Efficiency of stem cell based therapy in the treatment of diabetic foot ulcer: a meta-analysis.
Diabetic foot ulcer is a chronic, refractory, frequent complication in diabetic patient. Its treatment often requires multidisciplinary joint efforts, diverse strategies have been adopted to address this annoying issue, including stem cell-based therapy/acellular dermal matrix/negative pressure wound therapy etc. However, consensus has not been reached. To assess the current evidence regarding the efficiency and potential advantages of stem cell-based therapy compared with conventional standard treatment and/or placebo in the treatment of diabetic foot ulcer. A comprehensive search in PubMed, EmBase, Cochrane Central and Web of Science databases was conducted during December 2016 and a systematic review and meta-analysis of all relevant studies were performed. A total of 7 studies that involved 224 diabetic foot patients, classified as Wagner grades 1-5, were analyzed. The pooled results confirmed the benefits of using the stem cell treatment. Partial and/or complete healing were significantly higher in the stem cell group compared with the control group (77.4% vs. 31.9%; RR: 2.22; 95% CI, 1.65-2.98). Subgroup analysis on ABI and TCP02 also confirmed the results. The present meta-analysis indicates that stem cell-based therapy can enhance the healing of diabetic foot ulcers and is associated with lesser pain, lower amputation rate and improved prognosis compared with normal treatment. Well-designed randomized controlled trials are required in the future in order to confirm and update these findings.


Responding to clinicians who fail to follow patient safety practices: perceptions of physicians, nurses, trainees, and patients.
The field of patient safety grapples with the tension between a "no-blame" systems approach and the need to hold providers accountable for substandard performance. Attitudes of clinicians and patients regarding methods of promoting adherence to safety practices have not been described. We surveyed attending and resident physicians in the University of California, San Francisco (UCSF) Department of Medicine, nurses and inpatients at the UCSF Medical Center, and UCSF medical students regarding attitudes toward violations of 3 safety protocols: hand hygiene, fall risk assessment, and preoperative time-out. Responses to protocol lapses were grouped into 3 categories: feedback (universally endorsed and thus excluded from the analysis), public reporting, and penalty (fines, suspension, firing). We examined group differences regarding whether public reporting and penalties were ever appropriate and the number of transgressions at which public reporting and penalties were favored. Respondents favored both public reporting and penalties more frequently for not conducting a preoperative time-out or fall risk assessment than for hand-hygiene lapses (public reporting: time-out, odds ratio [OR]: 2.82 [95% confidence interval {CI}: 2.03-3.91]; fall, OR: 1.47 [95% CI: 1.09-1.98]. Penalty: time-out, OR: 4.29 [95% CI: 2.97-6.20]; fall, OR: 1.74 [95% CI: 1.27-2.37]). Penalties were endorsed more frequently than public reporting for all groups and scenarios. Attending physicians and patients expressed similar attitudes regarding public reporting and penalties, but patients favored penalties after significantly fewer transgressions (P < 0.05). After a decade emphasizing no-blame responses to patient safety hazards, both healthcare providers and patients now believe clinicians should be held accountable for following basic safety protocols.


[Evaluation of the content of harmful substances in the air of sewage treatment facilities of Astrakhan gas processing plant].
Despite the fact that the progress in regard to the degree of processing of natural gas and condensate in the Astrakhan gas processing plant is significant, necessary hygienic normalization of working environment on the part of the content of harmful substances in the air of working areas is still unable. Harmful substances were detected in the breathing zone of workers of sewage treatment plant almost constantly. In this connection there is a need in the further joint work hygienists, designers and manufacturers for the development and justification of new, more effective decisions - both on the part of as well technology as hardware design - with the purpose of improvement of working conditions.


The decision to receive influenza vaccination among nurses in North and South Dakota.
We examined the relationships between factors (intention, habit, facilitating conditions, and social, cognitive, and affective factors) and nurses' decisions about influenza vaccinations to understand why some get vaccinated while others do not. In a descriptive correlational design, the Triandis model of interpersonal behavior was used to examine the decision of nurses to receive influenza vaccinations. Participants were a random sample (N=193) of registered nurses in North and South Dakota drawn from the respective state nursing licensing board lists. Instrument construction and mail survey procedures followed Dillman's tailored design method. The response rate exceeded 80%. The findings revealed significant, positive correlations among all model variables. Item analysis showed that false beliefs about influenza disease and vaccinations were prevalent and that there was a wide variation in employer support for nurses getting vaccinated. Educational and social marketing strategies may improve nurse's knowledge about influenza disease and vaccine and increase vaccine uptake. Employers should be encouraged to promote and improve influenza vaccine accessibility in the workplace. Additional study is needed to understand how best to strengthen the influence of intention and habit on the decision of nurses to receive influenza vaccinations.


The purification and properties of microsomal palmitoyl-coenzyme A synthetase.
The isolation and purification of palmitoyl-CoA synthetase from rat liver microsomes is described. Several methods suitable for enzyme assay are described. The general properties and kinetic parameters of the purified enzyme were determined and are discussed in relationship to microsomal fatty acid activation.


Antigenic and virulence properties of Pasteurella haemolytica leukotoxin mutants.
Antigenic properties of two mutants of Pasteurella haemolytica, strains 59B0071 and 59B0072, that do not produce detectable leukotoxin were investigated. Western blot (immunoblot) analysis with a number of polyclonal sera from animals recovering from pasteurellosis revealed that both mutants secreted a variety of antigens that were also present in cultures of several wild-type strains. These antigens ranged from about 100 to 15 kDa. Mutant strain 59B0071 was found to be totally deficient in leukotoxin, as judged not only by Western blotting but also by cytotoxicity assays with bovine lymphoma (BL-3) cells or bovine polymorphonuclear cells as targets. The mutant strain 59B0071 had normal levels of a secreted sialylglycoprotease, however. When strains were tested for virulence in goat and cattle challenge experiments, a reduction in mortality and lung lesions was observed with the mutant 59B0071 in comparison with results obtained with wild-type strains. These results are consistent with an important role for leukotoxin in P. haemolytica virulence and suggest that leukotoxin-negative mutants may be useful tools in the investigation of other virulence properties involved in P. haemolytica infections.


