decision model, we analyzed the number of ABR and CDI cases avoided and the incremental healthcare costs per patient from a societal perspective over the time horizon of a hospital stay. In the sepsis population, the PCT-guided antibiotic prescription strategy was projected to reduce the number of ABR cases with circa 6%, the number of CDI cases with 21%, and societal costs with circa €1300 per patient. In the COPD population, the number of ABR and CDI cases is reduced with circa 50%, and societal cost savings ranged €1701, €2473, and €2435 per patient in Germany, the Netherlands, and the United Kingdom, respectively. Model outcomes were most sensitive to the impact of the PCT-guided strategy on the number of intensive care unit days and general hospital ward days. Taken together, a PCT biomarker-guided antibiotic management strategy is likely to reduce the number of ABR and CDI cases and generate cost savings in a population of patients hospitalized with suspected sepsis or with a COPD exacerbation.


Assessment of potential inhalant use by students.
Inhalant use is a significant health risk for today's youth, so school nurses need to be aware of its prevalence and life-threatening consequences. Numerous, readily available, inexpensive substances are being inhaled by a growing number of students. The effects of inhaling such substances can be devastating.


Effect of transglutaminase on some properties of cake enriched with various protein sources.
The effect of transglutaminase (TG) enzyme addition (0% and 0.09%) on batter and cake properties, prepared with different protein sources (nonfat dry milk [NFDM], soy flour, and soymilk) and flour types (type A with 11.4% protein and type B with 8.6% protein), was investigated. Specific gravity and pH of cake batters were determined, and physical and chemical analysis of the cake samples was performed. Soy products improved cake weight, volume, softness, protein, and fat contents. NFDM increased the crust redness and crumb lightness more than the other protein sources. TG enzyme addition affected the volume, softness, crust, and crumb color of the cake samples significantly (P < 0.05). The combination of TG enzyme and flour B with lower protein gave more puffed, symmetrical, and softer cake samples. TG had a potential application with different protein sources in cake production. Especially interactions between TG with soy flour and TG and wheat flour with high protein content were important in cake formulations due to the softening effect on crumb.


Solution structure of the N-terminal RNP domain of U1A protein: the role of C-terminal residues in structure stability and RNA binding.
The solution structure of a fragment of the human U1A spliceosomal protein containing residues 2 to 117 (U1A117) determined using multi-dimensional heteronuclear NMR is presented. The C-terminal region of the molecule is considerably more ordered in the free protein than thought previously and its conformation is different from that seen in the crystal structure of the complex with U1 RNA hairpin II. The residues between Asp90 and Lys98 form an alpha-helix that lies across the beta-sheet, with residues IIe93, IIe94 and Met97 making contacts with Leu44, Phe56 and IIe58. This interaction prevents solvent exposure of hydrophobic residues on the surface of the beta-sheet, thereby stabilising the protein. Upon RNA binding, helix C moves away from this position, changing its orientation by 135 degrees to allow Tyr13, Phe56 and Gln54 to stack with bases of the RNA, and also allowing Leu44 to contact the RNA. The new position of helix C in the complex with RNA is stabilised by hydrophobic interactions from IIe93 and IIe94 to IIe58, Leu 41, Val62 and His 10, as well as a hydrogen bond between Ser91 and Thr11. The movement of helix C mainly involves changes in the main-chain torsion angles of Thr89, Asp90 and Ser91, the helix thereby acting as a "lid" over the RNA binding surface.


[Transmission of bacteriophage T4 amber mutants. I. Temperature sensitivity of gene 26 T4 phage mutant amN131 multiplication in Escherichia coli B cells].
When studying the single cycle of the multiplication of gene 26 mutant amN131 of phage T4, like in temperature shift experiments, the yield of this mutant in non-permissive host depends greatly on the temperature. The burts size of phage in Escherichia coli B is found to be 3.3 phage particles at 25 degrees C, 1.6 at 30 degrees C, 0.051 at 37 degrees C and 0.0007 at 41 degrees C. In the case of permissive host (E. coli CR-63) the burst size per cell decreases from 158 to 49 phage particles at the same temperature interval. The results of the single-burst experiments indicate, that when the incubation temperature increases, the number of E. coli B cells, in which the phage particles maturate, also decreases. It results in the dependence of the transmission coefficient value on the temperature. The transmission coefficient in the conditions favourable for the maturation of the phage is found to be 0.80. It is shown by several methods that the temperature sensitivity of the multiplication of the mutant amN131 in bacterial cells is entirely due to amber mutation in genome of the phage. Therefore the amber mutants having high temperature sensitivity when maturating in non-permissive host cells exist among ordinary amber mutants of phage T4.


QT interval and QT dispersion during the induction of anesthesia and tracheal intubation: a comparison of remifentanil and fentanyl.
The aim of this paper was to determine if there were any significant differences between the effects of fentanyl delivered as a bolus or remifentanil delivered as a continuous infusion on the QT interval and QT dispersion (QTD) during the induction of anesthesia and tracheal intubation. This was a prospective, randomized and single blind study. A total of 50 ASA I-II patients scheduled to undergo elective minor abdominal surgery were divided into two groups. In the remifentanil group (N=25), patients received a continuous infusion (c.i.) of remifentanil (0.25 mcg/kg · min). In the fentanyl group (N=25), a bolus dose of fentanyl (2.0 mcg/kg) was administered. The QT interval, the difference between QTmax and QTmin (QTD), the heart rate-corrected QT (QTc) and the QT dispersion (QTcD) were calculated using a 12-lead computerized electrocardiogram (ECG). In both groups, there was no significant change in QT or QTc intervals during the study period. In the remifentanil group, a significant decrease in QTD and QTcD was observed during induction compared with baseline values (P<0.05). There was a significant increase in QTD at 1 min and in QTcD at 1 and 3 min after intubation in the fentanyl group (P<0.05). Both remifentanil and fentanyl did not prolong the QT interval. QTD decreased after the induction of anesthesia and did not increase after tracheal intubation in patients receiving c.i. remifentanil in comparison with fentanyl. Overall, remifentanil infusion may be the opioid-based treatment regimen of choice in patients at risk of dysrhythmias.


Histone 3 lysine 4, 9, and 27 demethylases expression profile in fertilized and cloned bovine and porcine embryos.
Epigenetic modifications in the C-terminal domain of histones coordinate important events during early development including embryo genome activation (EGA) and cell differentiation. In this study, the mRNA expression profile of the main lysine demethylases (KDMs) acting on the lysine 4 (H3K4), 9 (H3K9), and 27 (H3K27) of the histone H3 was determined at pre-, during and post-EGA stages of bovine and porcine embryos produced by in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT). In IVF embryos, mRNA abundance of most KDMs revealed a bell-shaped profile with peak expression around the EGA period, i.e. Day 3 for porcine (KDM2B, KDM5B, KDM5C, KDM4B, KDM4C, KDM6A, KDM6B, and KDM7A), and Day 4 for bovine (KDM1A, KDM5A, KDM5B, KDM5C, KDM3A, KDM4A, KDM4C, and KDM7A). The mRNA profile of KDM1A, KDM2B, KDM3A, KDM3B, KDM6A, and KDM6B differed between porcine and bovine IVF embryos. Several differences were also observed between SCNT and IVF, which includes a precocious peak in the mRNA expression of KDM1A, KDM3A, KDM4C, KDM5A, KDM5B, KDM5C, KDM6A, and KDM7A in bovine SCNT embryos; absence of mRNA peak for KDM4B, KDM4C, and KDM6A in porcine SCNT embryos; and early decreasing in KDM5B and KDM5C mRNA in porcine SCNT embryos. Based on the mRNA profile, this study has identified several KDMs that are likely involved in the regulation of the EGA transition, KDMs that may have a species-specific role in bovine and porcine embryos, and KDMs that are improperly expressed during cell reprogramming in SCNT embryos.


