A novel protein derived from the MUC1 gene by alternative splicing and frameshifting.
Genes that have been designated the name "MUC" code for proteins comprising mucin domains. These proteins may be involved in barrier and protective functions. The first such gene to be characterized and sequenced is the MUC1 gene. Here we report a novel small protein derived from the MUC1 gene by alternative splicing that does not contain the hallmark of mucin proteins, the mucin domain. This protein termed MUC1/ZD retains the same N-terminal MUC1 sequences as all of the other known MUC1 protein isoforms. The common N-terminal sequences comprise the signal peptide and a subsequent stretch of 30 amino acids. In contrast, the MUC1/ZD C-terminal 43 amino acids are novel and result from a reading frameshift engendered by a splicing event that forms MUC1/ZD. The expression of MUC1/ZD at the protein level in human tissues is demonstrated by Western blotting, immunohistochemistry, immunoprecipitation, and an ELISA. Utilization was made of affinity-purified MUC1/ZD-specific polyclonal antibodies as well as two different monoclonal antibodies that are monospecific for the MUC1/ZD protein. The MUC1/ZD protein is expressed in tissues as an oligomeric complex composed of monomers linked by disulfide bonds contributed by MUC1/ZD cysteine residues. MUC1/ZD protein expression did not parallel that of the tandem-repeat array-containing MUC1 protein. Results presented here demonstrate for the first time the expression of a novel MUC1 protein isoform MUC1/ZD, which is generated by an alternative splicing event that both deletes the tandem-repeat array and leads to a C-terminal reading frameshift.


Clinical Outcome Evaluation of Primary Total Knee Arthroplasty in Patients with Diabetes Mellitus.
BACKGROUND The aim of this study was to evaluate the safety and clinical outcome of primary total knee arthroplasty in patients with diabetes mellitus. MATERIAL AND METHODS Among the patients who were treated with total knee arthroplasty, there were 98 patients (116 knees) associated with diabetes. Osteoarthritis was diagnosed in 90 patients and rheumatoid arthritis was diagnosed in 8 patients. Various degrees of preoperative knee deformities were found in 82 knees. The average fasting blood glucose was 9.8±3.6 mmol/L at admission. RESULTS The clinical efficacy of TKA was satisfactory in patients with diabetes mellitus. Diabetic patients do not seem to have a significantly higher risk for infection and DVT after TKA. At the final follow-up time point, no prosthesis loosening was found and no revision was needed in any patients. The mean HSS scores increased and the excellent rate was 100%. CONCLUSIONS Using perioperative comprehensive assessment of heart and lung function, and by preventing infection and the formation of DVT, we achieved satisfactory early clinical efficacy of TKA in patients with diabetes mellitus.


Digital 3-D implant planning: Cerec meets Galileos.
Prosthetically based implant planning is necessary so that implants are set expediently and correctly during surgery. A clinical case is presented to describe how this can be performed today purely digitally. Prosthetic planning was undertaken with the Cerec CAD/CAM system. The data record created was transferred and superimposed on a CBCT 3-D radiograph. The position of the implant was planned taking the prosthetic planning into account.


Dual multimodular class A penicillin-binding proteins in Mycobacterium leprae.
The ponA gene of cosmid L222 of the Mycobacterium leprae genome library encodes a multimodular class A penicillin-binding protein (PBP), PBP1. The PBP, labelled with a polyhistidine sequence, has been produced in Escherichia coli, extracted from the membranes with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane-sulfonate (CHAPS) and purified by Ni2(+)-nitrilotriacetic acid-agarose chromatography. In contrast to the pon1-encoded class A PBP1, PBP1 undergoes denaturation at temperatures higher than 25 degrees C, it catalyzes acyl transfer reactions on properly structured thiolesters, and it binds penicillin with high affinity.


Italian Survey on Prevalence and Disease Management of Chronic Heart Failure and Chronic Obstructive Pulmonary Disease comorbidity in ambulatory patients. SUSPIRIUM study rationale and design.
Chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. Through shared risk factors and pathophysiological mechanisms, CHF and COPD frequently coexist. The concurrent disease has important therapeutic implications and independently predicts worsened mortality, impaired functional status, and health service use. However, assessment of the comorbidity varies widely according to the population studied, diagnostic criteria and measurement tools applied. Both syndromes have been studied extensively but largely separately, mostly in the domain of the pulmonologist for COPD and in the domain of the cardiologist for CHF. The aim of the study is to evaluate in an Italian outpatients setting (10 cardiology and 10 pulmonology centers from the same institution) the prevalence, clinical profile and the routine diagnostic, functional and therapeutic work-up applied by cardiologists and pulmonologists in the presence/suspicion of concurrent disease in patients in a stable phase of their disease. For this purpose, CHF and COPU outpatients will be enrolled in a multicenter, nationwide, prospective observational study. Risk estimation of comorbidity will be based on suspected, documented or patient-reported diagnosis of COPD/CHF. In the absence of documented concurrent diagnosis, each specialist will describe the diagnostic, functional and therapeutic work-up applied. The design of the study focused on the diagnostic validation of the CHF-COPD comorbidity aims to provide relevant new information on the assessment of the coexistent condition in the cardiac and pulmonary outpatients setting and on specialty-related different diagnostic and therapeutic strategies of comorbidity utilized in real life clinical practice. The symptomatic and prognostic benefits resulting from a combined approach to CHF/COPD could outweigh those attainable by treating either condition alone.


Antimycobacterial therapy in Crohn's disease: results of a controlled, double-blind trial with a multiple antibiotic regimen.
Several recent reports have suggested an association of atypical mycobacteria with Crohn's disease. The goal of this double-blind, placebo-controlled trial was to determine the efficacy of treatment with antimycobacterial drugs in maintaining clinical remission and in reducing active inflammatory lesions. Forty patients (15 male) with refractory, steroid-dependent Crohn's disease were randomized to receive 2 months of tapering steroids plus either a 9-month regimen of ethambutol, clofazimine, dapsone and 1-day dose only of rifampicin (n = 22), or identical placebo. Three patients (two on active drug) were unable to discontinue steroids, and one patient on active drug was withdrawn for side effects during the first 2 months. Three of the remaining 19 patients on active drug relapsed during the study period, compared with 11 of 17 on placebo (log likelihood ratio = 4.6; p = 0.03). Another patient was withdrawn in remission at 5 months for anemia related to dapsone. Nine patients whose disease relapsed or persisted on placebo were crossed over to active drug; five achieved sustained remission, two failed, and two were withdrawn for side effects. Substantial endoscopic or radiologic healing did not occur. This study suggests that the treatment regimen with rifampicin, ethambutol, clofazimine, and dapsone is effective in relief of symptoms and maintenance of remission in some Crohn's disease patients.


Molecular design driving tetraporphyrin self-assembly on graphite: a joint STM, electrochemical and computational study.
Tuning the intermolecular interactions among suitably designed molecules forming highly ordered self-assembled monolayers is a viable approach to control their organization at the supramolecular level. Such a tuning is particularly important when applied to sophisticated molecules combining functional units which possess specific electronic properties, such as electron/energy transfer, in order to develop multifunctional systems. Here we have synthesized two tetraferrocene-porphyrin derivatives that by design can selectively self-assemble at the graphite/liquid interface into either face-on or edge-on monolayer-thick architectures. The former supramolecular arrangement consists of two-dimensional planar networks based on hydrogen bonding among adjacent molecules whereas the latter relies on columnar assembly generated through intermolecular van der Waals interactions. Scanning Tunneling Microscopy (STM) at the solid-liquid interface has been corroborated by cyclic voltammetry measurements and assessed by theoretical calculations to gain multiscale insight into the arrangement of the molecule with respect to the basal plane of the surface. The STM analysis allowed the visualization of these assemblies with a sub-nanometer resolution, and cyclic voltammetry measurements provided direct evidence of the interactions of porphyrin and ferrocene with the graphite surface and offered also insight into the dynamics within the face-on and edge-on assemblies. The experimental findings were supported by theoretical calculations to shed light on the electronic and other physical properties of both assemblies. The capability to engineer the functional nanopatterns through self-assembly of porphyrins containing ferrocene units is a key step toward the bottom-up construction of multifunctional molecular nanostructures and nanodevices.


Paclitaxel and carboplatin in metastatic non-small cell lung cancer: preliminary results of a phase I study.
Given their known activity against non-small cell lung cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin were combined in this phase I study of patients with metastatic disease to determine the maximum tolerated dose and the dose-limiting toxicity of the combination. The initial dose of paclitaxel was fixed at 135 mg/m2 given as a 24-hour infusion with carboplatin administered in escalating doses in cohorts using Calvert's formula-dose (mg) = target AUC x (GFR + 25), where AUC is area under the concentration-time curve and GFR is glomerular filtration rate-based on target AUCs of 5, 7, 9, or 11 mg/mL.min. Dose escalations were based on cycle 1 toxicities. Filgrastim was not administered with the first cycle until two or more patients developed grade 4 or febrile neutropenia at the preceding dose level. Dose-limiting toxicity occurred in two patients at level 2 (cycle 1), and filgrastim was administered thereafter for the next four dose levels. Grade 4 thrombocytopenia was seen at level 4; thus, the carboplatin dose was de-escalated thereafter, and the paclitaxel dose escalated. Rare nonhematologic toxicities include fatigue, diarrhea, and nausea and vomiting. Among the first 30 patients, one had a complete response and 14 had partial responses, for an overall response rate of 50%. The combination of paclitaxel and carboplatin is active in non-small cell lung cancer, and the recommended phase II dose without filgrastim support is paclitaxel 175 mg/m2 via a 24-hour infusion with the carboplatin dose targeted to achieve an AUC of 7 mg/ mL.min.