Comparative analysis of CpG islands in four fish genomes.
There has been much interest in CpG islands (CGIs), clusters of CpG dinucleotides in GC-rich regions, because they are considered gene markers and involved in gene regulation. To date, there has been no genome-wide analysis of CGIs in the fish genome. We first evaluated the performance of three popular CGI identification algorithms in four fish genomes (tetraodon, stickleback, medaka, and zebrafish). Our results suggest that Takai and Jones' (2002) algorithm is most suitable for comparative analysis of CGIs in the fish genome. Then, we performed a systematic analysis of CGIs in the four fish genomes using Takai and Jones' algorithm, compared to other vertebrate genomes. We found that both the number of CGIs and the CGI density vary greatly among these genomes. Remarkably, each fish genome presents a distinct distribution of CGI density with some genomic factors (e.g., chromosome size and chromosome GC content). These findings are helpful for understanding evolution of fish genomes and the features of fish CGIs.


Resolution of protected silaproline for a gram scale preparation.
Silaproline is an analogue of proline, which exhibits similar conformational properties. Moreover, the presence of dimethylsilyl group confers to silaproline a higher lipophilicity as well as an improved resistance to biodegradation. This report describes the comparison of two routes to obtain Fmoc-(L) Sip-OH on the gram scale using chiral HPLC resolution.


Impacts of a recent storm surge on an Arctic delta ecosystem examined in the context of the last millennium.
One of the most ominous predictions related to recent climatic warming is that low-lying coastal environments will be inundated by higher sea levels. The threat is especially acute in polar regions because reductions in extent and duration of sea ice cover increase the risk of storm surge occurrence. The Mackenzie Delta of northwest Canada is an ecologically significant ecosystem adapted to freshwater flooding during spring breakup. Marine storm surges during the open-water season, which move saltwater into the delta, can have major impacts on terrestrial and aquatic systems. We examined growth rings of alder shrubs (Alnus viridis subsp. fruticosa) and diatoms preserved in dated lake sediment cores to show that a recent marine storm surge in 1999 caused widespread ecological changes across a broad extent of the outer Mackenzie Delta. For example, diatom assemblages record a striking shift from freshwater to brackish species following the inundation event. What is of particular significance is that the magnitude of this recent ecological impact is unmatched over the > 1,000-year history of this lake ecosystem. We infer that no biological recovery has occurred in this lake, while large areas of terrestrial vegetation remain dramatically altered over a decade later, suggesting that these systems may be on a new ecological trajectory. As climate continues to warm and sea ice declines, similar changes will likely be repeated in other coastal areas of the circumpolar Arctic. Given the magnitude of ecological changes recorded in this study, such impacts may prove to be long lasting or possibly irreversible.


Nerve growth factor enhances cough and airway obstruction via TrkA receptor- and TRPV1-dependent mechanisms.
Nerve growth factor (NGF) is an important mediator of airway hyper-responsiveness and hyperalgesia but its role in cough is unknown. In this study the effects of NGF on the cough reflex and airway calibre were investigated in guinea pigs. The involvement of the tropomyosin-related kinase A (TrkA) receptor and transient receptor potential vanilloid-1 (TRPV1), and the p38 mitogen-activated protein kinase (MAPK)-dependent pathway in any NGF-induced effects on cough and airway obstruction was also assessed. Guinea pigs were placed in a transparent whole-body plethysmograph box. Cough was assessed visually, acoustically and by analysis of the airflow signal. Airway obstruction was measured using enhanced pause (Penh) as an index. Exposure of guinea pigs to NGF did not induce a cough response nor a significant airway obstruction. However, exposure of guinea pigs to NGF immediately before citric acid inhalation resulted in a significant increase in the citric acid-induced cough and airway obstruction compared with vehicle-treated animals. Pretreatment with the TrkA receptor antagonist, K252a, or the TRPV1 antagonist, iodoresiniferatoxin, significantly inhibited the NGF-enhanced cough and airway obstruction. Exposure to NGF also increased p38 MAPK phosphorylation, but pretreatment with the p38 MAPK inhibitor, SB203580, did not affect either the NGF-enhanced cough or airway obstruction despite preventing the NGF-induced elevation in p38 MAPK phosphorylation. The data show that NGF can enhance both cough and airway obstruction via a mechanism that involves the activation of the TrkA receptor and TRPV1 but not the p38 MAPK-dependent pathway.


Identification and selection of cases and controls in the Pneumonia Etiology Research for Child Health project.
Methods for the identification and selection of patients (cases) with severe or very severe pneumonia and controls for the Pneumonia Etiology Research for Child Health (PERCH) project were needed. Issues considered include eligibility criteria and sampling strategies, whether to enroll hospital or community controls, whether to exclude controls with upper respiratory tract infection (URTI) or nonsevere pneumonia, and matching criteria, among others. PERCH ultimately decided to enroll community controls and an additional human immunodeficiency virus (HIV)-infected control group at high HIV-prevalence sites matched on age and enrollment date of cases; controls with symptoms of URTI or nonsevere pneumonia will not be excluded. Systematic sampling of cases (when necessary) and random sampling of controls will be implemented. For each issue, we present the options that were considered, the advantages and disadvantages of each, the rationale for the methods selected for PERCH, and remaining implications and limitations.


Multisite randomized efficacy trial of educational materials for young children with incarcerated parents.
Although children with incarcerated parents exhibit more behavior problems, health concerns, and academic difficulties than their peers, few interventions or resources are available to support affected children. This randomized, controlled, multisite efficacy trial evaluated Sesame Street's "Little Children, Big Challenges: Incarceration" initiative with children aged 3 to 8 years with a jailed father. Seventy-one diverse children and their caregivers were randomized to an educational outreach group (n = 32) or wait list control group (n = 39). Researchers observed children during jail visits and interviewed caregivers by phone 2 and 4 weeks later. The effects of the intervention on children's behavior and emotions occurring during a jail visit depended on what children had been told about the father's incarceration. Children who were told honest, developmentally appropriate explanations showed less negative affect at entry, an increase in negative affect when the intervention was administered, and a decrease in negative affect during the visit. Intervention group children who were told distortions, nothing, or explanations that were not developmentally appropriate showed more negative affect initially, and their negative affect remained relatively stable during their time in the jail. In addition, children who were told the simple, honest truth about the parent's incarceration (a recommendation in the educational materials) exhibited more positive affect during the visit, with a medium effect size. Caregivers in the educational outreach group reported more positive change in how they talked to children about the incarceration over time compared to the control group.


Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Münster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia Pediatrica.
To assess the effect of treatment intensification and that of extended intrathecal methotrexate substitution for cranial irradiation in intermediate-risk acute lymphoblastic leukemia (ALL) children treated with a Berlin-Frankfurt-Münster (BFM)-based intensive chemotherapy. Three hundred ninety-six children with non-B-ALL were enrolled onto the Associazione Italiana di Ematologia ed Oncologic Pediatrica (AIEOP) ALL 88 study. Standard risk (SR) included patients with low tumor burden (BFM risk index [RI], < 0.8); intermediate risk (IR) were patients with an RI > or = 0.8 but less than 1.2; and high risk (HR) were those with an RI > or = 1.2 or CNS involvement at diagnosis. The treatment schedule was a modified version of the ALL-BFM 86 study. CNS-directed treatment consisted of high-dose methotrexate (HD-MTX; 5 g/m2 for four courses) plus intrathecal methotrexate (IT-MTX; nine doses); IR patients additionally received extended IT-MTX (nine doses during continuation therapy); cranial irradiation was given only to HR patients. Of the 375 (94.7%) children who achieved remission, 1.3% had an adverse event other than relapse. The estimated event-free survival (EFS) at 6 years was 66.6% (SE 2.4) overall; 80.7% (4.5) in the SR patients, 77.5% (3.9) in the IR patients, and 54.5% (3.7) in the HR patients. Relapse occurred in 107 children (27.0%). Isolated CNS relapse occurred in 20 children (5.0%): 5 (6.3%) in the SR group, 1 (0.8%) in the IR group, and 14 (7.1%) in the HR group. The estimated 6-year CNS leukemia-free survival was 94.6% (1.2) overall: 93.5% (2.8) in the SR group, 99.1% (0.9) in the IR group, and 92.3% (2.0) in the HR group. Cranial irradiation may be omitted safely in IR ALL patients treated with BFM-based intensive chemotherapy when extended intrathecal chemotherapy is given. Because the CNS disease control was less complete in the SR group, these data challenge the effectiveness of HD-MTX for protection from CNS disease and support the protective role of extended intrathecal chemotherapy.


Elucidating Mechanisms of Molecular Recognition Between Human Argonaute and miRNA Using Computational Approaches.
MicroRNA (miRNA) and Argonaute (AGO) protein together form the RNA-induced silencing complex (RISC) that plays an essential role in the regulation of gene expression. Elucidating the underlying mechanism of AGO-miRNA recognition is thus of great importance not only for the in-depth understanding of miRNA function but also for inspiring new drugs targeting miRNAs. In this chapter we introduce a combined computational approach of molecular dynamics (MD) simulations, Markov state models (MSMs), and protein-RNA docking to investigate AGO-miRNA recognition. Constructed from MD simulations, MSMs can elucidate the conformational dynamics of AGO at biologically relevant timescales. Protein-RNA docking can then efficiently identify the AGO conformations that are geometrically accessible to miRNA. Using our recent work on human AGO2 as an example, we explain the rationale and the workflow of our method in details. This combined approach holds great promise to complement experiments in unraveling the mechanisms of molecular recognition between large, flexible, and complex biomolecules.


Stretch-Induced Uncrimping of Equatorial Sclera Collagen Bundles.
Stretch-induced collagen uncrimping underlies the nonlinear mechanical behavior of the sclera according to what is often called the process of recruitment. We recently reported experimental measurements of sclera collagen crimp and pressure-induced uncrimping. Our studies, however, were cross-sectional, providing statistical descriptions of crimp with no information on the effects of stretch on specific collagen bundles. Data on bundle-specific uncrimping is necessary to better understand the effects of macroscale input on the collagen microscale and tissue failure. Our goal in this project was to measure bundle-specific stretch-induced collagen uncrimping of sclera. Three goat eyes were cryosectioned sagittally (30 μm). Samples of equatorial sclera were isolated, mounted to a custom uni-axial stretcher and imaged with polarized light microscopy at various levels of clamp-to-clamp stretch until failure. At each stretch level, local strain was measured using image tracking techniques. The level of collagen crimping was determined from the bundle waviness, defined as the circular standard deviation of fiber orientation along a bundle. Eye-specific recruitment curves were then computed using eye-specific waviness at maximum stretch before sample failure to define fibers as recruited. Nonlinear mixed effect models were used to determine the associations of waviness to local strain and recruitment to clamp-to-clamp stretch. Waviness decreased exponentially with local strain (p < 0.001), whereas bundle recruitment followed a sigmoidal curve with clamp-to-clamp stretch (p < 0.001). Individual bundle responses to stretch varied substantially, but recruitment curves were similar across sections and eyes. In conclusion, uni-axial stretch caused measurable bundle-specific uncrimping, with the sigmoidal recruitment pattern characteristic of fiber-reinforced soft tissues.


[Construction of a tool for risk assessment of infectious diseases in a workplace--as a primary precaution].
We describe here a tool for risk assessment and management of infectious diseases in a workplace. This was constructed as a primary precaution for the prevention of infectious diseases in a workplace, not to be used as a countermeasure of diseases in the time of or after an occurrence. The tool grades risk levels of each of the factors influencing infectious diseases in the workplace and an assessment based on the total point are given. Ordinary workplaces should be chosen, such as factories and office buildings, not places where medical experts or hygienists work, such as hospitals, schools and concessionaries, etc. Three risk factors for infection are pathogens, route and human host. The factor of a pathogen is divided into two groups, spreadable (from human to human) and non-spreadable. The risk of spreadable pathogens is assessed by the ages of workers, CO2 concentration and air volume, and the combination of the existence of common places and collaborative work. The risk of non spreadable pathogens is evaluated by the ages of workers, air current and air volume, and existence of equipment generating aerosol. In cases where the total point is over 7, the risk is assessed as high level (group A) and daily measures must be taken, such as ensuring proper operation of the infection control committee, education, management of working conditions and management of working environments. In cases where the score is 5 or 6, the risk is assessed as intermediate level (group B) and daily measures are recommended, such as ensuring proper operation of the infection control committee and education. In the case of a score less than 4, the risk is assessed as low level (group C) and these daily measures are not necessary. Instead, an infection control committee should be organized and concrete measures should be taken upon an outbreak of an infectious disease.