DPP-4 inhibitor (sitagliptin)-induced seronegative rheumatoid arthritis.
Sitagliptin is a dipeptidyl peptidase-4 inhibitor commonly used in the treatment of type 2 diabetes mellitus for glycaemic control. Concerns have arisen regarding adverse events caused by this drug, particularly concerning arthralgias. Here, we report on a 56-year-old man being treated with sitagliptin who developed inflammatory arthritis after taking the drug for 6 months. The patient presented with pain, swelling and erythema in multiple joints and was eventually diagnosed with seronegative rheumatoid arthritis (RA) under the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria. His symptoms continued for several months after stopping sitagliptin and eventually went into remission after a tapered course of steroids, hydroxychloroquine and methotrexate. Furthermore, the patient is HLA-DRB3 positive, a genetic marker that is still being investigated for its role in the pathogenesis of RA and that may have been a predisposing factor in the development of this patient's inflammatory arthropathy.


Low energy physical activity recognition system on smartphones.
An innovative approach to physical activity recognition based on the use of discrete variables obtained from accelerometer sensors is presented. The system first performs a discretization process for each variable, which allows efficient recognition of activities performed by users using as little energy as possible. To this end, an innovative discretization and classification technique is presented based on the χ2 distribution. Furthermore, the entire recognition process is executed on the smartphone, which determines not only the activity performed, but also the frequency at which it is carried out. These techniques and the new classification system presented reduce energy consumption caused by the activity monitoring system. The energy saved increases smartphone usage time to more than 27 h without recharging while maintaining accuracy.


Increased mortality and tuberculosis treatment failure rate among human immunodeficiency virus (HIV) seropositive compared with HIV seronegative patients with pulmonary tuberculosis treated with "standard" chemotherapy in Kinshasa, Zaire.
To evaluate their treatment outcomes 170 human immunodeficiency virus (HIV) seropositive and 597 HIV seronegative patients with active pulmonary tuberculosis (TB) treated for 1 yr with "standard" chemotherapy, including streptomycin, isoniazid, and, in most cases, thiacetazone, were traced at completion of therapy. All 582 survivors were invited for reevaluation, and 385 patients, of whom 82 (21.3%) were HIV seropositive, were evaluated. Of those, 325 consenting patients, of whom 67 (20.6%) were HIV seropositive, were followed for 12 months. One year after TB had been diagnosed 47 (31.3%) of the 150 HIV seropositive and 22 (4.4%) of the 501 HIV seronegative patients traced had died (p = 10(-6]. During the subsequent year the mortality of 67 HIV seropositive patients (26.3/100 patient-years) was higher than that of the 303 HIV seronegative patients (2.2/100 patients-years, p = 10(-6]. HIV seropositive patients had a higher overall TB therapy failure rate 24 months after the diagnosis of TB than did HIV seronegative patients (21.1/100 patient-years versus 8.1/100 patient-years, p = 0.002), mainly because their relapse rate of pulmonary TB (18.1/100 patient-years) was higher than that of HIV seronegative patients (6.0/100 patient-years, p = 0.03). Given their higher relapse rate after 1 yr of "standard" chemotherapy, the public health impact of routine maintenance therapy in HIV seropositive patients with pulmonary TB who complete such therapy should be assessed in comparison to the introduction of rifampicin-based short-course antituberculosis chemotherapy in developing countries.


The population of paroxysmal nocturnal hemoglobinuria neutrophils deficient in decay-accelerating factor is also deficient in alkaline phosphatase.
In patients with paroxysmal nocturnal hemoglobinuria (PNH) the RBCs, neutrophils (PMNs), monocytes, and platelets derived from the abnormal clone are deficient in the complement-regulatory protein decay-accelerating factor (DAF). RBC acetylcholinesterase (AChE) and leukocyte alkaline phosphatase (LAP) activities are also characteristically low. DAF, AChE, and LAP are known to be anchored within cell membranes to glycophospholipid-containing phosphatidylinositol (PI). Because PNH progenitors contain DAF that appears to be lost with maturation, it has been proposed that this disorder results from abnormal tethering of these and possibly other proteins to membrane PI. We were puzzled, therefore, that our two PNH patients consistently had normal LAP levels. Consequently, we studied their isolated PMNs to compare DAF and LAP activities in individual cells. PMNs were separated by flow cytometry into DAF-positive and -negative populations by using rabbit anti-DAF antiserum and fluorescein-conjugated goat antirabbit IgG. In both patients the majority of PMNs were DAF deficient, and these cells contained very little alkaline phosphatase activity. In contrast, the smaller, DAF-positive cell populations were phosphatase replete. This is the first demonstration that abnormalities in DAF and LAP activity occur in the same PNH PMN population and strengthens the hypothesis that defective anchoring of proteins to membrane glycophospholipid underlies the pathophysiology of this disorder.


Percutaneous coronary intervention in side branch coronary arteries: Insights from the Japanese nationwide registry.
Performance of percutaneous coronary intervention (PCI) in side-branch vessels (SB-PCI) has not been fully investigated despite the technical advancement of PCI. We investigated 257,492 patients registered in the Japanese nationwide PCI registry from January to December 2018; 199,767 (78%) underwent PCI for major vessel PCI (MV-PCI), 21,555 (8.4%) underwent SB-PCI, and 24,862 (9.6%) underwent PCI for both vessels (SB + MV-PCI). The frequencies of primary composite adverse events, defined as in-hospital mortality and procedural complications (i.e., peri-procedural myocardial infarction, tamponade, new-onset cardiogenic shock, stent thrombosis, emergent surgery, and bleeding), and PCI for restenotic lesions were investigated. Their association with institutional frequency of each PCI was also investigated. Fewer drug-eluting stents (66% vs. 86%) and more drug-coated balloons (23% vs. 9%) were used in SB-PCI than in MV-PCI (p < 0.001). Pre-procedure non-invasive testing was similarly performed in SB-PCI and MV-PCI (57% vs. 61%). The composite endpoint was observed in 0.7%, 1.9%, and 2.2% of the SB-PCI, SB + MV-PCI, and MV-PCI groups, respectively (p < 0.001). Institutional frequency of SB-PCI was inversely associated with the composite-endpoint risk for all PCI procedures (odds ratio 1.37, 95% confidence interval 1.04-1.81 in the lowest tertile, with reference to the middle tertile, p = 0.02). Frequency of PCI for restenotic lesions was also inversely associated with the institutional frequency of MV-PCI (p < 0.001). SB-PCI was performed safely with a low frequency of acute complications, and higher SB-PCI frequency presented a lower risk of in-hospital adverse events, albeit with a cost of an increase in PCI for restenotic lesions.


Methanotrophic potential of Dutch canal wall biofilms is driven by Methylomonadaceae.
Global urbanization of waterways over the past millennium has influenced microbial communities in these aquatic ecosystems. Increased nutrient inputs have turned most urban waters into net sources of the greenhouse gases carbon dioxide (CO2) and methane (CH4). Here, canal walls of five Dutch cities were studied for their biofilm CH4 oxidation potential, alongside field observations of water chemistry, and CO2 and CH4 emissions. Three cities showed canal wall biofilms with relatively high biological CH4 oxidation potential up to 0.48 mmol gDW-1 d-1, whereas the other two cities showed no oxidation potential. Salinity was identified as the main driver of biofilm bacterial community composition. Crenothrix and Methyloglobulus methanotrophs were observed in CH4-oxidizing biofilms. We show that microbial oxidation in canal biofilms is widespread and is likely driven by the same taxa found across cities with distinctly different canal water chemistry. The oxidation potential of the biofilms was not correlated with the amount of CH4 emitted but was related to the presence or absence of methanotrophs in the biofilms. This was controlled by whether there was enough CH4 present to sustain a methanotrophic community. These results demonstrate that canal wall biofilms can directly contribute to the mitigation of greenhouse gases from urban canals.