Effectiveness of complementary and self-help treatments for depression.
To review the evidence for the effectiveness of complementary and self-help treatments for depression. Systematic literature search using PubMed, PsycLit, the Cochrane Library and previous review papers. Thirty-seven treatments were identified and grouped under the categories of medicines, physical treatments, lifestyle, and dietary changes. We give a description of each treatment, the rationale behind the treatment, a review of studies on effectiveness, and the level of evidence for the effectiveness studies. The treatments with the best evidence of effectiveness are St John's wort, exercise, bibliotherapy involving cognitive behaviour therapy and light therapy (for winter depression). There is some limited evidence to support the effectiveness of acupuncture, light therapy (for non-seasonal depression), massage therapy, negative air ionisation (for winter depression), relaxation therapy, S-adenosylmethionine, folate and yoga breathing exercises. Although none of the treatments reviewed is as well supported by evidence as standard treatments such as antidepressants and cognitive behaviour therapy, many warrant further research.


Nurse reported quality of care: a measure of hospital quality.
As the primary providers of round-the-clock bedside care, nurses are well positioned to report on hospital quality of care. Researchers have not examined how nurses' reports of quality correspond with standard process or outcomes measures of quality. We assess the validity of evaluating hospital quality by aggregating hospital nurses' responses to a single item that asks them to report on quality of care. We found that a 10% increment in the proportion of nurses reporting excellent quality of care was associated with lower odds of mortality and failure to rescue; greater patient satisfaction; and higher composite process of care scores for acute myocardial infarction, pneumonia, and surgical patients. Nurse reported quality of care is a useful indicator of hospital performance.


Illness perceptions and adherence to therapeutic regimens among patients with hypertension: a structural modeling approach.
Patients' lay views of illness are influential on adherence to therapeutic regimes. However, factors associate with non-adherence are not examined simultaneously. The purpose of the study was to test a hypothetical model of the relationships between illness perception and adherence to prescribed medication and self-management recommendations of hypertensive patients based on theoretical assumptions of the Common-Sense Model. A cross-sectional, descriptive, correlational design. Cardiovascular clinics of three teaching hospitals in central Taiwan. Three hundred and fifty-five hypertensive patients. Data were collected through face-to-face interviews using structured questionnaires, including the Illness Perception Questionnaire-Revised, the Medication Adherence Inventory, and the Inventory of Adherence to Self-Management. Data were analyzed by structural equation modeling using LISREL. The findings suggested that the illness identity may directly affect patient adherence to prescribed medications or indirectly affect patient adherence via control of the disease and cause. Control of the disease exhibited direct effects on adherence to prescribed medications and self-management, while the cause of the illness only showed direct effects on adherence to prescribed medications. The relationships were independent of systolic blood pressure, age, the total number of antihypertensive medication, and comorbidity. The findings of the study extend the utility of the Common-Sense Model, suggesting that adherence to therapeutic regimens may be enhanced by improving a sense of controllability. For patients who experience symptoms related to high blood pressure, barriers to adherence may be reduced by assessing and clarifying the meaning of illness identity and causal attributions.


Chemokine receptors as targets for cancer therapy.
Chemokines and their receptors play critical roles in leukocyte trafficking during inflammatory processes. Although the role of chemokine receptors (CKRs) in cancer biology is a relatively new field of study, a growing body of data suggest that a number of CKRs, including CXCR4, CCR4, CCR7, and CCR10, may play diverse of roles in cancer growth, cancer metastasis, cancer angiogenesis, or the composition of the cancer microenvironment. Preclinical models of cancer indicate that cancer antagonists, most notably those for CXCR4, can block cancer growth either directly or by altering the cancer stroma. Highthroughput screening methods to identify effective CKR antagonists have been developed, but specificity, potency, and drug-delivery of validated candidate compounds remain issues that result in the clinical failure of many initially promising candidates. The recent approval of a CCR5 receptor antagonist in HIV suggests that safe, effective small molecular antagonists for other CKRs may not be far away. There is still a clear need to extend our understanding of the signalling pathways by which CKRs facilitate cancer processes. Because of the role of CKRs in cancer cell survival, the combination of CKR antagonists with traditional chemotoxic agents or with immunotherapy is an alluring strategy since this increases the specificity of treatment to the cancer and potentially limits additional systemic side effects.


Incremental Shuttle Walk Test to Assess and Prescribe Exercise for Subjects With Bronchiectasis: Hallway Versus Treadmill.
The incremental shuttle walk test was initially developed to be carried out in a hallway (ISWT-H) but has been modified to be performed on a treadmill (ISWT-T). However, it is still unknown whether performance on ISWT-H and ISWT-T are similar in patients with bronchiectasis. In this study, we compared the performance, physiological responses, and perception of effort between the ISWT-T with a handrail and ISWT-H for subjects with bronchiectasis. We also sought to estimate and compare the prescription for training intensity with both tests. This was a cross-sectional study in which 24 subjects with bronchiectasis were evaluated on 2 different days (24 h apart). Distance walked (m) was compared between the ISWT-H and ISWT-T. A training session was held on a treadmill at 75% of the speed obtained from both tests. The walking distance, oxygen uptake (V̇O2 ), carbon dioxide production (V̇CO2 ), heart rate, and ventilation (V̇E) were measured. There was a difference in the walking distance between the ISWT-T and ISWT-H, but physiological responses for V̇O2 , V̇CO2 , heart rate, and V̇E were similar. However, the speed estimated for training was different, as were the V̇O2 , V̇CO2 , and heart rate. The ISWT-T with handrail and the ISWT-H are not interchangeable in subjects with bronchiectasis. A slower speed of training intensity may occur when the test is performed in a hallway, as originally described, and this may underestimate responses to aerobic training.


Mitotic chromosome assembly despite nucleosome depletion in Xenopus egg extracts.
The nucleosome is the fundamental structural unit of eukaryotic chromatin. During mitosis, duplicated nucleosome fibers are organized into a pair of rod-shaped structures (chromatids) within a mitotic chromosome. However, it remains unclear whether nucleosome assembly is indeed an essential prerequisite for mitotic chromosome assembly. We combined mouse sperm nuclei and Xenopus cell-free egg extracts depleted of the histone chaperone Asf1 and found that chromatid-like structures could be assembled even in the near absence of nucleosomes. The resultant "nucleosome-depleted" chromatids contained discrete central axes positive for condensins, although they were more fragile than normal nucleosome-containing chromatids. Combinatorial depletion experiments underscored the central importance of condensins in mitotic chromosome assembly, which sheds light on their functional cross-talk with nucleosomes in this process.


Relating biophysical properties across scales.
A distinguishing feature of a multicellular living system is that it operates at various scales, from the intracellular to organismal. Genes and molecules set up the conditions for the physical processes to act, in particular to shape the embryo. As development continues the changes brought about by the physical processes lead to changes in gene expression. It is this coordinated interplay between genetic and generic (i.e., physical and chemical) processes that constitutes the modern understanding of early morphogenesis. It is natural to assume that in this multiscale process the smaller defines the larger. In case of biophysical properties, in particular, those at the subcellular level are expected to give rise to those at the tissue level and beyond. Indeed, the physical properties of tissues vary greatly from the liquid to solid. Very little is known at present on how tissue level properties are related to cell and subcellular properties. Modern measurement techniques provide quantitative results at both the intracellular and tissue level, but not on the connection between these. In the present work we outline a framework to address this connection. We specifically concentrate on the morphogenetic process of tissue fusion, by following the coalescence of two contiguous multicellular aggregates. The time evolution of this process can accurately be described by the theory of viscous liquids. We also study fusion by Monte Carlo simulations and a novel Cellular Particle Dynamics (CPD) model, which is similar to the earlier introduced Subcellular Element Model (SEM; Newman, 2005). Using the combination of experiments, theory and modeling we are able to relate the measured tissue level biophysical quantities to subcellular parameters. Our approach has validity beyond the particular morphogenetic process considered here and provides a general way to relate biophysical properties across scales.


Structural and thermodynamic dissection of linear motif recognition by the E. coli sliding clamp.
Protein-protein interactions based on linear motif (LM) recognition play roles in many cell regulatory processes. The E. coli sliding clamp is a protein mediator of replisome formation, which uses a common surface pocket composed of two subsites (I and II) to interact with LMs in multiple binding partners. A structural and thermodynamic dissection of sliding clamp-LM recognition has been performed, providing support for a sequential binding model. According to the model, a hydrophobic C-terminal LM dipeptide submotif acts as an anchor to establish initial contacts within subsite I, and this is followed by formation of a stabilizing hydrogen-bonding network between the flanking LM residues and subsite II. Differential solvation/desolvation during positioning of the submotifs is proposed as a driver for the sequential binding. Our model provides general insights into linear motif recognition and should guide the design of small-molecule inhibitors of the E. coli sliding clamp, an emerging antibacterial target.


Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes.
We present evidence that human peripheral blood lymphocytes, free of contaminating monocytes, rapidly produce high levels of tumor necrosis factor (TNF) when stimulated with phorbol diester and calcium ionophore, and lower but significant levels of TNF when stimulated with mitogens. These two types of inducers act preferentially on T cells, both CD4+ and CD8+. NK cells produce TNF only when stimulated with phorbol diester and calcium ionophore, and they do so at a much lower level than T cells. The procedures used in the purification of lymphocytes and the differential ability to respond to various inducers allow us to exclude that monocytes or basophils contaminating the lymphocyte preparation participate in the production of TNF. In particular, LPS, a potent inducer of TNF production from monocytes, is unable to induce significant levels of TNF in the lymphocyte preparations. The TNF produced by lymphocytes has antigenic, physicochemical, and biochemical characteristics identical to those of the TNF produced by myeloid cell lines or monocytes upon stimulation with LPS. LT is also produced by lymphocyte preparations. Production of TNF and LT proteins in response to the different inducers is paralleled by accumulation of cytoplasmic TNF and LT mRNA. Both at mRNA and at protein levels, stimulation of T lymphocytes with phorbol diester and calcium ionophore preferentially induces TNF, whereas mitogen stimulation preferentially induces LT. Our data suggest that the TNF and LT genes, two closely linked genes encoding two partially homologous proteins with almost identical biological functions, are independently regulated in lymphocytes.