Digitally delivered education and exercises for patients with hand osteoarthritis-An observational study.
Hand osteoarthritis (OA) is a common form of OA, for which education and exercise are considered the first-line treatment. The aim of the present study was to examine pain and perceived hand function in participants following 3 months of digitally delivered first-line treatment for hand OA. Three-hundred-and-seventy-nine of 846 participants with clinical signs and symptoms of hand OA completed the study. The digital hand OA treatment program consists of video instructed daily exercises and patient education through text lessons. Pain (NRS, 0 no pain, 10 worst) was the primary outcome, and stiffness (NRS) and the Functional Index for Hand OsteoArthritis (FIHOA, 0 best, 30 worst) were among secondary outcomes. The McNemar test and linear mixed effect regression model were used to assess the changes in outcomes from baseline to 3-month. After three months, the digitally delivered program was associated with a significant decrease in pain intensity (mean change -1.30 (95% CI -1.49, -1.12)) and hand stiffness (mean change -0.81 (95% CI -1.02, -0.60)) but no conclusive changes in the FIHOA scores (mean change 0.3 (95% CI -0.2, 0.7)). The results agree with reports on face-to-face delivered first-line treatment for hand OA suggesting that digital treatment is a viable treatment option in patients with hand OA.


Cost-effectiveness of external cephalic version for term breech presentation.
External cephalic version (ECV) is recommended by the American College of Obstetricians and Gynecologists to convert a breech fetus to vertex position and reduce the need for cesarean delivery. The goal of this study was to determine the incremental cost-effectiveness ratio, from society's perspective, of ECV compared to scheduled cesarean for term breech presentation. A computer-based decision model (TreeAge Pro 2008, Tree Age Software, Inc.) was developed for a hypothetical base case parturient presenting with a term singleton breech fetus with no contraindications for vaginal delivery. The model incorporated actual hospital costs (e.g., $8,023 for cesarean and $5,581 for vaginal delivery), utilities to quantify health-related quality of life, and probabilities based on analysis of published literature of successful ECV trial, spontaneous reversion, mode of delivery, and need for unanticipated emergency cesarean delivery. The primary endpoint was the incremental cost-effectiveness ratio in dollars per quality-adjusted year of life gained. A threshold of $50,000 per quality-adjusted life-years (QALY) was used to determine cost-effectiveness. The incremental cost-effectiveness of ECV, assuming a baseline 58% success rate, equaled $7,900/QALY. If the estimated probability of successful ECV is less than 32%, then ECV costs more to society and has poorer QALYs for the patient. However, as the probability of successful ECV was between 32% and 63%, ECV cost more than cesarean delivery but with greater associated QALY such that the cost-effectiveness ratio was less than $50,000/QALY. If the probability of successful ECV was greater than 63%, the computer modeling indicated that a trial of ECV is less costly and with better QALYs than a scheduled cesarean. The cost-effectiveness of a trial of ECV is most sensitive to its probability of success, and not to the probabilities of a cesarean after ECV, spontaneous reversion to breech, successful second ECV trial, or adverse outcome from emergency cesarean. From society's perspective, ECV trial is cost-effective when compared to a scheduled cesarean for breech presentation provided the probability of successful ECV is > 32%. Improved algorithms are needed to more precisely estimate the likelihood that a patient will have a successful ECV.


Morphology transition in lipid vesicles due to in-plane order and topological defects.
Complex morphologies in lipid membranes typically arise due to chemical heterogeneity, but in the tilted gel phase, complex shapes can form spontaneously even in a membrane containing only a single lipid component. We explore this phenomenon via experiments and coarse-grained simulations on giant unilamellar vesicles of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine. When cooled from the untilted L(α) liquid-crystalline phase into the tilted gel phase, vesicles deform from smooth spheres to disordered, highly crumpled shapes. We propose that this shape evolution is driven by nucleation of complex membrane microstructure with topological defects in the tilt orientation that induce nonuniform membrane curvature. Coarse-grained simulations demonstrate this mechanism and show that kinetic competition between curvature change and defect motion can trap vesicles in deeply metastable, defect-rich structures.


[A Case of Advanced Gastric Cancer with Long-Term Survival Due to Successful Ramucirumab and Paclitaxel Therapy].
This is a case of a 70-year-old man. Two courses of docetaxel/cisplatin/S-1 combination therapy were administered after clinical trial registration with diagnosis of Stage Ⅳ gastric cancer(ypT3N3aM1). In June 2014, gastrectomy and splenectomy were performed. Postoperative S-1 adjuvant chemotherapy was administered; however, in September 2014, aorticl ymph node metastasis was diagnosed as recurrent. After recurrence, irinotecan/cisplatin therapy was administered. In February 2015, recurrent lymph node metastasis increased, and chemotherapy was changed to paclitaxel. In May 2015, numbness (Grade 2)of the fingers was observed, and treatment was changed to oxaliplatin/S-1. In February 2016, storage of ascites became remarkable; therefore, chemotherapy was discontinued as per policy. After that, we continued outpatient visit and observed increased recurrent lymph node metastasis on image evaluation; however, as the patient's general condition was good, chemotherapy was restarted. Ramucirumab/paclitaxel therapy started in February 2017. During the course of treatment, neutropenia(Grade 2)was observed as an adverse event, but therapy continuation was possible without loss of ramucirumab only with loss of paclitaxel. Thereafter, the recurrence of lymph node metastasis was reduced, and the ascites accumulation decreased. Until now, 1 year after the start of ramucirumab/paclitaxel therapy, the patient still visits the outpa- tient clinic.


Prolonged complete remission of metastatic HER2-positive breast cancer after continuous trastuzumab treatment: a case report and review of the literature.
Metastatic breast cancer is considered an incurable disease. Targeted treatments against the human epidermal growth factor receptor 2 (HER2), however, significantly improve survival in patients with metastatic HER2-positive breast cancer. Some patients may respond with prolonged complete remission. Evidence on safety of long-term trastuzumab and risk of relapse after trastuzumab cessation is limited. We present a case of an 81-year-old patient with HER2-amplified metastatic breast cancer (MBC) in the liver. Following taxane-based chemotherapy in combination with trastuzumab after local treatment resulted in a complete radiological remission after 21 months of trastuzumab maintenance therapy. The patient remains in complete remission 6 years later and continues to receive trastuzumab as maintenance therapy. Prolonged remission in cases with complete response under trastuzumab-based regimens for metastatic HER2-positive breast cancer can be observed in some patients. Reviewing the few available cases published in the literature, these patients share some common characteristics: hormone receptor negative disease and metastases to the liver. There is no evidence that trastuzumab maintenance treatment can be safely interrupted after a certain time period.