Path Learning in Individuals With Down Syndrome: The Floor Matrix Task and the Role of Individual Visuo-Spatial Measures.
Environment learning is essential in everyday life. In individuals with Down syndrome (DS), this skill has begun to be examined using virtual exploration. Previous studies showed that individuals with DS can learn and remember paths in terms of sequences of turns and straight stretches, albeit with some difficulty, and this learning is supported by their cognitive abilities. This study further investigates environment learning in the DS population, newly examining their ability to learn a path from actual movements, and to learn increasingly long paths, and how their performance relates to their visuo-spatial abilities and everyday spatial activities. A group of 30 individuals with DS and 30 typically-developing (TD) children matched for receptive vocabulary performed a 4 × 4 Floor Matrix task in a grid comprising 16 squares (total area 2.3 × 2.3 meters). The task involved repeating increasingly long sequences of steps by actually moving in the grid. The sequences were presented in two learning conditions, called Observation (when participants watched the experimenter's moves), or Map (when they were shown a map reproducing the path). Several visuo-spatial measures were also administered. The results showed a clear difference between the two groups' performance in the individual visuo-spatial measures. In the Floor Matrix task, after controlling for visuo-spatial reasoning ability, both groups benefited to the same degree from the Observation condition vis-à-vis the Map condition, and no group differences emerged. In the group with DS, visuo-spatial abilities were more predictive of performance in the Floor Matrix task in the Observation condition than in the Map condition. The same was true of the TD group, but this difference was much less clear-cut. The visuo-spatial working memory and visualization tasks were the strongest predictors of Floor Matrix task performance. Finally, the group with DS showed a significant relation between Floor Matrix task performance in the Observation condition and everyday spatial activity. These results enlarge on what we know about path learning in individuals with DS and its relation to their visuo-spatial abilities. These findings are discussed within the frame of spatial cognition and the atypical development domain.


Detection and phylogenetic characterization of arbovirus dual-infections among persons during a chikungunya fever outbreak, Haiti 2014.
In the context of recent arbovirus epidemics, questions about the frequency of simultaneous infection of patients with different arbovirus species have been raised. In 2014, a major Chikungunya virus (CHIKV) epidemic impacted the Caribbean and South America. As part of ongoing screening of schoolchildren presenting with acute undifferentiated febrile illness in rural Haiti, we used RT-PCR to identify CHIKV infections in 82 of 100 children with this diagnosis during May-August 2014. Among these, eight were infected with a second arbovirus: six with Zika virus (ZIKV), one with Dengue virus serotype 2, and one with Mayaro virus (MAYV). These dual infections were only detected following culture of the specimen, suggesting low viral loads of the co-infecting species. Phylogenetic analyses indicated that the ZIKV and MAYV strains differ from those detected later in 2014 and 2015, respectively. Moreover, CHIKV and ZIKV strains from co-infected patients clustered monophyletically in their respective phylogeny, and clock calibration traced back the common ancestor of each clade to an overlapping timeframe of introduction of these arboviruses onto the island.


Performance enhanced DDO-OFDM system with adaptively partitioned precoding and single sideband modulation.
As a promising solution for short-to-medium transmission systems, direct detection optical orthogonal frequency division multiplexing (DDO-OFDM) or discrete multi-tone (DMT) has been intensively investigated in last decade. Benefitting from the advantages of peak-to-average power (PAPR) reduction and signal-to-noise ratio (SNR) equalization, precoding techniques are widely applied to enhance the performance of DDO-OFDM systems. However, the conventional method of partitioning precoding sets limits the ability of precoding schemes to optimize the SNR variation and the allocation of modulation formats. Thus, the precoding transmission systems are hard to reach the capacity that traditional bit-power loading (BPL) techniques, like the Levin-Campello (LC) algorithm, can achieve. In this paper, we investigate the principle of SNR variation for precoded DDO-OFDM systems and theoretically demonstrate that the SNR equalization effect of precoding techniques is actually determined by the noise equalization process. Based on this fact, we propose an adaptively partitioned precoding (APP) algorithm to unlock the ability to control the SNR of each subcarrier. As demonstrated by the simulation and experimental results, the proposed APP algorithm achieves the transmission capacity as high as the LC algorithm and has nearly 1 dB PAPR reduction. Besides, the look-up table (LUT) operation ensures low complexity of the proposed APP algorithm compared with LC algorithm. To avoid severe chromatic dispersion (CD) induced spectral fading, single sideband (SSB) modulation is also implemented. We find that SSB modulation can reach the capacity of double sideband (DSB) modulation in optical back-to-back (OB2B) configuration by optimizing the modulation index. Therefore, the APP based SSB-DDO-OFDM scheme can sufficiently enhance the performance of cost-sensitive short-to-medium reach optical fiber communication systems.


A global partnership in medical education between Duke University and the National University of Singapore.
Duke University and the National University of Singapore (NUS) have partnered to launch a new medical school that brings the American style of postbaccalaureate medical education to Asia. The new institution, called the Duke-NUS Graduate Medical School (GMS) and located in Singapore adjacent to the Singapore General Hospital, admitted its inaugural class of students representing citizens of seven nations in August 2007. The project represents an investment of more than $350 million from three ministries of the Singapore government, and a commitment on Duke's part to provide senior leadership and recruit faculty from Duke, from other international locales, and from within Singapore itself. Graduating students who complete the four-year Duke curriculum will receive an MD degree awarded jointly by Duke and NUS, thereby distinguishing this school from medical education in most Asian institutions that award an MBBS degree after a five-year period of study that follows directly from secondary school. The emphasis of the Duke-NUS GMS is to prepare physician-scientists for academic careers, with plans for 20% of each class to complete a combined MD/PhD degree. This article describes events leading up to this partnership and details of the relationship, including curriculum, organizational structure, milestones, and goals.


Outcomes data made easy.
Dx Index is a quick and easy method for quantifying patients' oral health. A number scale from 1 to 10 provides an easy-to-understand assessment of the dental health status of either an individual or a large group. During routine oral examinations, areas such as decayed teeth, pocket depth, inflammation and oral hygiene are numbered by level. Reading the lowest number on a chart pertaining to these categories gives a rapid overall score of dental health.


Nonmyeloablative hematopoietic cell transplantation: status quo and future perspectives.
In nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT), high-dose cytotoxic therapy as the conceptual basis for treating hematopoietic malignancies has been replaced by graft-versus-tumor effects. The use of potent pre- and postgrafting immunosuppression derived from preclinical studies has allowed omission of myeloablative cytotoxic therapy without compromising hematopoietic donor cell engraftment. This results in a marked reduction in transplant-related toxicities that makes older or medically infirm patients candidates for this treatment option. This patient group is more representative of the population with cancer and would have been ineligible for conventional HSCT. Initial results in patients with a variety of hematologic malignancies have been encouraging with documented sustained cytogenetic and molecular remissions in a substantial number of sometimes heavily pretreated and previously refractory patients. Even though patients with hematologic malignancies will likely require conversion to full donor hematopoiesis for long-term disease control, a state of mixed hematopoietic chimerism might suffice to "cure" the disease phenotypes in various nonmalignant diseases. Strategies aimed at optimizing peritransplant immunosuppression may eventually eliminate the need for pretransplant total body irradiation, which is relevant for minimizing late toxicities. Enhancing graft-versus-tumor effects by virtue of postgrafting vaccination of recipients against tumor-specific antigens may help to use this transplant approach more effectively in the treatment of solid tumors.


Exploring Parkinson's disease prevalence in regional, rural and remote Australia: A systematic scoping review.
Idiopathic Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Due to ageing populations, prevalence estimates for PD are set to increase in western countries including Australia. This study aims to investigate the prevalence of PD in regional, rural and remote areas of Australia, to inform the provision of equitable PD-specific care. A scoping review, following the Joanna Briggs Institute methodology for scoping reviews and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), was conducted. An electronic search of four databases and the search engine google scholar was completed in May 2022 and updated in September 2023. Article screening and quality appraisal were undertaken independently by at least two reviewers. Of 514 records screened, six articles (between 1966 and 2019) were identified and included for review. Wide variations in PD prevalence were evident, ranging from 0.58 to 8.5 per 1000 people. Two studies suggested prevalence may be higher in regional, rural and remote areas of Australia than in urban localities. The limited number of studies identified, and wide variation in prevalence rates makes it difficult to draw firm conclusions to inform heath care planning and resource allocation. A paucity of reliable prevalence data indicates the need for well-designed, country-specific epidemiological studies to be conducted to estimate the actual impacts of the disease to inform public health planning, particularly in regional, rural and remote areas where access to PD-specific care is already inequitable.