Optimal citric acid concentration for dentinal demineralization.
A number of acids have been shown to have a peak concentration above which the rate of enamel demineralization diminishes. Citric acid, used to demineralize dentin in periodontal regenerative procedures, is one such acid. The purpose of this study was to ascertain if there were an optimal concentration of citric acid with which to demineralize dentin. Various concentrations of citric acid were applied to bovine dentin and then examined with atomic absorption spectrophotometry to measure the amount of calcium dissolved in each concentration. The ppm calcium/% citric acid solution rose from 0.38 +/- 0.38 ppm/0% (control) to a peak of 7.54 +/- 2.26 ppm/24%, then fell to 2.43 +/- 0.59 ppm/80%, suggesting that there may be a peak concentration beyond which effective dentinal demineralization diminishes. The peak solution was pH = 1.42.


Tumor-Derived Cell Lines as Molecular Models of Cancer Pharmacogenomics.
Compared with normal cells, tumor cells have undergone an array of genetic and epigenetic alterations. Often, these changes underlie cancer development, progression, and drug resistance, so the utility of model systems rests on their ability to recapitulate the genomic aberrations observed in primary tumors. Tumor-derived cell lines have long been used to study the underlying biologic processes in cancer, as well as screening platforms for discovering and evaluating the efficacy of anticancer therapeutics. Multiple -omic measurements across more than a thousand cancer cell lines have been produced following advances in high-throughput technologies and multigroup collaborative projects. These data complement the large, international cancer genomic sequencing efforts to characterize patient tumors, such as The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). Given the scope and scale of data that have been generated, researchers are now in a position to evaluate the similarities and differences that exist in genomic features between cell lines and patient samples. As pharmacogenomics models, cell lines offer the advantages of being easily grown, relatively inexpensive, and amenable to high-throughput testing of therapeutic agents. Data generated from cell lines can then be used to link cellular drug response to genomic features, where the ultimate goal is to build predictive signatures of patient outcome. This review highlights the recent work that has compared -omic profiles of cell lines with primary tumors, and discusses the advantages and disadvantages of cancer cell lines as pharmacogenomic models of anticancer therapies.


Posterior revision surgery using an intraarticular distraction technique with cage grafting to treat atlantoaxial dislocation associated with basilar invagination.
The treatment of atlantoaxial dislocation (AAD) and basilar invagination (BI) is challenging, especially in symptomatic patients with a history of previous surgery. Although seldom reported, posterior revision surgery to revise prior constructs can be advantageous over an anterior or combined approach. The authors describe their experience in performing posterior revision surgery using Goel's technique. The authors reviewed patients with AAD and BI who had undergone previous posterior surgery at the cranio-cervical junction between January 2016 and September 2017. All of these patients underwent revision surgery from a posterior approach. The Japanese Orthopaedic Association (JOA) score was used to assess clinical symptoms before and after surgery. The distance from the tip of the odontoid to Chamberlain's line, atlantodental interval (ADI), and clivus-canal angle (CCA) were used for radiographic assessment before and after surgery. Twelve consecutive patients were reviewed. Prior surgeries were as follows: 4 patients (4/12) with posterior osseous decompression without fusion, 7 (7/12) with reduction and fusion without decompression, and 1 (1/12) with posterior osseous decompression and reduction and fusion. With the use of Goel's technique for revision in these cases, distraction using facet spacers afforded release of the anterior soft tissue from a posterior approach. The occiput was fixated to C2 using a cantilever technique, and autologous cancellous bone was grafted into the intraarticular joints. In all 12 patients, complete reduction of BI and AAD were achieved without injury to nerves or vessels. All patients had evidence of bony fusion on CT scans within 18 months of follow-up. Posterior revision surgery using Goel's technique is an effective and safe revision salvage surgery for symptomatic patients with AAD and BI.


A controlled multi-center study evaluating the efficacy of Vivité skin care in the treatment of photoaging of the face, eye and mouth.
To determine the efficacy of a skin care system developed with a partially neutralized glycolic compound and natural antioxidants when compared to Cetaphil moisturizing regimen for the treatment of photoaging of the face, eye and mouth. A total of 36 patients between 35 and 65 years of age were randomized on a 3:1 ratio to use either Vivité Skin Care System or Cetaphil cleanser and moisturizer for 60 days. Facial skin was evaluated at baseline, day 30 and day 60. Subjects were required to fill out a self-evaluation of facial skin quality before, during, and after treatment. Investigators evaluated facial wrinkling using a common wrinkling scale as well as a visual evaluation of skin texture in a masked manner. A similar proportion of patients in each group had a 1-point improvement on the hyperpigmentation scale (42% of Vivité patients, 44% of Cetaphil patients). There were no statistically significant between-group differences in investigator rating of wrinkles. Subjectively, patients preferred Vivité to Cetaphil for noticeable improvement in fine lines or wrinkles (37.6-0%, respectively) at the first follow-up. By the final follow-up, more than half the patients in the Vivité group continued to notice an improvement in fine lines or wrinkles, compared with fewer than 25% in the Cetaphil group. More than twice the number of patients in the Vivité group noticed improvement in skin elasticity or tightness compared with those in the Cetaphil group. Patients reported that the Vivité skin care system improved the appearance of wrinkling and improved skin texture associated with moderate photoaging of the face, eye and mouth areas. Vivité had a higher patient preference rating than a commonly used moisturizing regimen. There were no differences noted in the physician evaluations.


Informal carers' experiences of caring for a person with heart failure in a community setting.
Heart failure (HF) is a life-limiting condition with a poor prognosis and unpredictable disease trajectory. HF brings physical and emotional challenges for patients and their carers. Predominantly the informal carer population consists of older females, however, caring is evolving as longevity increases and complex conditions are becoming more commonplace. Consequently, more men and younger people are contributing to daily care. The aim of this study was to explore the positive as well as negative dimensions of caring in HF across a range of carer characteristics. Fourteen semi-structured interviews were conducted with informal carers of people with HF in the UK (median age 71; female 10). Interviews were transcribed verbatim and analysed with the assistance of NVivo10 using Interpretative Phenomenological Analysis. Findings from the study demonstrated that most participants considered caring as integral to their relationships. Dimensions facilitating positivity in caring included compassion, thoughtfulness and understanding. An ability to cope was influenced by a range of attributes including quality of relationships in the carer/patient dyad and with formal social care providers who offered access to tailored and timely information and support. The unpredictable HF disease trajectory influenced the carer experience and enhanced the challenges encountered. The information needs of carers were not always adequately met and younger adult carers expressed particular difficulties with appropriate information and support. Expectations of our informal carer population are increasing and evolving. Health and social care policy requires innovative proposals for the funding and delivery of health and social care that has the contribution made by informal carers at its core.


Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial.
The primary analysis of the JGOG 3016 trial showed that a dose-dense paclitaxel and carboplatin regimen significantly improves progression-free and overall survival compared with the conventional regimen as first-line chemotherapy for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. We report the long-term follow-up results for survival. This randomised controlled trial was done at 85 centres in Japan. Patients with stage II-IV ovarian cancer were randomly assigned to receive conventional treatment (carboplatin area under the curve [AUC] 6 mg/mL per min and paclitaxel 180 mg/m(2) on day 1) or dose-dense treatment (carboplatin AUC 6 mg/mL per min on day 1 and paclitaxel 80 mg/m(2) on days 1, 8, and 15). The treatments were repeated every 3 weeks for six cycles; responding patients had three additional cycles. The randomisation was done centrally by telephone or fax, stratified by residual disease, stage, and histological type. The primary endpoint was progression-free survival; overall survival was a secondary endpoint. Long-term information on adverse events was not collected. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00226915. 637 patients were enrolled, of whom 631 were analysed (312 assigned to the dose-dense regimen, 319 to the conventional regimen). Median follow-up was 76·8 months (IQR 68·9-85·6). Median progression-free survival was significantly longer in the dose-dense treatment group than in the conventional treatment group (28·2 months [95% CI 22·3-33·8] vs 17·5 months [15·7-21·7]; hazard ratio [HR] 0·76, 95% CI 0·62-0·91; p=0·0037). Median overall survival was 100·5 months (95% CI 65·2-∞) in the dose-dense treatment group and 62·2 months (52·1-82·6) in the conventional treatment group (HR 0·79, 95% CI 0·63-0·99; p=0·039). Dose-dense treatment offers better survival than conventional treatment and is a potential new standard of care for first-line chemotherapy for patients with advanced epithelial ovarian cancer.


Distinct distal regulatory elements control tyrosinase expression in melanocytes and the retinal pigment epithelium.
Pigment cells of mammals are characterized by two different developmental origins: cells of the retinal pigment epithelium (RPE) originate from the optic cup of the developing forebrain, whereas melanocytes arise from the neural crest. The pigmentation gene tyrosinase is expressed in all pigment cells but differentially regulated in melanocytes and RPE. The tyrosinase promoter does not confer strong expression in pigment cells in vivo, while inclusion of a distal regulatory element at position -15 kb is necessary and sufficient to provide strong expression in melanocytes. Nevertheless, the regulatory elements responsible for correct spatial and temporal tyrosinase expression in the RPE remained unidentified so far. In this report, we show that a 186 kb BAC containing the tyrosinase gene provides transgene expression in both RPE and melanocytes indicating the presence of regulatory sequences required for expression in the RPE. A deletion analysis of the BAC was performed demonstrating that a RPE-regulatory element resides between -17 and -75 kb. Using multi-species comparative genomic analysis we identified three conserved sequences within this region. When tested in transgenic mice one of these sequences located at -47 kb targeted expression to the RPE. In addition, deletion of this regulatory element within a tyrosinase::lacZ BAC provided evidence that this sequence is not only sufficient but also required for correct spatial and temporal expression in the RPE. The identification of this novel element demonstrates that tyrosinase gene expression is controlled by separate distal regulatory sequences in melanocytes and RPE.