Neuronal excitability changes depend on the time course of cellular edema induced by water intoxication in young rats.
The aim of the study was to determine whether the functional state of neurons is affected by the duration of the induced cellular edema and by the age of animals tested. The cellular edema was induced by water intoxication and neuronal functions were tested by the standard method of electrical stimulation of neurons of the cerebral cortex. water intoxication was induced by standard method of fractionated hyperhydration. Excitability of cortical neurons was tested by cortical stimulation with the intensity required to induce cortical afterdischarge (AD). Animals were divided into three experimental groups (B, C, D) and three control groups (AB, AC, AD). Experimental groups differed in age of water intoxication (12 or 25 days) and age of excitability testing (25 or 35 days). Changes in the duration of AD (seconds) were statistically evaluated. Duration of cortical afterdischarges (AD) in the control groups was at the level literature data. In all experimental groups (B, C, D), excitability of cortical neurons was markedly inhibited. AD was possible to induce only in some of the animals and its average duration was significantly shorter than in control groups. This inhibitory effect can be explained by persistent impairment of astrocyte-to-neuron communication, which plays a key role in the process of formation of structural and functional changes during cellular edema. Some of the functional manifestations of the developing edema are influenced by the age of experimental animals. At least some events of this process are not influenced by the age of experimental animals.


Phenoplant: a web resource for the exploration of large chlorophyll fluorescence image datasets.
Image analysis is increasingly used in plant phenotyping. Among the various imaging techniques that can be used in plant phenotyping, chlorophyll fluorescence imaging allows imaging of the impact of biotic or abiotic stresses on leaves. Numerous chlorophyll fluorescence parameters may be measured or calculated, but only a few can produce a contrast in a given condition. Therefore, automated procedures that help screening chlorophyll fluorescence image datasets are needed, especially in the perspective of high-throughput plant phenotyping. We developed an automatic procedure aiming at facilitating the identification of chlorophyll fluorescence parameters impacted on leaves by a stress. First, for each chlorophyll fluorescence parameter, the procedure provides an overview of the data by automatically creating contact sheets of images and/or histograms. Such contact sheets enable a fast comparison of the impact on leaves of various treatments, or of the contrast dynamics during the experiments. Second, based on the global intensity of each chlorophyll fluorescence parameter, the procedure automatically produces radial plots and box plots allowing the user to identify chlorophyll fluorescence parameters that discriminate between treatments. Moreover, basic statistical analysis is automatically generated. Third, for each chlorophyll fluorescence parameter the procedure automatically performs a clustering analysis based on the histograms. This analysis clusters images of plants according to their health status. We applied this procedure to monitor the impact of the inoculation of the root parasitic plant Phelipanche ramosa on Arabidopsis thaliana ecotypes Col-0 and Ler. Using this automatic procedure, we identified eight chlorophyll fluorescence parameters discriminating between the two ecotypes of A. thaliana, and five impacted by the infection of Arabidopsis thaliana by P. ramosa. More generally, this procedure may help to identify chlorophyll fluorescence parameters impacted by various types of stresses. We implemented this procedure at http://www.phenoplant.org freely accessible to users of the plant phenotyping community.


Combined 23-Gauge PPV and Scleral Buckle Versus 23-Gauge PPV Alone for Primary Repair of Pseudophakic Rhegmatogenous Retinal Detachment.
This review compares 23-gauge pars plana vitrectomy (PPV) alone versus combined 23-gauge pars plana vitrectomy and scleral buckle (PPV/SB) for primary repair of pseudophakic rhegmatogenous retinal detachment (RRD). A retrospective review of 70 eyes that underwent 23-gauge PPV and 43 eyes that received 23-gauge PPV/SB for pseudophakic RRD. Minimum follow-up was 3 months. Outcome measures included anatomical success, visual acuity, and complication rates. The 23-gauge PPV group achieved primary anatomical success in 58 of 70 cases (83%). Primary success in the PPV/SB group occurred in 36 of 43 cases (84%). Final anatomical success was achieved in all 113 cases (100%). The difference in primary success rates was not statistically significant (P = 1.000, Fisher exact test). Average visual acuity for macula-on RRDs in the PPV group showed a +0.07 logMAR improvement (P = .580) versus a +1.34 improvement (P < .001) in macula-off PPV cases. SB/PPV macula-on cases showed a decrease in logMAR visual acuity by -0.06 (P = .380) while macula-off SB/PPV cases improved by +1.28 (P = .002). There were no significant complications in either group. Both 23-gauge PPV and PPV/SB are effective procedures for repairing pseudophakic RRD and exhibit similar rates of success.


Advancing science or advancing careers? Researchers' opinions on success indicators.
The way in which we assess researchers has been under the radar in the past few years. Critics argue that current research assessments focus on productivity and that they increase unhealthy pressures on scientists. Yet, the precise ways in which assessments should change is still open for debate. We circulated a survey with Flemish researchers to understand how they work, and how they would rate the relevance of specific indicators used in research assessments. We found that most researchers worked far beyond their expected working schedule. We also found that, although they spent most of their time doing research, respondents wished they could dedicate more time to it and spend less time writing grants and performing other activities such as administrative duties and meetings. When looking at success indicators, we found that indicators related to openness, transparency, quality, and innovation were perceived as highly important in advancing science, but as relatively overlooked in career advancement. Conversely, indicators which denoted of prestige and competition were generally rated as important to career advancement, but irrelevant or even detrimental in advancing science. Open comments from respondents further revealed that, although indicators which indicate openness, transparency, and quality (e.g., publishing open access, publishing negative findings, sharing data, etc.) should ultimately be valued more in research assessments, the resources and support currently in place were insufficient to allow researchers to endorse such practices. In other words, current research assessments are inadequate and ignore practices which are essential in contributing to the advancement of science. Yet, before we change the way in which researchers are being assessed, supporting infrastructures must be put in place to ensure that researchers are able to commit to the activities that may benefit the advancement of science.


Molecular mechanisms of pulmonary vascular development.
In this era of rapidly advancing vascular biology research, a vast array of growth factors and signaling molecules have been recognized as key players in the mechanisms that control lung vascular development. In the lung, vascular development is a complex, multistep process that includes specialization of primitive cells to vascular progenitors; formation of primitive vascular networks; remodeling with local regression and branching; specialization toward arteries, veins, and lymphatics; stabilization of vessels by matrix production and recruitment of supporting cells; and maintenance of the vascular structure. This complex, highly organized process requires exquisite orchestration of the regulatory activity of multiple molecules in a specific temporospatial order. Most of these molecules are members of 3 major growth factor families that have been recently identified. They are the vascular endothelial growth factor, angiopoietin, and ephrin families. Understanding the functional reach of several members of these growth factor families is integral to an appreciation of the etiology and pathogenesis of developmental lung vascular disorders affecting newborns. This review summarizes recent advances in the molecular bases of lung vascular development and some of the pulmonary diseases resulting from aberrant vascular growth, including bronchopulmonary dysplasia, alveolar capillary dysplasia, congenital cystic pulmonary disorders, congenital pulmonary hemangiomatosis, and lung hypoplasia.