Klebsiella neonatal injections: mechanism of broadening aminoglycoside resistance.
Kanamycin resistance in eight strains of Klebsiella pneumoniae isolated during an outbreak of infection in a neonatal intensive care unit was found to be transferable and mediated by neomycin phosphotransferase. After gentamicin was used to control infections caused by kanamycin-resistant organisms, a strain resistant to gentamicin emerged. Gentamicin resistance in this ninth strain was not transferable and was accompanied by resistance to tobramycin, amikacin, and streptomycin. Enzymatic modifications of aminoglycosides other than neomycin and kanamycin could not be demonstrated either by filter binding assays or by electrophoresis of a radioactive aminoglycoside substrate. The strain with broad aminoglycoside resistance contained six plasmid deoxyribonucleic acid bands, none of which appeared to be different in molecular weight from plasmid deoxyribonucleic acid bands in strains isolated before the institution of gentamicin therapy. The broadening of resistance was accompanied by reduced uptake of radioactively labeled streptomycin and gentamicin. The relationship between aminoglycoside resistance and reduced drug transport in the absence of any enzymatic modification is discussed.


The physics and ecology of mining carbon dioxide from the atmosphere by ecosystems.
Reforesting and managing ecosystems have been proposed as ways to mitigate global warming and offset anthropogenic carbon emissions. The intent of our opinion piece is to provide a perspective on how well plants and ecosystems sequester carbon. The ability of individual plants and ecosystems to mine carbon dioxide from the atmosphere, as defined by rates and cumulative amounts, is limited by laws of physics and ecological principles. Consequently, the rates and amount of net carbon uptake are slow and low compared to the rates and amounts of carbon dioxide we release by fossil fuels combustion. Managing ecosystems to sequester carbon can also cause unintended consequences to arise. In this paper, we articulate a series of key take-home points. First, the potential amount of carbon an ecosystem can assimilate on an annual basis scales with absorbed sunlight, which varies with latitude, leaf area index and available water. Second, efforts to improve photosynthesis will come with the cost of more respiration. Third, the rates and amount of net carbon uptake are relatively slow and low, compared to the rates and amounts and rates of carbon dioxide we release by fossil fuels combustion. Fourth, huge amounts of land area for ecosystems will be needed to be an effective carbon sink to mitigate anthropogenic carbon emissions. Fifth, the effectiveness of using this land as a carbon sink will depend on its ability to remain as a permanent carbon sink. Sixth, converting land to forests or wetlands may have unintended costs that warm the local climate, such as changing albedo, increasing surface roughness or releasing other greenhouse gases. We based our analysis on 1,163 site-years of direct eddy covariance measurements of gross and net carbon fluxes from 155 sites across the globe.


Hospital course and discharge criteria for children hospitalized with bronchiolitis.
For children hospitalized with bronchiolitis, there is uncertainty about the expected inpatient clinical course and when children are safe for discharge. Examine the time to clinical improvement, risk of clinical worsening after improvement, and develop discharge criteria. Prospective multiyear cohort study. Sixteen US hospitals. Consecutive hospitalized children age <2 years with bronchiolitis. We defined clinical improvement using: (1) retraction severity, (2) respiratory rate, (3) room air oxygen saturation, and (4) hydration status. After meeting improvement criteria, children were considered clinically worse based on the inverse of ≥1 of these criteria or need for intensive care. Among 1916 children, the median number of days from onset of difficulty breathing until clinical improvement was 4 (interquartile range, 3-7.5 days). Of the total, 1702 (88%) met clinical improvement criteria, with 4% worsening (3% required intensive care). Children who worsened were age <2 months (adjusted odds ratio [AOR]: 3.51; 95% confidence interval [CI]: 2.07-5.94), gestational age <37 weeks (AOR: 1.94; 95% CI: 1.13-3.32), and presented with severe retractions (AOR: 5.55; 95% CI: 2.12-14.50), inadequate oral intake (AOR: 2.54; 95% CI: 1.39-4.62), or apnea (AOR: 2.87; 95% CI: 1.45-5.68). Readmissions were similar for children who did and did not worsen. Although children hospitalized with bronchiolitis had wide-ranging recovery times, only 4% worsened after initial improvement. Children who worsened were more likely to be younger, premature infants presenting in more severe distress. For children hospitalized with bronchiolitis, these data may help establish more evidence-based discharge criteria, reduce practice variability, and safely shorten hospital length-of-stay.


Management of anxiety and depression in patients with COPD.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and disability in the elderly. The two common psychiatric conditions in COPD patients are anxiety and depression. This article reviews the level of evidence available on the management of anxiety and depression in patients with COPD. Depression and anxiety are associated with a greater level of physical disability, impaired quality of life, increased usage of healthcare services, noncompliance with medical treatment and elevated risk of mortality. The findings of the available literature suggest that antidepressant drug therapy, pulmonary rehabilitation, cognitive behavioral therapy, education and self-management are inconclusive in the treatment of anxiety and depression. This review also highlights our current understanding of the etiology of anxiety and depression, and assessment tools and implications for treatment. The collaborative care model (CCM) has been shown to be beneficial in the treatment of depression and acceptable for older patients in primary-care settings. It is worth investigating the benefits of CCM in patients with COPD. Healthcare providers should invest more time and resources into staff training to overcome barriers in the detection and treatment of depression and anxiety in order to improve the quality of life and survival in patients with COPD. Expected future considerations and developments in this field are also discussed.


Mutations in sdh (succinate dehydrogenase genes) alter the thiamine requirement of Salmonella typhimurium.
Mutants lacking the first enzyme in de novo purine synthesis (PurF) can synthesize thiamine if increased levels of pantothenate are present in the culture medium (J. L. Enos-Berlage and D. M. Downs, J. Bacteriol. 178:1476-1479, 1996). Derivatives of purF mutants that no longer required pantothenate for thiamine-independent growth were isolated. Analysis of these mutants demonstrated that they were defective in succinate dehydrogenase (Sdh), an enzyme of the tricarboxylic acid cycle. Results of phenotypic analyses suggested that a defect in Sdh decreased the thiamine requirement of Salmonella typhimurium. This reduced requirement correlated with levels of succinyl-coenzyme A (succinyl-CoA), which is synthesized in a thiamine pyrophosphate-dependent reaction. The effect of succinyl-CoA on thiamine metabolism was distinct from the role of pantothenate in thiamine synthesis.


Therapy-related leukemia and myelodysplasia: susceptibility and incidence.
Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is an increasingly recognized treatment complication in patients treated with radiotherapy or chemotherapy for previous hematologic malignancies or solid tumors. Distinct clinical entities have been described according to the primary treatment, corresponding to defined genetic lesions. Chromosome 7 and/or 5 losses or deletions are typical of alkylating agent-induced AML, while development of t-AML with balanced translocations involving chromosome bands 11q23 and 21q22 has been related to previous therapy with drugs targeting DNA-topoisomerase II. In addition, antimetabolites, and in particular the immunosuppressant azathioprine, have been shown to induce defective DNA-mismatch repair. This could promote survival of misrepaired cells giving rise to the leukemic clone. Individual predisposing factors, including polymorphisms in detoxification and DNA repair enzymes have been identified. Their combination may significantly increase the risk of t-MDS/AML. Among patients with hematologic malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased risk of t-MDS/AML, particularly when receiving MOPP-based, and escalated BEACOPP regimens, and when alkylators are combined with radiotherapy. Patients with Hodgkin's and non-Hodgkin's lymphoma are at highest risk when total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation therapy. The addition of granulocyte-colony-stimulating factor and radiotherapy plays a significant role in t-AML following treatment of children with acute lymphoblastic leukemia. In non-hematologic malignancies, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of both lymphoid as well as myeloid leukemia. In all cases the risk of t-MDS/AML drops sharply by 10 years after treatment.