Mechanical pre-treatment of mobile phones and its effect on the Printed Circuit Assemblies (PCAs).
The recycling of Waste Electrical and Electronic Equipment (WEEE) has attracted a notable amount of interest during the last few decades due to the high metal concentrations and substantial increase in the growth rate of WEEE. In addition, higher recovery and recycling rates required by the European Union demand more comprehensive treatment of WEEE. However, complex product design and the presence of harmful substances together with low concentrations of special metals present challenges for processing. This study examines the effect of mechanical treatment of mobile phones on metal concentrations in the printed circuit assembly (PCA) fraction compared to manual dismantling. The designed mechanical treatment process including crushing, sieving, magnetic-, eddy current- and sensor-based separation was able to separate plastics, ferrous metals, PCA and stainless steel for further treatment. The process separated PCA with an efficiency of 85%. However, the quality of the separated PCAs was poor compared with "pure" manually dismantled PCAs. The primary crushing of mobile phones destroys PCAs thus resulting in the loss of especially precious metals used in the connector coatings and in the surface-mounted components. As a result, the theoretical value of the produced PCA fraction is only half compared to using manual dismantling. However, high labour costs in western countries and low capacity may hinder the feasibility of hand dismantling.


Ganoderma lucidum inhibits proliferation of human breast cancer cells by down-regulation of estrogen receptor and NF-kappaB signaling.
Ganoderma lucidum, an oriental medical mushroom, has been used in Asia for the prevention and treatment of a variety of diseases, including cancer. We have previously demonstrated that G. lucidum inhibits growth and induces cell cycle arrest at G0/G1 phase through the inhibition of Akt/NF-kappaB signaling in estrogen-independent human breast cancer cells. However, the molecular mechanism(s) responsible for the inhibitory effects of G. lucidum on the proliferation of estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) breast cancer cells remain to be elucidated. Here, we show that G. lucidum inhibited the proliferation of breast cancer MCF-7 and MDA-MB-231 cells by the modulation of the estrogen receptor (ER) and NF-kappaB signaling. Thus, G. lucidum down-regulated the expression of ERalpha in MCF-7 cells but did not effect the expression of ERbeta in MCF-7 and MDA-MB-231 cells. In addition, G. lucidum inhibited estrogen-dependent as well as constitutive transactivation activity of ER through estrogen response element (ERE) in a reporter gene assay. G. lucidum decreased TNF-alpha-induced (MCF-7) as well as constitutive (MDA-MB-231) activity of NF-kappaB. The inhibition of ER and NF-kappaB pathways resulted in the down-regulation of expression of c-myc, finally suppressing proliferation of estrogen-dependent as well as estrogen-independent cancer cells. Collectively, these results suggest that G. lucidum inhibits proliferation of human breast cancer cells and contain biologically active compounds with specificity against estrogen receptor and NF-kappaB signaling, and implicate G. lucidum as a suitable herb for chemoprevention and chemotherapy of breast cancer.


The formation mechanism of the initial C-C chain in ethanol synthesis on γ-AlOOH(100).
An in-depth understanding of the reaction mechanism at the molecular level is the key to guide the synthesis of ethanol over the CuZnAl catalyst, which is one of the major challenges for ethanol application in energy. Reported herein is a density functional theory study of ethanol synthesis from mixed methanol and syngas on the γ-AlOOH(100) surface. The possible elementary reactions are unambiguously identified and for the first time we confirm the high reactivity of the γ-AlOOH(100) surface for the initial C-C chain formation via CO insertion into CH3, which has a 62.8 kJ mol-1 (0.65 eV) activation barrier that is significantly lower than the barriers previously reported. And its corresponding reaction energy is -288.2 kJ mol-1 (-2.99 eV). Bader charge analyses indicate that it is advantageous for the nucleophilic attack of CO to the neighboring CH3 on the γ-AlOOH(100) surface. Our calculations show that ethanol synthesis starts with CH3OH dissociation, goes through CH3O dissociation to yield CH3, subsequently, CO inserts into CH3 to form CH3CO, which is further hydrogenated to yield CH3CHO and eventually obtain C2H5OH. And the formation of intermediate CH3 is the rate-determining step of the overall reaction. The results not only provide new mechanistic insights into the role of γ-AlOOH but also may be useful for the rational designing and optimizing of the CuZnAl catalyst for ethanol synthesis.


Sclerostin Antibody Increases Callus Size and Strength but does not Improve Fracture Union in a Challenged Open Rat Fracture Model.
Open fractures remain a challenge in orthopedics. Current strategies to intervene are often inadequate, particularly in severe fractures or when treatment is delayed. Sclerostin is a negative regulator of bone growth and sclerostin-neutralizing antibodies (Scl-Ab) can increase bone mass and strength. The application of these antibodies to improve orthopedic repair has shown varied results, and may be dependent on the location and severity of the bony injury. We examined Scl-Ab treatment within an established rat osteotomy model with periosteal stripping analogous to open fracture repair. In one study, Scl-Ab was given 25 mg/kg bi-weekly, either from the time of fracture or from 3 weeks post-fracture up to an end-point of 12 weeks. A second study treated only delayed union open fractures that did not show radiographic union by week 6 post-fracture. Outcome measures included radiographic union, microCT analysis of bone volume and architecture, and histology. In the first study, Scl-Ab given from either 0 or 3 weeks significantly improved callus bone volume (+52%, p < 0.05 and +58%, p < 0.01) at 12 weeks, as well as strength (+48%, p < 0.05 and +70%, p < 0.05). Despite these improvements, union rate was not changed. In the second study treating only established delayed fractures, bony callus volume was similarly increased by Scl-Ab treatment; however, this did not translate to increased biomechanical strength or union improvement. Sclerostin antibody treatment has limited effects on the healing of challenging open fractures with periosteal stripping, but shows the greatest benefits on callus size and strength with earlier intervention.


Planning for community care. Long-stay populations of hospitals scheduled for rundown or closure.
Using the Community Placement Questionnaire, the long-stay populations of five hospitals were surveyed. The results suggest that there is little need for large hospitals if adequate community provision is made. However, a small number of patients continue to accumulate for whom community placement is hard to envisage. Investigating the characteristics of the 'new long-stay' patients suggests that the usual definition should be extended to include those over 65 years old with no diagnosis of dementia and those in hospital for 1-10 years. About 20% of 'new long-stay' patients have organic diagnoses and the needs of this group require assessment.


Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles.
The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, most mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs because of chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future antimitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel.


Mapping cardiac surface mechanics with structured light imaging.
Cardiovascular disease often manifests as a combination of pathological electrical and structural heart remodeling. The relationship between mechanics and electrophysiology is crucial to our understanding of mechanisms of cardiac arrhythmias and the treatment of cardiac disease. While several technologies exist for describing whole heart electrophysiology, studies of cardiac mechanics are often limited to rhythmic patterns or small sections of tissue. Here, we present a comprehensive system based on ultrafast three-dimensional (3-D) structured light imaging to map surface dynamics of whole heart cardiac motion. Additionally, we introduce a novel nonrigid motion-tracking algorithm based on an isometry-maximizing optimization framework that forms correspondences between consecutive 3-D frames without the use of any fiducial markers. By combining our 3-D imaging system with nonrigid surface registration, we are able to measure cardiac surface mechanics at unprecedented spatial and temporal resolution. In conclusion, we demonstrate accurate cardiac deformation at over 200,000 surface points of a rabbit heart recorded at 200 frames/s and validate our results on highly contrasting heart motions during normal sinus rhythm, ventricular pacing, and ventricular fibrillation.


Relative sensitivities of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Cyp1a-1 and Cyp1a-2 gene expression and immunotoxicity in female B6C3F1 mice.
Improvements in risk assessment require better linkage of exposure to response by the determination of target tissue dose. The relative sensitivity of several responses in female B6C3F1 mice was compared on the basis of administered and target tissue dose spanning 3 orders of magnitude. Twenty-four hours after administration, [3H]TCDD was detected in the heart, spleen, kidney, uterus, thymus, lung, and liver, and the highest concentrations were noted in the liver, uterus, and lung. At doses from 5 to 25 ng/kg, hepatic [3H]TCDD levels associated with the cytosolic and nuclear subcellular fractions increased from 12 to 62% of the total liver levels and then decreased at higher doses. At the two lowest doses used in the enzyme induction study, 5 and 10 ng/kg, the levels of specifically bound nuclear Ah receptor complex liganded with [3H]TCDD were 2.3 and 2.5 fmol/mg protein. Slightly higher levels of nuclear Ah receptor complex were observed at doses between 25 and 100 ng/kg (i.e., 3.6 to 4.2 fmol/mg protein) and a steep dose-dependent increase in nuclear Ah receptor levels was noted at doses of 500, 1000, and 5000 ng/kg (8.0, 39.3, and 92.8 fmol/mg protein, respectively). The dose-dependent effects of [3H]TCDD on hepatic Cyp1a-1 and Cyp1a-2 mRNA levels, ethoxyresorufin O-deethylase (EROD) activity, and the splenic antibody plaque-forming cell (PFC) response to sheep red blood cells were also determined; the latter response was determined 9 days after administration of TCDD. Statistically significant induction of hepatic Cyp1a-1 was observed at lower doses (25 ng/kg) than any other marker, followed by induction of EROD and PFCs expressed per spleen or per 10(6) cells which was observed at 100 ng TCDD/kg and at higher doses. Cyp1a-2 was elevated significantly relative to control at doses > or = 1000 ng/kg. The ED50 value for PFCs/10(6) cells was the lowest of the variables analyzed and was not statistically significantly different from control (91 +/- 92 ng/kg). A 50% increase in Cyp1a-2 and Cyp1a-1 mRNA levels was observed at doses of 736 +/- 132 and 1630 +/- 431 ng/kg, respectively. Due to variability in response in PFCs/spleen and the submaximal induction of EROD activity, ED50 values could not be calculated for these responses. The analyses indicate that the immunosuppressive response (when normalized for the number of spleen cells) may be depressed by administered doses as low as 90 ng TCDD/kg body weight. A 50% increase in Cyp1a-1 or Cyp1a-2 was observed at higher administered doses (1630 or 736 ng/kg, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)