Efficient CO2 electroreduction on facet-selective copper films with high conversion rate.
Tuning the facet exposure of Cu could promote the multi-carbon (C2+) products formation in electrocatalytic CO2 reduction. Here we report the design and realization of a dynamic deposition-etch-bombardment method for Cu(100) facets control without using capping agents and polymer binders. The synthesized Cu(100)-rich films lead to a high Faradaic efficiency of 86.5% and a full-cell electricity conversion efficiency of 36.5% towards C2+ products in a flow cell. By further scaling up the electrode into a 25 cm2 membrane electrode assembly system, the overall current can ramp up to 12 A while achieving a single-pass yield of 13.2% for C2+ products. An insight into the influence of Cu facets exposure on intermediates is provided by in situ spectroscopic methods supported by theoretical calculations. The collected information will enable the precise design of CO2 reduction reactions to obtain desired products, a step towards future industrial CO2 refineries.


Cloning and characterization of a phosphopantetheinyl transferase from Streptomyces verticillus ATCC15003, the producer of the hybrid peptide-polyketide antitumor drug bleomycin.
Phosphopantetheinyl transferases (PPTases) catalyze the posttranslational modification of carrier proteins by the covalent attachment of the 4'-phosphopantetheine (P-pant) moiety of coenzyme A to a conserved serine residue, a reaction absolutely required for the biosynthesis of natural products including fatty acids, polyketides, and nonribosomal peptides. PPTases have been classified according to their carrier protein specificity. In organisms containing multiple P-pant-requiring pathways, each pathway has been suggested to have its own PPTase activity. However, sequence analysis of the bleomycin biosynthetic gene cluster in Streptomyces verticillus ATCC15003 failed to reveal an associated PPTase gene. A general approach for cloning PPTase genes by PCR was developed and applied to the cloning of the svp gene from S. verticillus. The svp gene is mapped to an independent locus not clustered with any of the known NRPS or PKS clusters. The Svp protein was overproduced in Escherichia coli, purified to homogeneity, and shown to be a monomer in solution. Svp is a PPTase capable of modifying both type I and type II acyl carrier proteins (ACPs) and peptidyl carrier proteins (PCPs) from either S. verticillus or other Streptomyces species. As compared to Sfp, the only 'promiscuous' PPTase known previously, Svp displays a similar catalytic efficiency (k(cat)/K(m)) for the BlmI PCP but a 346-fold increase in catalytic efficiency for the TcmM ACP. PPTases have recently been re-classified on a structural basis into two subfamilies: ACPS-type and Sfp-type. The development of a PCR method for cloning Sfp-type PPTases from actinomycetes, the recognition of the Sfp-type PPTases to be associated with secondary metabolism with a relaxed carrier protein specificity, and the availability of Svp, in addition to Sfp, should facilitate future endeavors in engineered biosynthesis of peptide, polyketide, and, in particular, hybrid peptide-polyketide natural products.


Human motor cortex: sensory input data from single neuron recordings.
Recordings were made from single neurons in the hand area of the human motor cortex while peripheral physiologic stimuli were applied. Such cells responded only to active and passive hand movements. Tactile and autditory (click) stimuli were itneffective. The majority of cells were activated only by movements of the contralateral hand, but a significant number (4 of 16) could be excited if a given movement was made by either hand. Of the cells responding to active movement, some showed an increased discharge before onset of the voluntary action. Such cells were excited by the same movement executed passively, a result that indicates sensory feedback from receptors activated by that movement.


Relationship between renal mass and atrial natriuretic peptide release. 2. Acute effects of various degrees of renal damage on atrial natriuretic peptide release in rats.
We studied basal serum atrial natriuretic peptide (ANP) levels and the response to acute salt loading in rats with different grades of functional renal mass reduction. The six groups of rats studied included 2 controls, i.e. unoperated (n = 12) and sham-operated (n = 24) groups. Each of the 4 experimental groups (n = 24 in each) underwent one of the following procedures: bilateral nephrectomy; unilateral nephrectomy; bilateral ureteral ligation; unilateral ureteral ligation. Basal ANP was assessed in the intact controls and operated groups 4, 8, 16 and 24 h after surgery. In addition, ANP was determined in the sham-operated controls and in the experimental groups 1 h following acute intravenous saline loading performed 4 h after surgery with central venous pressure monitoring. Basal ANP dropped significantly following bilateral nephrectomy but was not significantly altered after unilateral nephrectomy or the two modalities of ureteral ligation. In all 4 experimental groups ANP failed to rise after saline loading. We conclude that substantial renal damage results in early impairment in ANP secretion suggesting the existence of a renal physiological stimulus controlling ANP release by cardiac atria.


Advance directives and physicians' orders in nursing home residents with dementia in Flanders, Belgium: prevalence and associated outcomes.
Advance care planning (ACP) is an important element of high-quality care in nursing homes, especially for residents having dementia who are often incompetent in decision-making toward the end of life. The aim of this study was describe the prevalence of documented ACP among nursing home residents with dementia in Flanders, Belgium, and associated clinical characteristics and outcomes. All 594 nursing homes in Flanders were asked to participate in a retrospective cross-sectional postmortem survey in 2006. Participating homes identified all residents who had died over the last two months. A structured questionnaire was mailed to the nurses closely involved in the deceased resident's care regarding the diagnosis of dementia and documented care planning, i.e. advance patient directives, authorization of a legal representative, and general practitioners' treatment orders (GP orders). In 345 nursing homes (58% response rate), nurses identified 764 deceased residents with dementia of whom 62% had some type of documented care plan, i.e. advance patient directives in 3%, a legal representative in 8%, and GP orders in 59%. Multivariate logistic regression showed that the presence of GP orders was positively associated with receiving specialist palliative care in the nursing home (OR 3.10; CI, 2.07-4.65). Chances of dying in a hospital were lower if there was a GP order (OR 0.38; CI, 0.21-0.70). Whereas GP orders are relatively common among residents with dementia, advance patient directives and a legal representative are relatively uncommon. Nursing home residents receiving palliative care are more likely to have a GP order. GP orders may affect place of death.