Activation of the EBV/C3d receptor (CR2, CD21) on human B lymphocyte surface triggers tyrosine phosphorylation of the 95-kDa nucleolin and its interaction with phosphatidylinositol 3 kinase.
We previously demonstrated that CR2 activation on human B lymphocyte surface triggered tyrosine phosphorylation of a p95 component and its interaction with p85 subunit of phosphatidylinositol 3' (PI 3) kinase. Despite identical molecular mass of 95 kDa, this tyrosine phosphorylated p95 molecule was not CD19, the proto-oncogene Vav, or the adaptator Gab1. To identify this tyrosine phosphorylated p95 component, we first purified it by affinity chromatography on anti-phosphotyrosine mAb covalently linked to Sepharose 4B, followed by polyacrylamide gel electrophoresis. Then, the isolated 95-kDa tyrosine phosphorylated band was submitted to amino acid analysis by mass spectrometry; the two different isolated peptides were characterized by amino acid sequences 100% identical with two different domains of nucleolin, localized between aa 411--420 and 611--624. Anti-nucleolin mAb was used to confirm the antigenic properties of this p95 component. Functional studies demonstrated that CR2 activation induced, within a brief span of 2 min, tyrosine phosphorylation of nucleolin and its interaction with Src homology 2 domains of the p85 subunit of PI 3 kinase and of 3BP2 and Grb2, but not with Src homology 2 domains of Fyn and Gap. These properties of nucleolin were identical with those of the p95 previously described and induced by CR2 activation. Furthermore, tyrosine phosphorylation of nucleolin was also induced in normal B lymphocytes by CR2 activation but neither by CD19 nor BCR activation. These data support that tyrosine phosphorylation of nucleolin and its interaction with PI 3 kinase p85 subunit constitute one of the earlier steps in the specific intracellular signaling pathway of CR2.


To do good might hurt bad: exploring nurses' understanding and approach to suffering in forensic psychiatric settings.
Patients in forensic psychiatric settings not only have to deal with their mental illness, but also memories of criminal activities and being involuntarily hospitalized. The aim of the present study was to explore how nurses working in forensic psychiatric services understand and approach patients' experiences of suffering. Data were generated by semistructured interviews with psychiatric nurses from two different forensic psychiatric units in Sweden. Data were analysed by means of a hermeneutic approach inspired by Ricoeur's hermeneutics. The findings are reflected in four main themes: (i) ignoring suffering; (ii) explaining suffering as a natural and inevitable part of daily life in the forensic context; (iii) ascribing meaning to suffering; and, (iv) being present in suffering. To engage in alleviating suffering is a struggle that demands courage and the strength to reflect on its character and consequences. To encounter suffering means that nurses are not only confronted with patients' suffering, but also their own reactions to those patients. If suffering is not recognized or encountered, there is a risk that actions may have a negative impact on patients.


Harms associated with psychoactive substances: findings of the UK National Drug Survey.
Nutt and colleagues' 'rational' scale to assess the harms of commonly used drugs was based on ratings by a panel of experts. This survey aimed to assess drug users' views of the harms of drugs using the same scale. As users' drug choices are not solely based on harms, we additionally assessed perceived benefits. The survey was hosted at http://www.nationaldrugsurvey.org. UK residents reported their experience of 20 commonly used substances; those with direct experience of a substance rated its physical, dependence-related and social harms as well as benefits. A total of 1501 users completed the survey. There was no correlation between the classification of the 20 drugs under the Misuse of Drugs Act and ranking of harms by users. Despite being unclassified substances, alcohol, solvents and tobacco were rated within the top ten most harmful drugs. There was a remarkably high correlation (r = 0.896) overall between rankings by users' and by experts. Ecstasy, cannabis and LSD were ranked highest by users on both acute and chronic benefits. These findings imply that users are relatively well informed about the harms associated with the drugs they use. They also suggest that the current UK legal classification system is not acting to inform users of the harms of psychoactive substances.


Radiation-induced thyroid stunning: differential effects of (123)I, (131)I, (99m)Tc, and (211)At on iodide transport and NIS mRNA expression in cultured thyroid cells.
Recent clinical and experimental data demonstrate that thyroid stunning is caused by previous irradiation and may influence the efficacy of (131)I radiation therapy of thyroid cancer and possibly hyperthyroidism. To avoid stunning, many clinics have exchanged (131)I for (123)I for pretherapeutic diagnostic imaging and dose planning. Furthermore, recent in vitro studies indicate that (131)I irradiation reduces iodide uptake by downregulating the expression of the sodium iodide symporter (NIS). The rationale for this study was therefore to study effects on iodide transport and NIS messenger RNA (mRNA) expression in thyrocytes exposed to both (123)I and (131)I in addition to some other potentially interesting radionuclides. Thyrotropin-stimulated thyroid cell monolayers were exposed to 0.5 Gy of (123)I, (131)I, (99m)Tc, or (211)At, all being radionuclides transported via NIS, in the culture medium for 6 h, or to various absorbed doses of (123)I or (131)I for 48 h. NIS mRNA expression was analyzed using quantitative reverse-transcriptase polymerase chain reaction. Iodide transport and NIS mRNA expression were reduced by all radionuclides. At the same absorbed dose, iodide transport was reduced the most by (211)At, followed by (123)I and (99m)Tc (equally potent), whereas (131)I was least effective. The onset of NIS downregulation was rapid (<1 d after irradiation) in cells exposed to (123)I or (211)At and was delayed in cells irradiated with (131)I or (99m)Tc. Iodide transport and NIS expression were recovered only for (211)At. (123)I reduced the iodine transport and the NIS mRNA expression more efficiently than did (131)I at an equivalent absorbed dose, with a relative biological effectiveness of about 5. The stunning effect per unit absorbed dose is more severe for (123)I than for (131)I. Despite the lower absorbed dose per unit activity for (123)I than for (131)I, stunning by (123)I cannot be excluded in patients. The degree to which iodide transport capacity and NIS mRNA expression are reduced seems to be related to the biological effectiveness of the type of radiation delivering the absorbed dose to the target, with (211)At (which has the highest relative biological effectiveness) causing the highest degree of stunning per unit absorbed dose in the present study.


Primordial gravity wave fossils and their use in testing inflation.
A new effect is described by which primordial gravity waves leave a permanent signature in the large scale structure of the Universe. The effect occurs at second order in perturbation theory and is sensitive to the order in which perturbations on different scales are generated. We derive general forecasts for the detectability of the effect with future experiments and consider observations of the prereionization gas through the 21 cm line. It is found that the Square Kilometer Array will not be competitive with current cosmic microwave background constraints on primordial gravity waves from inflation. However, a more futuristic experiment could, through this effect, provide the highest ultimate sensitivity to tensor modes and possibly even measure the tensor spectral index. It is thus a potentially quantitative probe of the inflationary paradigm.


Site-specific 2D IR spectroscopy: a general approach for the characterization of protein dynamics with high spatial and temporal resolution.
The conformational heterogeneity and dynamics of protein side chains contribute to function, but investigating exactly how is hindered by experimental challenges arising from the fast timescales involved and the spatial heterogeneity of protein structures. The potential of two-dimensional infrared (2D IR) spectroscopy for measuring conformational heterogeneity and dynamics with unprecedented spatial and temporal resolution has motivated extensive effort to develop amino acids with functional groups that have frequency-resolved absorptions to serve as probes of their protein microenvironments. We demonstrate the full advantage of the approach by selective incorporation of the probe p-cyanophenylalanine at six distinct sites in a Src homology 3 domain and the application of 2D IR spectroscopy to site-specifically characterize heterogeneity and dynamics and their contribution to cognate ligand binding. The approach revealed a wide range of microenvironments and distinct responses to ligand binding, including at the three adjacent, conserved aromatic residues that form the recognition surface of the protein. Molecular dynamics simulations performed for all the labeled proteins provide insight into the underlying heterogeneity and dynamics. Similar application of 2D IR spectroscopy and site-selective probe incorporation will allow for the characterization of heterogeneity and dynamics of other proteins, how heterogeneity and dynamics are affected by solvation and local structure, and how they might contribute to biological function.


Visuomotor adaptation: how forgetting keeps us conservative.
Even when provided with feedback after every movement, adaptation levels off before biases are completely removed. Incomplete adaptation has recently been attributed to forgetting: the adaptation is already partially forgotten by the time the next movement is made. Here we test whether this idea is correct. If so, the final level of adaptation is determined by a balance between learning and forgetting. Because we learn from perceived errors, scaling these errors by a magnification factor has the same effect as subjects increasing the amount by which they learn from each error. In contrast, there is no reason to expect scaling the errors to affect forgetting. The magnification factor should therefore influence the balance between learning and forgetting, and thereby the final level of adaptation. We found that adaptation was indeed more complete for larger magnification factors. This supports the idea that incomplete adaptation is caused by part of what has been learnt quickly being forgotten.