Prediction and treatment of asthma in preschool children at risk: study design and baseline data of a prospective cohort study in general practice (ARCADE).
Asthma is a difficult diagnosis to establish in preschool children. A few years ago, our group presented a prediction rule for young children at risk for asthma in general practice. Before this prediction rule can safely be used in practice, cross-validation is required. In addition, general practitioners face many therapeutic management decisions in children at risk for asthma. The objectives of the study are: (1) identification of predictors for asthma in preschool children at risk for asthma with the aim of cross-validating an earlier derived prediction rule; (2) compare the effects of different treatment strategies in preschool children. In this prospective cohort study one to five year old children at risk of developing asthma were selected from general practices. At risk was defined as 'visited the general practitioner with recurrent coughing (>or= 2 visits), wheezing (>or=1) or shortness of breath (>or=1) in the previous 12 months'. All children in this prospective cohort study will be followed until the age of six. For our prediction rule, demographic data, data with respect to clinical history and additional tests (specific immunoglobulin E (IgE), fractional exhaled nitric oxide (FENO), peak expiratory flow (PEF)) are collected. History of airway specific medication use, symptom severity and health-related quality of life (QoL) are collected to estimate the effect of different treatment intensities (as expressed in GINA levels) using recently developed statistical techniques. In total, 1,938 children at risk of asthma were selected from general practice and 771 children (40%) were enrolled. At the time of writing, follow-up for all 5-year olds and the majority of the 4-year olds is complete. The total and specific IgE measurements at baseline were carried out by 87% of the children. Response rates to the repeated questionnaires varied from 93% at baseline to 73% after 18 months follow-up; 89% and 87% performed PEF and FENO measurements, respectively. In this study a prediction rule for asthma in young children, to be used in (general) practice, will be cross-validated. Our study will also provide more insight in the effect of treatment of asthma in preschool children.


Diverse evolution of [[Ph(2)P(CH(2))(n)PPh(2)]Pt(mu-S)(2)Pt[Ph(2)P(CH(2))(n)PPh(2)]] (n = 2, 3) metalloligands in CH(2)Cl(2).
The nucleophilicity of the [Pt(2)S(2)] core in [[Ph(2)P(CH(2))(n)PPh(2)]Pt(mu-S)(2)Pt[Ph(2)P(CH(2))(n)PPh(2)]] (n = 3, dppp (1); n = 2, dppe (2)) metalloligands toward the CH(2)Cl(2) solvent has been thoroughly studied. Complex 1, which has been obtained and characterized by X-ray diffraction, is structurally related to 2 and consists of dinuclear molecules with a hinged [Pt(2)S(2)] central ring. The reaction of 1 and 2 with CH(2)Cl(2) has been followed by means of (31)P, (1)H, and (13)C NMR, electrospray ionization mass spectrometry, and X-ray data. Although both reactions proceed at different rates, the first steps are common and lead to a mixture of the corresponding mononuclear complexes [Pt[Ph(2)P(CH(2))(n)PPh(2)](S(2)CH(2))], n = 3 (7), 2 (8), and [Pt[Ph(2)P(CH(2))(n)PPh(2)]Cl(2)], n = 3 (9), 2 (10). Theoretical calculations give support to the proposed pathway for the disintegration process of the [Pt(2)S(2)] ring. Only in the case of 1, the reaction proceeds further yielding [Pt(2)(dppp)(2)[mu-(SCH(2)SCH(2)S)-S,S']]Cl(2) (11). To confirm the sequence of the reactions leading from 1 and 2 to the final products 9 and 11 or 8 and 10, respectively, complexes 7, 8, and 11 have been synthesized and structurally characterized. Additional experiments have allowed elucidation of the reaction mechanism involved from 7 to 11, and thus, the origin of the CH(2) groups that participate in the expansion of the (SCH(2)S)(2-) ligand in 7 to afford the bridging (SCH(2)SCH(2)S)(2-) ligand in 11 has been established. The X-ray structure of 11 is totally unprecedented and consists of a hinged [(dppp)Pt(mu-S)(2)Pt(dppp)] core capped by a CH(2)SCH(2) fragment.


AGO1 defines a novel locus of Arabidopsis controlling leaf development.
An allelic series of the novel argonaute mutant (ago1-1 to ago1-6) of the herbaceous plant Arabidopsis thaliana has been isolated. The ago1 mutation pleotropically affects general plant architecture. The apical shoot meristem generates rosette leaves and a single stem, but axillary meristems rarely develop. Rosette leaves lack a leaf blade but still show adaxial/abaxial differentiation. Instead of cauline leaves, filamentous structures without adaxial/abaxial differentiation develop along the stem and an abnormal inflorescence bearing infertile flowers with filamentous organs is produced. Two independent T-DNA insertions into the AGO1 locus led to the isolation of two corresponding genomic sequences as well as a complete cDNA. The AGO1 locus was mapped close to the marker mi291a on chromosome 1. Antisense expression of the cDNA resulted in a partial mutant phenotype. Sense expression caused some transgenic lines to develop goblet-like leaves and petals. The cDNA encodes a putative 115 kDa protein with sequence similarity to translation products of a novel gene family present in nematodes as well as humans. No specific function has been assigned to these genes. Similar proteins are not encoded by the genomes of yeast or bacteria, suggesting that AGO1 belongs to a novel class of genes with a function specific to multicellular organisms.


Eye health promotion and the prevention of blindness in developing countries: critical issues.
This review explores the role of health promotion in the prevention of avoidable blindness in developing countries. Using examples from eye health and other health topics from developing countries, the review demonstrates that effective eye health promotion involves a combination of three components: health education directed at behaviour change to increase adoption of prevention behaviours and uptake of services; improvements in health services such as the strengthening of patient education and increased accessibility and acceptability; and advocacy for improved political support for blindness prevention policies. Current eye health promotion activities can benefit by drawing on experiences gained by health promotion activities in other health topics especially on the use of social research and behavioural models to understand factors determining health decision making and the appropriate choice of methods and settings. The challenge ahead is to put into practice what we know does work. An expansion of advocacy-the third and most undeveloped component of health promotion-is essential to convince governments to channel increased resources to eye health promotion and the goals of Vision 2020.


Cancer incidence among Danish stone workers.
The lung cancer incidence of 2071 Danish stone workers was followed for a 42-year period. The expected numbers of cancer cases were based on the incidence rates for all Danish men after adjustment for region, and the data were analyzed separately for skilled and unskilled stone workers. The standardized incidence ratio (SIR) for lung cancer was 200 (44 observed, 22.0 expected) for all skilled stone workers, 808 (7 observed, 0.9 expected) for skilled sandstone cutters in Copenhagen, 119 (8 observed, 6.5 expected) for skilled granite cutters in Bornholm, 181 (24 observed, 13.2 expected) for all unskilled stone workers, 246 (17 observed, 6.9 expected) for unskilled workers in the road and building material industry, and 111 (7 observed, 6.3 expected) for unskilled workers in the stonecutting industry. Smoking was unlikely alone to explain the excess risk, and the available data on levels of exposure in the Danish stone industry point to a possible dose-response relationship between exposure to respirable silica dust and the incidence of lung cancer.


A kinematic analysis of rugby lineout throwing.
To characterize rugby union lineout throwing technique, three experienced male rugby players performed throwing trials under varying conditions of distance and trajectory. Motion analysis permitted the recovery of joint centre coordinates at 120 Hz and the construction of a three-dimensional linked segment model for calculation of joint angle and centre of mass time histories. All participants exhibited greater accuracy at shorter throwing distances, although the accuracy decrement was less in players of higher standard. Participants demonstrated different alterations in technique when performing throws of longer distances, either showing increased magnitudes of upper-body joint angle velocities (less accurate thrower) or lower-body joint velocities (more accurate thrower). The most elite thrower exhibited greater consistency in timing of peak joint angle velocities, with an overall standard deviation of 0.008 s compared with 0.027 s for the least accurate thrower. Data from participants of lesser ability suggest that changes are made to both magnitudes and timing of joint kinematics, which leads to increased variability in performance. The implications for players and coaches include the need to develop core strength to permit limited changes to the timing and magnitude of upper-body joint actions while allowing sufficient end-point velocity to be imparted on the ball.


Generalised linear mixed models analysis of risk factors for contamination of Danish broiler flocks with Salmonella typhimurium.
We present a retrospective observational study of risk factors associated with the occurrence of Salmonella typhimurium (ST) in Danish broiler flocks. The study is based on recordings from 1994 in the ante-mortem database maintained by the Danish Poultry Council. The epidemiological units are the broiler flocks (about 4000 flocks) which are clustered within producers. Broiler flocks with ST-infected parent stocks show increased risk of salmonella infection, and also the hatchery affects the salmonella status significantly. Among the rearing factors, only the use of medicine as well as the time of rearing, and the sampling method are significant. Epidemiological control would seem most efficient on starting at the top levels of the production hierarchy from which a major part of the ST contamination is derived. A secondary purpose of the study is to evaluate different statistical approaches and software for the analysis of a moderately-sized data set of veterinary origin. We compare the results from five analyses of the generalised linear mixed model (GLMM) type. The first observation is that the results agree reasonably well and lead to similar conclusions. A closer look reveals certain patterns of bias and estimation accuracy that correspond well with theoretical findings and practical experience reported in the statistical literature.


Characterizing the transmission dynamics and control of ebola virus disease.
Carefully calibrated transmission models have the potential to guide public health officials on the nature and scale of the interventions required to control epidemics. In the context of the ongoing Ebola virus disease (EVD) epidemic in Liberia, Drake and colleagues, in this issue of PLOS Biology, employed an elegant modeling approach to capture the distributions of the number of secondary cases that arise in the community and health care settings in the context of changing population behaviors and increasing hospital capacity. Their findings underscore the role of increasing the rate of safe burials and the fractions of infectious individuals who seek hospitalization together with hospital capacity to achieve epidemic control. However, further modeling efforts of EVD transmission and control in West Africa should utilize the spatial-temporal patterns of spread in the region by incorporating spatial heterogeneity in the transmission process. Detailed datasets are urgently needed to characterize temporal changes in population behaviors, contact networks at different spatial scales, population mobility patterns, adherence to infection control measures in hospital settings, and hospitalization and reporting rates.