Functional diversification accompanies gene family expansion of MED2 homologs in Candida albicans.
Gene duplication facilitates functional diversification and provides greater phenotypic flexibility to an organism. Expanded gene families arise through repeated gene duplication but the extent of functional divergence that accompanies each paralogous gene is generally unexplored because of the difficulty in isolating the effects of single family members. The telomere-associated (TLO) gene family is a remarkable example of gene family expansion, with 14 members in the more pathogenic Candida albicans relative to two TLO genes in the closely-related species C. dubliniensis. TLO genes encode interchangeable Med2 subunits of the major transcriptional regulatory complex Mediator. To identify biological functions associated with each C. albicans TLO, expression of individual family members was regulated using a Tet-ON system and the strains were assessed across a range of phenotypes involved in growth and virulence traits. All TLOs affected multiple phenotypes and a single phenotype was often affected by multiple TLOs, including simple phenotypes such as cell aggregation and complex phenotypes such as virulence in a Galleria mellonella model of infection. No phenotype was regulated by all TLOs, suggesting neofunctionalization or subfunctionalization of ancestral properties among different family members. Importantly, regulation of three phenotypes could be mapped to individual polymorphic sites among the TLO genes, including an indel correlated with two phenotypes, growth in sucrose and macrophage killing. Different selective pressures have operated on the TLO sequence, with the 5' conserved Med2 domain experiencing purifying selection and the gene/clade-specific 3' end undergoing extensive positive selection that may contribute to the impact of individual TLOs on phenotypic variability. Therefore, expansion of the TLO gene family has conferred unique regulatory properties to each paralog such that it influences a range of phenotypes. We posit that the genetic diversity associated with this expansion contributed to C. albicans success as a commensal and opportunistic pathogen.


A computational profiling of changes in gene expression and transcription factors induced by vFLIP K13 in primary effusion lymphoma.
Infection with Kaposi's sarcoma associated herpesvirus (KSHV) has been linked to the development of primary effusion lymphoma (PEL), a rare lymphoproliferative disorder that is characterized by loss of expression of most B cell markers and effusions in the body cavities. This unique clinical presentation of PEL has been attributed to their distinctive plasmablastic gene expression profile that shows overexpression of genes involved in inflammation, adhesion and invasion. KSHV-encoded latent protein vFLIP K13 has been previously shown to promote the survival and proliferation of PEL cells. In this study, we employed gene array analysis to characterize the effect of K13 on global gene expression in PEL-derived BCBL1 cells, which express negligible K13 endogenously. We demonstrate that K13 upregulates the expression of a number of NF-κB responsive genes involved in cytokine signaling, cell death, adhesion, inflammation and immune response, including two NF-κB subunits involved in the alternate NF-κB pathway, RELB and NFKB2. In contrast, CD19, a B cell marker, was one of the genes downregulated by K13. A comparison with K13-induced genes in human vascular endothelial cells revealed that although there was a considerable overlap among the genes induced by K13 in the two cell types, chemokines genes were preferentially induced in HUVEC with few exceptions, such as RANTES/CCL5, which was induced in both cell types. Functional studies confirmed that K13 activated the RANTES/CCL5 promoter through the NF-κB pathway. Taken collectively, our results suggest that K13 may contribute to the unique gene expression profile, immunophenotype and clinical presentation that are characteristics of KSHV-associated PEL.


[Therapy of systemic candidiasis].
Deep seated candidosis are the most common invasive fungal infections occurring in various categories of patients including those with cancer, burns as well as patients with AIDS or undergoing organ transplantation. Various clinical entities have to be distinguished with implications for diagnostic procedures as well as for adequate therapy. During the last decade, tremendous progress has been achieved leading to a major reduction of mortality attributable for candidaemia from 80% (in the seventies) to 40% in the nineties, mainly due to early empiric antifungal and better prophylaxis treatment. Other antifungal strategies than conventional amphotericin B are now available and have been shown effective, in particular, new modalities to administer amphotericin B including various lipid formulations, but also new azoles and mainly the triazoles such as fluconazole and itraconazole. Fluconazole has been shown effective as prophylaxis of candidosis including in patients undergoing bone marrow transplantation as well as in treatment of oropharyngeal candidosis and for candidaemia occurring in non-neutropenic patients. More limited data are available on itraconazole so far in particular in patients with documented invasive candidosis, but preliminary reports are encouraging. Oral therapy with systemic efficacy is more easy to recommend and allows ambulatory treatment. Candidosis is not a benign disease and in every single patient with fungemia antifungal treatment is mandatory.


Rho1p-Bni1p-Spa2p interactions: implication in localization of Bni1p at the bud site and regulation of the actin cytoskeleton in Saccharomyces cerevisiae.
Rho1p is a yeast homolog of mammalian RhoA small GTP-binding protein. Rho1p is localized at the growth sites and required for bud formation. We have recently shown that Bni1p is a potential target of Rho1p and that Bni1p regulates reorganization of the actin cytoskeleton through interactions with profilin, an actin monomer-binding protein. Using the yeast two-hybrid screening system, we cloned a gene encoding a protein that interacted with Bni1p. This protein, Spa2p, was known to be localized at the bud tip and to be implicated in the establishment of cell polarity. The C-terminal 254 amino acid region of Spa2p, Spa2p(1213-1466), directly bound to a 162-amino acid region of Bni1p, Bni1p(826-987). Genetic analyses revealed that both the bni1 and spa2 mutations showed synthetic lethal interactions with mutations in the genes encoding components of the Pkc1p-mitogen-activated protein kinase pathway, in which Pkc1p is another target of Rho1p. Immunofluorescence microscopic analysis showed that Bni1p was localized at the bud tip in wild-type cells. However, in the spa2 mutant, Bni1p was not localized at the bud tip and instead localized diffusely in the cytoplasm. A mutant Bni1p, which lacked the Rho1p-binding region, also failed to be localized at the bud tip. These results indicate that both Rho1p and Spa2p are involved in the localization of Bni1p at the growth sites where Rho1p regulates reorganization of the actin cytoskeleton through Bni1p.