Photoperiodic regulation of the reproductive axis in male zebra finches, Taeniopygia guttata.
In arid central Australia, breeding of zebra finches (Taeniopygia guttata) tends to take place immediately after the aperiodic rainfall-this being irrespective of the time of year. As a result, zebra finches have traditionally been considered nonphotoperiodic. Despite this, there are some published reports of photoperiodic effects on behavior in zebra finches. Therefore, we transferred singly housed male zebra finches from a photoperiod of 14 h light and 10 h dark per day (14L:10D) to either 20L:4D or 8L:16D. Control birds remained exposed to 14L:10D. Plasma LH, testicular volume, and body mass were assessed at the start of the experiment and at intervals for a period of 56 days. Testicular mass was measured at the end of the 56-day period. Plasma LH increased significantly in the 20L:4D group after 14 days, but decreased again by 56 days, presumably an effect of increased gonadal steroid negative feedback. Plasma LH did not change significantly in the other two groups. Testicular volume increased steadily in the 20L:4D group during the treatment period and it was significantly higher than that of the 8L:16D group at the end of the experiment. After 56 days of treatment, combined testicular mass in the 20L:4D group was much greater than that of the 8L:16D group, but not quite statistically different from the 14L:10D group. There was no statistical difference in testicular mass between the 14L and 8L groups. Body mass did not differ between any of the groups at any time in the experiment. Our results are consistent with zebra finches being photoperiodic to some degree, despite their opportunistic breeding strategy. When considered in conjunction with recent reports of photoperiodic responses in tropical avian species, these data suggest that the ability to respond to changing photoperiod is more common among avian species than previously hypothesized.


Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs.
Both isoforms of cyclo-oxygenase, COX-1 and COX-2, are inhibited to varying degrees by all of the available nonsteroidal anti-inflammatory drugs (NSAIDs). Because inhibition of COX-1 by NSAIDs is linked to gastrointestinal ulcer formation, those drugs that selectively inhibit COX-2 may have less gastrointestinal toxicity. We measured the extent to which NSAIDs and other anti-inflammatory or analgesic drugs inhibit COX-1 and COX-2 in humans. Aliquots of whole blood from 16 healthy volunteers were incubated ex vivo with 25 antiinflammatory or analgesic drugs at six concentrations ranging from 0 (control) to 100 microM (n = 5 for each). Blood was assayed for serum-generated thromboxane B2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E2 synthesis measured. Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others (eg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX-1 inhibitory potency in blood (P < 0.001) and with COX-1 selectivity (P < 0.01), but not with COX-2 inhibitory potency. Even COX-2 "selective" NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. No currently marketed NSAID, even those that are COX-2 selective, spare gastric COX activity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.


Ambient air pollution and inflammatory effects in a Canadian pregnancy cohort.
Epidemiologic studies have consistently reported associations between air pollution and pregnancy outcomes including preeclampsia and gestational diabetes. However, the biologic mechanisms underlying these relationships remain unclear as few studies have collected relevant biomarker data. We examined relationships between ambient PM2.5 and NO2 with markers of inflammation during pregnancy in a prospective cohort of Canadian women. We analyzed data from 1170 women enrolled in the Maternal-Infant Research on Environmental Chemicals study. Daily residential PM2.5 and NO2 exposures during pregnancy were estimated using satellite-based and land-use regression models and used to create 14-day and 30-day exposure windows before blood-draw. Inflammatory markers C-reactive protein, interleukin-6, interleukin-8, and tumor necrosis factor-α were measured in third trimester plasma samples. Multivariable linear regression was used to estimate associations for an interquartile range (IQR) increase in PM2.5 and NO2 and markers of inflammation, while adjusting for individual-level confounders. Fourteen-day (IQR: 6.85 µg/m3) and 30-day (IQR: 6.15 µg/m3) average PM2.5 exposures before blood-draw were positively associated with C-reactive protein after adjustment for covariates (24.6% [95% CI = 9.4, 41.9] and 17.4% [95% CI = 1.0, 35.0] increases, respectively). This association was found to be robust in several sensitivity analyses. Neither PM2.5 nor NO2 exposures were associated with interleukin-6, interleukin-8, or tumor necrosis factor-α. Exposure to ambient PM2.5 is positively associated with maternal inflammatory pathways in late pregnancy. This may contribute to positive associations between ambient PM2.5 and risk of adverse pregnancy outcomes.


A rule based system for the detection of metabolic diseases.
In this paper, we will present the first model which supports the automatic detection of metabolic defects. Our model is based on the theory of formal languages and on the knowledge of metabolic networks. The simulation program is the first interactive simulation shell which allows the analysis and synthesis of metabolic networks. Moreover, this formalization is a new concept in the research field of metabolic engineering [8] which allows us to produce a hypothesis for the metabolic therapy.


Improved spatial speckle contrast model for tissue blood flow imaging: effects of spatial correlation among neighboring camera pixels.
Speckle contrast analysis is the basis of laser speckle imaging (LSI), a simple, inexpensive, noninvasive technique used in various fields of medicine and engineering. A common application of LSI is the measurement of tissue blood flow. Accurate measurement of speckle contrast is essential to correctly measure blood flow. Variables, such as speckle grain size and camera pixel size, affect the speckle pattern and thus the speckle contrast. We studied the effects of spatial correlation among adjacent camera pixels on the resulting speckle contrast values. We derived a model that accounts for the potential correlation of intensity values in the common experimental situation where the speckle grain size is larger than the camera pixel size. In vitro phantom experiments were performed to test the model. Our spatial correlation model predicts that speckle contrast first increases, then decreases as the speckle grain size increases relative to the pixel size. This decreasing trend opposes what is observed with a standard speckle contrast model that does not consider spatial correlation. Experimental data are in good agreement with the predictions of our spatial correlation model. We present a spatial correlation model that provides a more accurate measurement of speckle contrast, which should lead to improved accuracy in tissue blood flow measurements. The associated correlation factors only need to be calculated once, and open-source software is provided to assist with the calculation.


Solid-state single photon sources: the nanowire antenna.
We design several single-photon-sources based on the emission of a quantum dot embedded in a semiconductor (GaAs) nanowire. Through various taper designs, we engineer the nanowire ends to realize efficient metallic-dielectric mirrors and to reduce the divergence of the far-field radiation diagram. Using fully-vectorial calculations and a comprehensive Fabry-Perot model, we show that various realistic nanowire geometries may act as nanoantennas (volume of approximately 0.05 lambda(3)) that assist funnelling the emitted photons into a single monomode channel. Typically, very high extraction efficiencies above 90% are predicted for a collection optics with a numerical aperture NA=0.85. In addition, since no frequency-selective effect is used in our design, this large efficiency is achieved over a remarkably broad spectral range, Deltalambda=70 nm at lambda=950 nm.


Regulation of gastric emptying.
Studies carried out in the years since William Beaumont's direct observations of gastric motility have provided increased understanding of the physiological roles of the stomach and of the mechanisms for the regulation of gastric motility. Tonic contractions of the proximal stomach are of primary importance for transfer of liquids from the stomach to the duodenum. Peristaltic contractions of the distal stomach are of primary importance for reducing the size of solid food particles and for transfer of solids to the duodenum. Because gastric emptying requires a net antral-duodenal pressure gradient, contractions of the duodenum also influence the rate of gastric emptying. Gastrointestinal hormones, including gastrin, cholecystokinin, secretin, somatostatin, and others, are released by contact of chyme with the intestinal mucosa, and affect contractions of the proximal stomach, distal stomach, and duodenum. Neural reflexes that arise from the stomach act through autonomic motor nerves to allow regulation by the central nervous system of gastric motility. gamma-Aminobutyric acid, opioids, and bombesin may serve as central neurochemical regulators of gastric motility.