Bioprospecting metagenomes: glycosyl hydrolases for converting biomass.
Throughout immeasurable time, microorganisms evolved and accumulated remarkable physiological and functional heterogeneity, and now constitute the major reserve for genetic diversity on earth. Using metagenomics, namely genetic material recovered directly from environmental samples, this biogenetic diversification can be accessed without the need to cultivate cells. Accordingly, microbial communities and their metagenomes, isolated from biotopes with high turnover rates of recalcitrant biomass, such as lignocellulosic plant cell walls, have become a major resource for bioprospecting; furthermore, this material is a major asset in the search for new biocatalytics (enzymes) for various industrial processes, including the production of biofuels from plant feedstocks. However, despite the contributions from metagenomics technologies consequent upon the discovery of novel enzymes, this relatively new enterprise requires major improvements. In this review, we compare function-based metagenome screening and sequence-based metagenome data mining, discussing the advantages and limitations of both methods. We also describe the unusual enzymes discovered via metagenomics approaches, and discuss the future prospects for metagenome technologies.


Adolescent Big Five personality and pubertal development: Pubertal hormone concentrations and self-reported pubertal status.
In early adolescence, levels of conscientiousness and agreeableness have been found to temporarily decrease, with levels of neuroticism increasing, indicating a dip in personality maturation. It is unknown whether these changes are related to the process of puberty, a major developmental milestone with numerous changes for children. Here, we first replicated the dip in personality maturity in early adolescence (N = 2640, age range 8-18, 51% girls, 65% non-Hispanic white, 21% Hispanic/Latino, 10% African American, 9% other, roughly 33% of families received means-tested public assistance) and tested associations between the Big Five personality dimensions and pubertal development and timing across late childhood and adolescence (n = 1793). Pubertal development was measured using both hormonal assays (DHEA, testosterone, and progesterone) and self-reports of secondary sex characteristics. Of hormonal measures, only higher DHEA concentrations were associated with lower conscientiousness and openness. Nonparametric moderation analyses using LOSEM indicated Complex Age × Sex interactions involving all three hormones. Self-reported pubertal development was associated with lower extraversion, conscientiousness, agreeableness, and openness. More advanced pubertal timing was also related to lower levels of extraversion, conscientiousness, and agreeableness. All associations were small. As some evidence was found for small associations between pubertal development and lower levels of conscientiousness and agreeableness, a dip in personality maturation in these personality traits may be partly due to pubertal development in early adolescence. Overall, results did not indicate that pubertal development was the primary explanation of the maturity dip in adolescent personality. Many small influences likely accumulate to explain the dip in personality maturity in early adolescence. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Controversial issues in Gleason and International Society of Urological Pathology (ISUP) prostate cancer grading: proposed recommendations for international implementation.
The Gleason Grading system has been used for over 50 years to prognosticate and guide the treatment for patients with prostate cancer. At consensus conferences in 2005 and 2014 under the guidance of the International Society of Urological Pathology (ISUP), the system has undergone major modifications to reflect modern diagnostic and therapeutic practices. The 2014 consensus conference yielded recommendations regarding cribriform, mucinous, glomeruloid and intraductal patterns, the most significant of which was the removal of any cribriform pattern from Gleason grade 3. Furthermore, a Gleason score grouping system was endorsed which consisted of five grades where Gleason score 6 (3+3) was classified as grade 1 which better reflected the mostly indolent behaviour of these tumours. Another issue discussed at the meeting and subsequently endorsed was that in Gleason score 7 cases, the percentage pattern 4 should be recorded. This is especially important in situations where modern active surveillance protocols expand to include men with low volume pattern 4. While major progress was made at the conference, several issues were either not resolved or not discussed at all. Most of these items relate to details of assignment of Gleason score and ISUP grade in specific specimen types and grading scenarios. This detailed review looks at the 2014 ISUP conference results and subsequent literature from an international perspective and proposes several recommendations. The specific issues addressed are percentage pattern 4 in Gleason score 7 tumours, percentage patterns 4 and 5 or 4/5 in Gleason score 8-10 disease, minor (≤5%) high grade patterns when either 2 or 3 patterns are present, level of reporting (core, specimen, case), dealing with grade diversity among site (highest and composite scores) and reporting scores in radical prostatectomy specimens with multifocal disease. It is recognised that for many of these issues, a strong evidence base does not exist, and further research studies are required. The proposed recommendations mostly reflect consolidated expert opinion and they are classified as established if there was prior agreement by consensus and provisional if there was no previous agreement or if the item was not discussed at prior consensus conferences. For some items there are reporting options that reflect the local requirements and diverse practice models of the international urological pathology community. The proposed recommendations provide a framework for discussion at future consensus meetings.


[Antidepressants are frequently prescribed but still critized; a perspective on causes and solutions].
From around 1980, antidepressants (ad) have increasingly been prescribed, for longer periods of time, especially selective serotonin reuptake inhibitors (ssris). Paradoxically, their effectiveness is still doubted, especially outside the psychiatric profession.
 AIM: To explain increase and offer a perspective on causes and solutions, and to indicate how to reach consensus.
 METHOD: Position paper with critical analysis and synthesis of relevant literature.
 RESULTS: The rise in AD prescriptions results from: 1. increased safety and ease of prescribing, 2. increased presentation and recognition of depression in primary care, 3. extension of indication criteria, 4. effective marketing strategies, and 5. effectiveness in acute phase (aad) and of relapse/recurrence prevention in continuation/maintenance phases (coad).Critics point to: 1. low added value of aad relative to placebo, 2. many drop-outs and non-responders, 3. relapse/recurrence prevention with coad works only for responders to aad, 4. relapse/recurrence after AD discontinuation often involves withdrawal symptoms, and 5. publication bias, selective reporting, selective patient selection, and suboptimal blinding, resulting in overestimated effectiveness and underestimated disadvantages.Factors that keep fueling the controversy are: 1. critics stress the net effectiveness of AD whereas proponents point at gross effectiveness which includes spontaneous recovery and placebo effect; 2. persistence of distrust in industry-funded rcts; 3. ideological positions, reinforced by conflicts of interest and selective citations; 4. lack of rcts with relevant long-term outcome measurements.
 CONCLUSION: Although consensus is difficult to achieve given the ideological component, there are options. Three factors are critically important: confer to establish which data convince the opposition, response prediction (what works for whom), and rcts with long-term functional outcomes.


[Development and implementation of Animals-Assisted Therapy in a university hospital].
This report refers to the experience of the Board of Nursing of Hospital São Paulo, Universidade de São Paulo, in the development and implantation of Animal-Assisted Therapy, as one of its projects humanization of hospital: 'Projeto Amicão'. Aiming to offer patients a positive experience that differs from the routine of the hospital environment, some units of the Hospiral São Paulo received the visit of an animal for sessions of Animal-Assisted Therapy. The results achieved among patients and its companions and health professionals were positive, in addition to arouse the attention and the interest of other health institutions and the media. It is thus evidenced the importance of reporting the experience of 'Projeto Amicão' in the hospital.


[A girl with self-harm treated with N-acetylcysteine (NAC)].
Deliberate and recurrent self-harm could be regarded as addictive behaviour that can be treated with medication. In addiction, the dopaminergic mesolimbic reward system is activated. Pain caused by cutting stimulates the reward system through the opioid system. Glutamatergic neurotransmission follows the same pathway and plays a role in addiction as well. In this case-study a 17-year-old girl was successfully treated with N-acetylcysteine (nac) in order to reduce the frequency of self-cutting. In addition, in this case nac reduced the symptoms of attention deficit/hyperactivity disorder and depression. nac modulates the glutamatergic neurotransmission. This article provides possible explanations for the effect of nac in this case.


Sex and flagellation.
The centriole is one of the cell's more enigmatic structures. It lives a Jekyll and Hyde existence, changing from the basal body, which seeds the production of cilia and flagellae, into the centriole, in which guise it is of uncertain function. Recent work has indicated the possibility of DNA tightly packed into the structure's core. This finding sheds light on theories of the evolutionary origins of the centriole and of its possible involvement in the evolution of sex. Recent experimental work has been testing this latter possibility.


Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice.
Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock-in (KI) mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6months, by 12months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug-evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.


[Possibilities of antioxidant therapy for asthenia and cognitive deficit in elderly patients with chronic brain ischemia].
To evaluate the effect of the antioxidant mexidol on the oxidant-antioxidant potential of low-density lipoprotein (LDL), asthenic and anxious symptoms, and cognitive function of neurodynamic type in elderly patients with chronic brain ischemia (CBI). Thirty women (mean age 66.7 years) with grade 1-2 dyscirculatory encephalopathy (DE) were examined. Trends for asthenic, anxious, and cognitive symptoms of neurodynamic type were estimated using the standard tests (MFI-20, Hamilton Anxiety Rating Scale, Schulte Tables, Wechsler test) on days 1, 15, and 60 of mexidol treatment (for 60 days). LDLs were isolated from blood by heparin precipitation. The baseline level of lipid peroxidation products was determined and the concentrations of fat-soluble antioxidants (a-tocopherol, retinol, beta-carotene, and xanthins) were examined in the isolated LDLs on days 1 and 5 of the study. A 60-day mexidol therapy cycle statistically significantly caused a reduction in asthenic and anxious symptoms in elderly patients with CBI and induced positive changes in the symptoms of cognitive neurodynamics. Assessing the specific features of the pharmacodynamics of the antioxidant mexidol used in the elderly patients for 15 days revealed a statistically significant positive effect on the oxidative potential of LDLs as a decreased predisposition to their antioxidative processes in vivo. The drug's effect in elevating the levels of a-tocopherol and beta-carotene was altered insignificantly (without statistically significant changes), which reflects the pharmacodynamic features of the drug in the elderly patients. The 60-day cycle of therapy with the antioxidant mexidol has a positive impact on asthenic and neurotic symptoms in the elderly patients with CBI. Mexidol is well tolerated and safe when used long.