Constitutive Activation of AKT2 in Humans Leads to Hypoglycemia Without Fatty Liver or Metabolic Dyslipidemia.
The activating p.Glu17Lys mutation in AKT2, a kinase mediating many of insulin's metabolic actions, causes hypoinsulinemic hypoglycemia and left-sided hemihypertrophy. The wider metabolic profile and longer-term natural history of the condition has not yet been reported. To characterize the metabolic and cellular consequences of the AKT2 p.Glu17Lys mutation in two previously reported males at the age of 17 years. Body composition analysis using dual-energy X-ray absorptiometry, overnight profiling of plasma glucose, insulin, and fatty acids, oral glucose tolerance testing, and magnetic resonance spectroscopy to determine hepatic triglyceride content was undertaken. Hepatic de novo lipogenesis was quantified using deuterium incorporation into palmitate. Signaling in dermal fibroblasts was studied ex vivo. Both patients had 37% adiposity. One developed hypoglycemia after 2 hours of overnight fasting with concomitant suppression of plasma fatty acids and ketones, whereas the other maintained euglycemia with an increase in free fatty acids. Blood glucose excursions after oral glucose were normal in both patients, albeit with low plasma insulin concentrations. In both patients, plasma triglyceride concentration, hepatic triglyceride content, and fasting hepatic de novo lipogenesis were normal. Dermal fibroblasts of one proband showed low-level constitutive phosphorylation of AKT and some downstream substrates, but no increased cell proliferation rate. The p.Glu17Lys mutation of AKT2 confers low-level constitutive activity upon the kinase and produces hypoglycemia with suppressed fatty acid release from adipose tissue, but not fatty liver, hypertriglyceridemia, or elevated hepatic de novo lipogenesis. Hypoglycemia may spontaneously remit.


Safety and efficacy of drug-eluting balloons in the treatment of drug-eluting in-stent restenosis: experience of a tertiary care hospital.
The advent of drug-eluting balloons (DEBs) is a promising development for coronary revascularization procedures, especially for in-stent restenosis (ISR). This study aims to highlight our experience with DEBs in the treatment of drug-eluting ISR at a tertiary care hospital in Pakistan. All patients presenting to our institution from August 2008 to February 2011 with significant drug-eluting in-stent restenosis (DES-ISR) who were eligible to receive treatment via DEB were included in the analysis. Patient baseline characteristics and angiographic data about the lesion characteristics were obtained. Postprocedural and follow-up endpoints, including cardiac death, myocardial infarction, and repeat revascularization, ie, major adverse cardiovascular events (MACE), were included in the analysis. A total of 26 patients received treatment with DEB in the study period, with a significant number having major predisposing factors for the development of ischemic heart disease (IHD; 46% diabetics; 92% hypertensives). The culprit lesion was most commonly identified in the left anterior descending (31%), with presence of American College of Cardiology/American Heart Association lesion type C in 68% of patients. The SeQuent Please paclitaxel-eluting balloon (B. Braun) was used for revascularization. Patients were followed for a median of 16 months. Only 5 patients (19%) developed MACE during this period. Our experience demonstrates the effectiveness of DEBs in the treatment of drug-eluting ISR, especially in complex lesions with patients having significant risk factors for development of IHD. However, further studies are needed to define their indications in this role.


Effectiveness of an Electronic Communication Tool on Transitions in Care From the Intensive Care Unit: Protocol for a Cluster-Specific Pre-Post Trial.
Transitions in care are vulnerable periods in health care that can expose patients to preventable errors due to incomplete or delayed communication between health care providers. Transitioning critically ill patients from intensive care units (ICUs) to other patient care units (PCUs) is particularly risky, due to the high acuity of the patients and the diversity of health care providers involved in their care. Instituting structured documentation to standardize written communication between health care providers during transitions has been identified as a promising means to reduce communication breakdowns. We developed an evidence-informed, computer-enabled, ICU-specific structured tool-an electronic transfer (e-transfer) tool-to facilitate and standardize the composition of written transfer summaries in the ICUs of one Canadian city. The tool consisted of 10 primary sections with a user interface combination of structured, automated, and free-text fields. Our overarching goal is to evaluate whether implementation of our e-transfer tool will improve the completeness and timeliness of transfer summaries and streamline communications between health care providers during high-risk transitions. This study is a cluster-specific pre-post trial, with randomized and staggered implementation of the e-transfer tool in four hospitals in Calgary, Alberta. Hospitals (ie, clusters) were allocated randomly to cross over every 2 months from control (ie, dictation only) to intervention (ie, e-transfer tool). Implementation at each site was facilitated with user education, point-of-care support, and audit and feedback. We will compare transfer summaries randomly sampled over 6 months postimplementation to summaries randomly sampled over 6 months preimplementation. The primary outcome will be a binary composite measure of the timeliness and completeness of transfer summaries. Secondary measures will include overall completeness, timeliness, and provider ratings of transfer summaries; hospital and ICU lengths of stay; and post-ICU patient outcomes, including ICU readmission, adverse events, cardiac arrest, rapid response team activation, and mortality. We will use descriptive statistics (ie, medians and means) to describe demographic characteristics. The primary outcome will be compared within each hospital pre- and postimplementation using separate logistic regression models for each hospital, with adjustment for patient characteristics. Participating hospitals were cluster randomized to the intervention between July 2018 and January 2019. Preliminary extraction of ICU patient admission lists was completed in September 2019. We anticipate that evaluation data collection will be completed by early 2021, with first results ready for publication in spring or summer 2021. This study will report the impact of implementing an evidence-informed, computer-enabled, ICU-specific structured transfer tool on communication and preventable medical errors among patients transferred from the ICU to other hospital care units. ClinicalTrials.gov NCT03590002; https://www.clinicaltrials.gov/ct2/show/NCT03590002. DERR1-10.2196/18675.


Dietary and lifestyle predictors of age at natural menopause and reproductive span in the Shanghai Women's Health Study.
Modifiable factors predicting the onset of menopause, a transition with important implications for women's health, have not been fully characterized. We evaluated the impact of dietary, lifestyle and reproductive factors on age at natural menopause and reproductive span in Chinese women. Study participants were Chinese women aged 40 to 70 who experienced natural menopause and participated in a population-based, prospective study, the Shanghai Women's Health Study (N = 33,054). Dietary intake at the baseline survey was assessed by food-frequency questionnaire. Regression (beta) coefficients, calculated by multivariable linear regression, were used to estimate the effects of dietary, lifestyle, and reproductive patterns on age at menopause and the number of reproductive years, adjusting for potential confounding factors. Early menarche, younger age at first live birth, older age at last live birth, longer duration of breast-feeding, and higher parity were associated with longer reproductive years (Ptrend < 0.01 for all). Higher body mass index at age 20, mid-life weight gain, and leisure-time physical activity during adolescence and adulthood predicted later menopause and longer reproductive span (Ptrend < 0.01 for all). Total intake of calories, fruits, and protein was positively associated with later menopause (Ptrend < 0.05 for all) and longer reproductive span (Ptrend < 0.05), except for carbohydrates (Ptre(nd) = 0.06), and long-term tea consumption predicted longer reproductive span (Ptrend = 0.03). Vegetable, fat, soy, and fiber intakes did not significantly affect reproductive span or age at menopause. Smoking was inversely associated with both early age at menopause and shorter reproductive span (Ptrend < 0.01). In addition to reproductive factors, intake of fruits and protein, smoking, tea consumption, lifetime patterns of physical activity, and weight gain influenced the onset of menopause and/or reproductive span in Chinese women.


Standardized Architecture for a Mega-Biobank Phenomic Library: The Million Veteran Program (MVP).
Electronic health records (EHRs) provide a wealth of data for phenotype development in population health studies, and researchers invest considerable time to curate data elements and validate disease definitions. The ability to reproduce well-defined phenotypes increases data quality, comparability of results and expedites research. In this paper, we present a standardized approach to organize and capture phenotype definitions, resulting in the creation of an open, online repository of phenotypes. This resource captures phenotype development, provenance and process from the Million Veteran Program, a national mega-biobank embedded in the Veterans Health Administration (VHA). To ensure that the repository is searchable, extendable, and sustainable, it is necessary to develop both a proper digital catalog architecture and underlying metadata infrastructure to enable effective management of the data fields required to define each phenotype. Our methods provide a resource for VHA investigators and a roadmap for researchers interested in standardizing their phenotype definitions to increase portability.