Herpes zoster vaccine: A health economic evaluation for Switzerland.
Herpes zoster (HZ) or "shingles" results from a reactivation of the varicella zoster virus (VZV) acquired during primary infection (chickenpox) and surviving in the dorsal root ganglia. In about 20% of cases, a complication occurs, known as post-herpetic neuralgia (PHN). A live attenuated vaccine against VZV is available for the prevention of HZ and subsequent PHN. The present study aims to update an earlier evaluation estimating the cost-effectiveness of the HZ vaccine from a Swiss third party payer perspective. It takes into account updated vaccine prices, a different age cohort, latest clinical data and burden of illness data. A Markov model was developed to simulate the lifetime consequences of vaccinating 15% of the Swiss population aged 65-79 y. Information from sentinel data, official statistics and published literature were used. Endpoints assessed were number of HZ and PHN cases, quality-adjusted life years (QALYs), costs of hospitalizations, consultations and prescriptions. Based on a vaccine price of CHF 162, the vaccination strategy accrued additional costs of CHF 17,720,087 and gained 594 QALYs. The incremental cost-effectiveness ratio (ICER) was CHF 29,814 per QALY gained. Sensitivity analyses showed that the results were most sensitive to epidemiological inputs, utility values, discount rates, duration of vaccine efficacy, and vaccine price. Probabilistic sensitivity analyses indicated a more than 99% chance that the ICER was below 40,000 CHF per QALY. Findings were in line with existing cost-effectiveness analyses of HZ vaccination. This updated study supports the value of an HZ vaccination strategy targeting the Swiss population aged 65-79 y.


Grain Boundary Segregation in Pd-Cu-Ag Alloys for High Permeability Hydrogen Separation Membranes.
Dense metal membranes that are based on palladium (Pd) are promising for hydrogen separation and production due to their high selectivity and permeability. Optimization of alloy composition has normally focused on bulk properties, but there is growing evidence that grain boundaries (GBs) play a crucial role in the overall performance of membranes. The present study provides parameters and analyses of GBs in the ternary Pd-Ag-Cu system, based on first-principles electronic structure calculations. The segregation tendency of Cu, Ag, and vacancies towards 12 different coherent ∑ GBs in Pd was quantified using three different procedures for relaxation of supercell lattice constants, representing the outer bounds of infinitely elastic and stiff lattice around the GBs. This demonstrated a clear linear correlation between the excess volume and the GB energy when volume relaxation was allowed for. The point defects were attracted by most of the GBs that were investigated. Realistic atomic-scale models of binary Pd-Cu and ternary Pd-Cu-Ag alloys were created for the ∑5(210) boundary, in which the strong GB segregation tendency was affirmed. This is a starting point for more targeted engineering of alloys and grain structure in dense metal membranes and related systems.


Pyridoxal isonicotinoyl hydrazone analogs induce apoptosis in hematopoietic cells due to their iron-chelating properties.
Analogs of pyridoxal isonicotinoyl hydrazone (PIH) are of interest as iron chelators for the treatment of secondary iron overload and cancer. PIH, salicylaldehyde isonicotinoyl hydrazone (SIH), and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (NIH), the toxicity of which vary over two orders of magnitude, were selected for a study of their mechanisms of toxicity. PIH analogs and their iron complexes caused concentration- and time-dependent apoptosis in Jurkat T lymphocytes and K562 cells. Bcl-2 overexpression was partially anti-apoptotic, suggesting mitochondrial mediation of apoptosis. Since the pan-caspase inhibitor zVAD-fmk did not reduce lysosomal and mitochondrial destabilization, these events occur upstream of caspase activation. In contrast, phosphatidylserine externalization and the development of apoptotic morphology were inhibited significantly, indicating the role of caspases in mediating these later events. Since overexpression of CrmA had no effect on apoptosis, caspase-8 is not likely involved. Fe(3+) complexes of SIH and NIH, which accumulated in 59Fe-labeled mouse reticulocytes during incubation with the chelators, also caused apoptosis. BSA, which promotes release of the complexes from cells, reduced the toxicity of SIH and NIH, suggesting that the induction of apoptosis by PIH analogs involves toxic effects mediated by their Fe(3+) complexes. Moreover, analogs of these agents lacking the iron-chelating moiety were non-toxic.


Microperimetry Reliability Assessed From Fixation Performance.
Microperimetry provides an accurate assessment of central retinal sensitivity due to its fundus-tracking capability, but it has limited reliability indicators. One method currently employed, fixation loss, samples the optic nerve blind spot for positive responses; however, it is unclear if these responses arise from unintentional button presses or from tracking failure leading to stimuli misplacement. We investigated the relationship between blind spot scotoma positive responses (termed scotoma responses) and fixation. Part 1 of the study involved a custom grid of 181 points centered on the optic nerve that was constructed to map physiological blind spots in primary and simulated eccentric fixation positions. Scotoma responses and the 63% and 95% fixation bivariate contour ellipse areas (BCEA63 and BCEA95) were analyzed. In Part 2, fixation data from controls and patients with retinal diseases (234 eyes from 118 patients) were collected. Part 1, a linear mixed model of 32 control participants, demonstrated significant (P < 0.001) correlation between scotoma responses and BCEA95. In Part 2, the upper 95% confidence intervals for BCEA95 were 3.7 deg2 for controls, 27.6 deg2 for choroideremia, 23.1 deg2 for typical rod-cone dystrophies, 21.4 deg2 for Stargardt disease, and 111.3 deg2 for age-related macular degeneration. Incorporating all pathology groups into an overall statistic resulted in an upper limit BCEA95 = 29.6 deg2. Microperimetry reliability is significantly correlated to fixation performance, and BCEA95 provides a surrogate marker for test accuracy. Examinations of healthy individuals and patients with retinal disease are deemed unreliable if BCEA95 > 4 deg2 and BCEA95 > 30 deg2, respectively. Microperimetry reliability should be assessed using fixation performance as summarized by BCEA95 rather than the level of fixation losses.


Quantitative passive soil vapor sampling for VOCs--Part 4: Flow-through cell.
This paper presents a controlled experiment comparing several quantitative passive samplers for monitoring concentrations of volatile organic compound (VOC) vapors in soil gas using a flow-through cell. This application is simpler than conventional active sampling using adsorptive tubes because the flow rate does not need to be precisely measured and controlled, which is advantageous because the permeability of subsurface materials affects the flow rate and the permeability of geologic materials is highly variable. Using passive samplers in a flow-through cell, the flow rate may not need to be known exactly, as long as it is sufficient to purge the cell in a reasonable time and minimize any negative bias attributable to the starvation effect. An experiment was performed in a 500 mL flow-through cell using a two-factor, one-half fraction fractional factorial test design with flow rates of 80, 670 and 930 mL min(-1) and sample durations of 10, 15 and 20 minutes for each of five different passive samplers (passive Automatic Thermal Desorption Tube, Radiello®, SKC Ultra, Waterloo Membrane Sampler™ and 3M™ OVM 3500). A Summa canister was collected coincident with each passive sampler and analyzed by EPA Method TO-15 to provide a baseline for comparison of the passive sampler concentrations. The passive sampler concentrations were within a factor of 2 of the Summa canister concentrations in 32 of 35 cases. Passive samples collected at the low flow rate and short duration showed low concentrations, which is likely attributable to insufficient purging of the cell after sampler placement.


Negative transcriptional regulation of connexin 43 by Tbx2 in rat immature coronal sutures and ROS 17/2.8 cells in culture.
Tbx2 is a member of the T-box family of transcriptional regulatory genes with an extensive but not yet fully understood role in embryonic development. This study explores the potential role of Tbx2 in calvarial morphogenesis. To explore the hypothesis that Tbx2 has a negative regulatory effect on the expression of connexin 43 (Cx43), a protein necessary for cell-to-cell communication; document the presence of Tbx2 protein in the developing cranial sutures; and determine the spatial pattern of expression of this developmentally regulated transcription factor in calvariae. The osteoblast-like cell line ROS 17/2.8 was stably transfected with sense or antisense Tbx2. Immunohistochemistry and Western blotting was used to study Tbx2 and Cx43 expression in these cells and sections of embedded developing coronal sutures. The ROS 17/2.8 cells transfected with antisense Tbx2 showed a decrease in expression of Tbx2 protein and an increase in expression of endogenous Cx43. The reverse is seen with sense-transfected cells. Both of these proteins are expressed in rat developing coronal sutures. The pattern of Tbx2 expression in the developing was also reciprocal to the pattern of Cx43 expression. Tbx2 protein is concentrated in the center of the sutural blastema, an area devoid of Cx43 protein localization. Conversely, Tbx2 protein expression is low in the periphery of the sutures, in which there is high Cx43 protein expression. Taken together, these studies suggest that Tbx2 protein is a negative regulator of Cx43 expression at the transcriptional level in cranial sutures in vivo.


Cyclic AMP levels in several macroalgae and their relation to light quantity and quality.
Total cAMP levels were measured in the macroalgae Dictyota dichotoma, Gelidium sesquipedale and Ulva rigida under different light conditions in order to study its regulation either by phytochrome or photosynthesis. Incubation in red or far-red light did not promote a phytochrome-like response; instead, it showed a synergistic effect upon cAMP accumulation. cAMP levels seemed to depend on the amount of energy applied. The correlation between photosynthetic oxygen evolution and cAMP variations at sub-saturating white light irradiance pointed to photosynthetic electron transport as involved in the regulation of cAMP accumulation at least in G. sesquipedale and U. rigida. Inhibitors of thylakoidal and mitochondrial electron transport chains reduced cAMP levels in 70 to 99%. We conclude that cAMP accumulation could be regulated by photosynthetic activity rather than phytochrome in the macroalgae studied.