HPV E6/E7 mRNA combined with thin-prep cytology test for the diagnosis of residual/recurrence after loop electrosurgical excision procedure in patients with cervical intraepithelial neoplasia.
To evaluate the diagnostic value of combining HPV E6/E7 mRNA testing with Thin-Prep cytology (TCT) for residual/recurrence detection, a total of 289 patients who underwent loop electrosurgical excision procedure (LEEP) for high-grade cervical lesions were included. Patients were followed up at different time points, and residual/recurrent lesions were confirmed through vaginoscopy. TCT, HPV-DNA, and HPV E6/E7 mRNA tests were conducted. Diagnostic performance, including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy, was assessed. Among the patients, 76 cases showed residual lesions/recurrence, while 213 cases showed no residual/recurrence. Positive margins in the cervical-vaginal and cervical canal areas were associated with a higher risk of residual/recurrence. The combined HPV E6/E7 mRNA and TCT test showed higher diagnostic efficacy than individual tests at 6-, 12-, and 24-months follow-up. The combined test consistently demonstrated higher specificity and sensitivity, with significantly larger area under the curve (AUC) values compared to the individual tests.


Contractile effects of neuropeptide Y in human subcutaneous resistance arteries are mediated by Y1 receptors.
The aim of our study was to determine the neuropeptide Y (NPY) receptor subtype responsible for the NPY-induced contraction of human subcutaneous (s.c.) resistance arteries. To elucidate this, we used (a) in vitro studies of NPY agonists: NPY, peptide YY (PYY), and Pro34NPY induced equally strong and equipotent concentration-dependent contractions of human s.c. resistance arteries, whereas NPY13-36 and NPY18-36 had no contractile effects; (b) in vitro studies using the NPY Y1-receptor antagonist, BIBP3226, which in nanomolar concentrations inhibited the contractile effect of NPY, causing a rightward shift of the concentration-response curve. pEC50 for NPY alone, 8.41 +/- 0.21; NPY + BIBP3226, 10 nM, 7.79 +/- 0.21; NPY + BIBP3226, 100 nM, 7.18 +/- 0.18; NPY + BIBP3226, 1 microM, 6.32 +/- 0.05 (n = 5-8). Schild-plot analysis indicated competitive antagonism: pA2 = 8.53 +/- 0.22 and slope = 0.99 +/- 0.14; (c) with reverse transcriptase-polymerase chain reaction (RT-PCR), we detected messenger RNA (mRNA) encoding the human NPY Y1 receptor and a splice variant of the receptor in human s.c. resistance arteries. On the basis of the agonists' potency order, the antagonistic effect of BIBP3226 on the NPY-induced contraction, and the presence of mRNA encoding the NPY Y1 receptor, we conclude that the NPY-induced contraction of human s.c. resistance arteries is mediated by NPY Y1 receptors.


Elastic registration of prostate MR images based on estimation of deformation states.
Magnetic resonance imaging (MRI) is being used increasingly for image-guided targeted biopsy and focal therapy of prostate cancer. In this paper, a combined rigid and deformable registration technique is proposed to register pre-treatment diagnostic 3T magnetic resonance (MR) images of the prostate, with the identified target tumor(s), to intra-treatment 1.5T MR images. The pre-treatment T2-weighted MR images were acquired with patients in a supine position using an endorectal coil in a 3T scanner, while the intra-treatment T2-weighted MR images were acquired in a 1.5T scanner before insertion of the needle with patients in the semi-lithotomy position. Both the rigid and deformable registration algorithms employ an intensity-based distance metric defined based on the modality independent neighborhood descriptors (MIND) between images. The optimization routine for estimating the rigid transformation parameters is initialized using four pairs of manually selected approximate corresponding points on the boundaries of the prostate. In this paper, the problem of deformable image registration is approached from the perspective of state estimation for dynamical systems. The registration algorithm employs a rather generic dynamic linear elastic model of the tissue deformation discretized by the finite element method (FEM). We use the model in a classical state estimation framework to estimate the deformation of the prostate based on the distance metric between pre- and intra-treatment images. Our deformable registration results using 17 sets of prostate MR images showed that the proposed method yielded a target registration error (TRE) of 1.87 ± 0.94 mm,2.03 ± 0.94 mm, and 1.70 ± 0.93 mm for the whole gland (WG), central gland (CG), and peripheral zone (PZ), respectively, using 76 manually-identified fiducial points. This was an improvement over the 2.67 ± 1.31 mm, 2.95 ± 1.43 mm, and 2.34 ± 1.11 mm, respectively for the WG, CG, and PZ after rigid registration alone. Dice similarity coefficients (DSC) in the WG, CG and PZ were 88.2 ± 5.3, 85.6 ± 7.6 and 68.7 ± 6.9 percent, respectively. Furthermore, the mean absolute distances (MAD) between surfaces was 1.26 ± 0.56 mm and 1.27 ± 0.55 mm in the WG and CG, after deformable registration. These results indicate that the proposed registration technique has sufficient accuracy for localizing prostate tumors in MRI-guided targeted biopsy or focal therapy of clinically localized prostate cancer.


Genomics, Morphoproteomics, and Treatment Patterns of Patients with Alveolar Soft Part Sarcoma and Response to Multiple Experimental Therapies.
Overexpression of transcription factor 3 in alveolar soft part sarcoma(ASPS) results in upregulation of cell proliferation pathways. No standard treatment algorithm exists for ASPS; multikinase inhibitors[tyrosine kinase inhibitor (TKI)] and immune checkpoint inhibitors (ICI) have shown clinical benefit. To date, no studies have reported on management strategies or sequencing of therapy. We evaluated ASPS treatment patterns and responses in an experimental therapeutics clinic. Genomic and morphoproteomic analysis was performed to further elucidate novel targets. We retrospectively reviewed patients with ASPS treated on clinical trials. Demographic and clinical next-generation sequencing (NGS) profiles were collected. AACR GENIE database was queried to further evaluate aberrations in ASPS. Morphoproteomic analysis was carried out to better define the biology of ASPS with integration of genomic and proteomic findings. Eleven patients with ASPS were identified; 7 received NGS testing and mutations in CDKN2A (n = 1) and hepatocyte growth factor (n = 1) were present. Ten patients were treated with TKIs with stable disease as best response and 4 patients with ICI (three partial responses). Within GENIE, 20 patients were identified harboring 3 called pathogenic mutations. Tumor mutation burden was low in all samples. Morphoproteomic analysis confirmed the expression of phosphorylated c-Met. In addition, fatty acid synthase and phosphorylated-STAT3 were detected in tumor cell cytoplasm and nuclei. Patients with ASPS have a quiescent genome and derive clinical benefit from VEGF-targeting TKIs. Morphoproteomic analysis has provided both additional correlative pathways and angiogenic mechanisms that are targetable for patients with ASPS. Our study suggests that sequential therapy with TKIs and immune checkpoint inhibitors is a reasonable management strategy.


Factors affecting the interest of rehabilitation professionals indirectly supporting preventive care projects.
[Purpose] To identify the factors affecting the interest of rehabilitation professionals who indirectly support preventive care projects. [Participants and Methods] Rehabilitation professionals (physical therapists, occupational therapists, and speech-language-hearing therapists) working in 617 hospitals and other health facilities in A Prefecture, Japan. On the basis of their degree of interest in the activities of their respective preventive care projects, the professionals were classified into three groups after evaluating their responses to a self-reporting questionnaire (1,851 parts in total). The subsequent comparisons were performed among the three groups and their responses to the remaining questions. [Results] Analysis of the responses provided by 354 of the 374 rehabilitation professionals who answered the questionnaire revealed the following factors affecting their degree of interest in the preventive care projects indirectly supported by them: advanced age; abundant years of experience practicing; being speech-language-hearing-therapists; experience in post-graduate training; and considering the scope of support as a part of the community. Furthermore, the vast majority of individuals in the group showing superior interest had experience in activities related to indirect support. [Conclusion] Confirmation of the extent to which indirect support by rehabilitation professionals is effective for preventive care services is essential, since such support is difficult to demonstrate, unlike direct support.