Comparison of the clinical performance of upper abdominal PET/DCE-MRI with and without concurrent respiratory motion correction (MoCo).
To compare the clinical performance of upper abdominal PET/DCE-MRI with and without concurrent respiratory motion correction (MoCo). MoCo PET/DCE-MRI of the upper abdomen was acquired in 44 consecutive oncologic patients and compared with non-MoCo PET/MRI. SUVmax and MTV of FDG-avid upper abdominal malignant lesions were assessed on MoCo and non-MoCo PET images. Image quality was compared between MoCo DCE-MRI and non-MoCo CE-MRI, and between fused MoCo PET/MRI and fused non-MoCo PET/MRI images. MoCo PET resulted in higher SUVmax (10.8 ± 5.45) than non-MoCo PET (9.62 ± 5.42) and lower MTV (35.55 ± 141.95 cm3) than non-MoCo PET (38.11 ± 198.14 cm3; p < 0.005 for both). The quality of MoCo DCE-MRI images (4.73 ± 0.5) was higher than that of non-MoCo CE-MRI images (4.53±0.71; p = 0.037). The quality of fused MoCo-PET/MRI images (4.96 ± 0.16) was higher than that of fused non-MoCo PET/MRI images (4.39 ± 0.66; p < 0.005). MoCo PET/MRI provided qualitatively better images than non-MoCo PET/MRI, and upper abdominal malignant lesions demonstrated higher SUVmax and lower MTV on MoCo PET/MRI.


Modelling optimum use of attractive toxic sugar bait stations for effective malaria vector control in Africa.
The development of insecticide resistance and the increased outdoor-biting behaviour of malaria vectors reduce the efficiency of indoor vector control methods. Attractive toxic sugar baits (ATSBs), a method targeting the sugar-feeding behaviours of vectors both indoors and outdoors, is a promising supplement to indoor tools. The number and configuration of these ATSB stations needed for malaria control in a community needs to be determined. A hypothetical village, typical of those in sub-Saharan Africa, 600 × 600 m, consisting of houses, humans and essential resource requirements of Anopheles gambiae (sugar sources, outdoor resting sites, larval habitats) was simulated in a spatial individual-based model. Resource-rich and resource-poor environments were simulated separately. Eight types of configurations and different densities of ATSB stations were tested. Anopheles gambiae population size, human biting rate (HBR) and entomological inoculation rates (EIR) were compared between different ATSB configurations and densities. Each simulated scenario was run 50 times. Compared to the outcomes not altered by ATSB treatment in the control scenario, in resource-rich and resource-poor environments, respectively, the optimum ATSB treatment reduced female abundance by 98.22 and 91.80 %, reduced HBR by 99.52 and 98.15 %, and reduced EIR by 99.99 and 100 %. In resource-rich environments, n × n grid design, stations at sugar sources, resting sites, larval habitats, and random locations worked better in reducing vector population and HBRs than other configurations (P < 0.0001). However, there was no significant difference of EIR reductions between all ATSB configurations (P > 0.05). In resource-poor environments, there was no significant difference of female abundances, HBRs and EIRs between all ATSB configurations (P > 0.05). The optimum number of ATSB stations was about 25 for resource-rich environments and nine for resource-poor environments. ATSB treatment reduced An. gambiae population substantially and reduced EIR to near zero regardless of environmental resource availability. In resource-rich environments, dispersive configurations worked better in reducing vector population, and stations at or around houses worked better in preventing biting and parasite transmission. In resource-poor environments, all configurations worked similarly. Optimum numbers of bait stations should be adjusted according to seasonality when resource availability changes.


Structural and metabolic correlates of episodic memory in relation to the depth of encoding in normal aging.
This study set out to establish the relationship between changes in episodic memory retrieval in normal aging on the one hand and gray matter volume and (18)FDG uptake on the other. Structural MRI, resting-state (18)FDG-PET, and an episodic memory task manipulating the depth of encoding and the retention interval were administered to 46 healthy subjects divided into three groups according to their age (young, middle-aged, and elderly adults). Memory decline was found not to be linear in the course of normal aging: Whatever the retention interval, the retrieval of shallowly encoded words was impaired in both the middle-aged and the elderly, whereas the retrieval of deeply encoded words only declined in the elderly. In middle-aged and elderly subjects, the reduced performance in the shallow encoding condition was mainly related to posterior mediotemporal volume and metabolism. By contrast, the impaired retrieval of deeply encoded words in the elderly group was mainly related to frontal and parietal regions, suggesting the adoption of inefficient strategic processes.


Specialized pro-resolving mediator network: an update on production and actions.
Today, persistent and uncontrolled inflammation is appreciated to play a pivotal role in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other diseases of public health concern (e.g. Coronavirus Disease 2019 (COVID-19) and periodontal disease). The ideal response to initial challenge in humans is a self-limited inflammatory response leading to complete resolution. The resolution phase is now widely recognized as a biosynthetically active process, governed by a superfamily of endogenous chemical mediators that stimulate resolution of inflammatory responses, namely specialized proresolving mediators (SPMs). Because resolution is the natural ideal response, the SPMs have gained attention. SPMs are mediators that include ω-6 arachidonic acid-derived lipoxins, ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-derived resolvins, protectins and maresins, cysteinyl-SPMs, as well as n-3 docosapentaenoic acid (DPA)-derived SPMs. These novel immunoresolvents, their biosynthetic pathways and receptors have proven to promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via specific cellular and molecular mechanisms. As of 17 August, 2020, PubMed.gov reported >1170 publications for resolvins, confirming their potent protective actions from many laboratories worldwide. Since this field is rapidly expanding, we provide a short update of advances within 2-3 years from human and preclinical animal studies, together with the structural-functional elucidation of SPMs and identification of novel SPM receptors. These new discoveries indicate that SPMs, their pathways and receptors could provide a basis for new approaches for treating inflammation-associated diseases and for stimulating tissue regeneration via resolution pharmacology and precision nutrition.


[Association of C reactive protein levels with metabolic syndrome in adults: a population-based study].
Metabolic syndrome is highly prevalent among adults in Chile and represents a health risk. To determine the relationship between metabolic syndrome (MetS) and its components, with C reactive protein levels (CRP) as an inflammation marker. The population studied consisted of 736 individuals born in a hospital from Valparaíso Region, aged between 32-38 years at the time of the study. MetS was identified according to the Adult Treatment Panel (ATP) III guidelines and inflammation was measured using ultra-sensitive CRP. This parameter was classified as normal for values from 0 to 3 mg/L, high for values from 3.01 to 10 mg/L and very high for values > 10 mg/L. Median CRP was in the normal range (1.9 mg/L, interquartile range 0.7-5.2) and was higher among women than men (2.2 and 1.4 mg/L respectively, p < 0.01). Twenty seven percent of participants had MetS. One-fourth had high blood glucose values, one-third had high triglyceride levels and 28% had blood pressure values over those established as normal in MetS. Elevated waist circumference (WC) and low HDL cholesterol were found among almost 50% of participants. A relationship between MetS and high CRP was only found among men with an Odds ratio (OR) of 2.04 (95% confidence intervals (CI): 1.11-3.73). The same association was observed for high triglyceride levels with an OR of 2.02 (CI: 1.17-3.49) and high WC with an OR of 3.89 (CI: 2.06-7.36). Among women, the only relationship observed was between abdominal obesity and very high CRP with an OR of 2. 65 (CI: 1.20-5.84). Metabolic syndrome, high triglyceride levels, and abdominal obesity were associated with inflammation only in men.


Abnormally fertilized oocytes can result in healthy live births: improved genetic technologies for preimplantation genetic testing can be used to rescue viable embryos in in vitro fertilization cycles.
To test whether abnormally fertilized oocyte (AFO)-derived blastocysts are diploid and can be rescued for clinical use. Longitudinal-cohort study from January 2015 to September 2016 involving IVF cycles with preimplantation genetic testing for aneuploidy (PGT-A). Ploidy assessment was incorporated whenever a blastocyst from a monopronuclear (1PN) or tripronuclear zygote (2PN + 1 smaller PN; 2.1 PN) was obtained. Private IVF clinics and genetics laboratories. A total of 556 women undergoing 719 PGT-A cycles. Conventional chromosome analysis was performed on trophectoderm biopsies by quantitative polymerase chain reaction. For AFO-derived blastocysts, ploidy assessment was performed on the same biopsy with the use of allele ratios for hetorozygous SNPs analyzed by means of next-generation sequencing (1:1 = diploid; 2:1 = triploid; loss of heterozygosity = haploid). Balanced-diploid 1PN- and 2.1PN-derived blastocysts were transferred in the absence of normally fertilized transferable embryos. Ploidy constitution and clinical value of AFO-derived blastocysts in IVF PGT-A cycles. Of the 5,026 metaphase II oocytes injected, 5.2% and 0.7% showed 1PN and 2.1PN, respectively. AFOs showed compromised embryo development (P<.01). Twenty-seven AFO-derived blastocysts were analyzed for ploidy constitution. The 1PN-derived blastocysts were mostly diploid (n = 9/13; 69.2%), a few were haploid (n = 3/13; 23.1%), and one was triploid (n = 1/13; 7.7%). The 2.1PN-derived blastocysts were also mostly diploid (n = 12/14; 85.7%), and the remainder were triploid. Twenty-six PGT-A cycles resulted in one or more AFO-derived blastocysts (n = 26/719; 3.6%). Overall, eight additional balanced-diploid transferable embryos were obtained from AFOs. In three cycles, the only balanced-diploid blastocyst produced was from an AFO (n = 3/719; 0.4%). Three AFO-derived live births were achieved: one from a 1PN zygote and two from 2.1PN zygotes. Enhanced PGT-A technologies incorporating reliable ploidy assessment provide an effective tool to rescue AFO-derived blastocysts for clinical use.