Prognostic value of lactate dehydrogenase for in-hospital mortality in severe and critically ill patients with COVID-19.
Background: Lactate dehydrogenase (LDH) has been proved to be a prognostic factor for the severity and poor outcomes of coronavirus disease 2019 (COVID-19). In most studies, patients with various levels of COVID-19 severity were pooled and analyzed which may prevent accurate evaluation of the relationship between LDH and disease progression and in-hospital death. In this study, we aimed to evaluate the association of LDH with in-hospital mortality in severe and critically ill patients with COVID-19. Methods: This single-center retrospective study enrolled 119 patients. Survival curves were plotted using Kaplan-Meier method and compared by log-rank test. Multivariate Cox regression models were used to determine the independent risk factors for in-hospital mortality. Receiver-operator curves (ROCs) were constructed to evaluate the predictive accuracy of LDH and other prognostic biomarkers. Results: Compared to the survival group, LDH levels in the dead group were significantly higher [559.5 (172, 7575) U/L vs 228 (117, 490) U/L, (P < 0.001)]. In Multivariate Cox regression, it remained an independent risk factor for in-hospital mortality (Hazard ratio 5.985, 95.0%CI: 1.498-23.905; P=0.011). A cutoff value of 353.5 U/L predicted the in-hospital mortality with a sensitivity of 94.4% and a specificity of 89.2% respectively. Conclusion: LDH is a favorable prognostic biomarker with high accuracy for predicting in-hospital mortality in severe and critically ill patients with COVID-19. This may direct physicians worldwide to effectively prioritize resources for patients at high risk of death and to implement more aggressive treatments at an earlier phase to save patients' lives.


Probing the triplet correlation function in liquid water by experiments and molecular simulations.
Despite very significant developments in scattering experiments like X-ray and neutron diffraction, it has been challenging to elucidate the nature of tetrahedral molecular configurations in liquid water. A key question is whether the pair correlation functions, which can be obtained from scattering experiments, are sufficient to describe the tetrahedral ordering of water molecules. In our previous study (Dhabal et al., J. Chem. Phys., 2014, 141, 174504), using data-sets generated from reverse Monte Carlo and molecular dynamics simulations, we showed that the triplet correlation functions contain important information on the tetrahedrality of water in the liquid state. In the present study, X-ray scattering experiments and molecular dynamics (MD) simulations are used to link the isothermal pressure derivative of the structure factor with the triplet correlation functions for water. Triplet functions are determined for water up to 3.3 kbar at 298 K to display the effect of pressure on the water structure. The results suggest that triplet functions (H[combining tilde](q)) obtained using a rigid-body TIP4P/2005 water model are consistent with the experimental results. The triplet functions obtained in experiment as well as in simulations evince that in the case of tetrahedral liquids, exertion of higher pressure leads to a better agreement with the Kirkwood superposition approximation (KSA). We further validate this observation using the triplet correlation functions (g(3)(r,s,t)) calculated directly from simulation trajectory, revealing that both H[combining tilde](q) in q-space and g(3)(r,s,t) in real-space contain similar information on the tetrahedrality of liquids. This study demonstrates that the structure factor, even though it has only pair correlation information of the liquid structure, can shed light on three-body correlations in liquid water through its isothermal pressure derivative term.


Taenia crassiceps infection attenuates multiple low-dose streptozotocin-induced diabetes.
Taenia crassiceps, like other helminths, can exert regulatory effects on the immune system of its host. This study investigates the effect of chronic T. crassiceps infection on the outcome of Multiple Low Dose Streptozotocin-Induced Diabetes (MLDS). Healthy or previously T. crassiceps-infected mice received MLDS and type 1 diabetes (T1D) symptoms were evaluated for 6 weeks following the induction of MLDS. T. crassiceps-infected mice displayed lower blood glucose levels throughout the study. A significantly lower percentage of T. crassiceps-infected mice (40%) developed T1D compared to the uninfected group (100%). Insulitis was remarkably absent in T. crassiceps-infected mice, which had normal pancreatic insulin content, whereas uninfected mice showed a dramatic reduction in pancreatic insulin. Infected mice that received MLDS did not show an increase in their regulatory T cell population, however, they had a greater number of alternatively activated macrophages, higher levels of the cytokine IL-4, and lower levels of TNF-alpha. Therefore, infection with T. crassiceps causes an immunomodulation that modifies the incidence and development of MLDS-induced autoimmune diabetes.


Diabetic Ketoacidosis in Coronavirus Disease Patients With Type 2 Diabetes Mellitus.
The occurrence of diabetes is increasing globally and carries a variety of complications, such as thromboembolism, acute cerebrovascular accidents, and diabetic ketoacidosis (DKA). Although DKA is not commonly associated with type 2 diabetes (T2D), it can manifest in patients who have underlying comorbidities predisposed to DKA. Since the emergence of the coronavirus disease (COVID-19) pandemic, we have seen many cases and studies on the underlying pathophysiology of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia with or without respiratory failure. We have also learned that the angiotensin-converting enzyme receptor is one of the major entry sites of SARS-CoV-2 infection, and it might be one of the causes that predispose patients to DKA. However, few studies exist that explore the development of DKA in T2D with SARS-CoV-2 infection. We present two cases of patients with DKA and COVID-19 treated with an insulin regimen with no further complications.


The Role of Forensic Psychiatry in Substance Abuse - Practice and Research in Taiwan.
Substance abuse is an increasingly important medical and legal problem in Taiwan. This article reviews limited studies in Taiwan on the prevalence of substance abuse and psychiatric co-morbidity, and assessment of substance use disorder, with emphasis on their relation to forensic psychiatry. Complicated interaction exists among substance abuse, criminal behavior, and various mental disorders (including antisocial personality disorder). Forensic psychiatry can play an important role in both treatment and research aimed at overcoming the problems of substance abuse. Also discussed are the necessity in merging genetic analysis methods with forensic psychiatric assessment, and the implementation of treatment and rehabilitation programs for criminal offenders co-morbid with psychiatric illness.


Cross-cultural acceptability and utility of the strengths and difficulties questionnaire: views of families.
Screening children for behavioural difficulties requires the use of a tool that is culturally valid. We explored the cross-cultural acceptability and utility of the Strengths and Difficulties Questionnaire for pre-school children (aged 3-5) as perceived by families in New Zealand. A qualitative interpretive descriptive study (focus groups and interviews) in which 65 participants from five key ethnic groups (New Zealand European, Māori, Pacific, Asian and other immigrant parents) took part. Thematic analysis using an inductive approach, in which the themes identified are strongly linked to the data, was employed. Many parents reported they were unclear about the purpose of the tool, affecting its perceived value. Participants reported not understanding the context in which they should consider the questions and had difficulty understanding some questions and response options. Māori parents generally did not support the questionnaire based approach, preferring face to face interaction. Parents from Māori, Pacific Island, Asian, and new immigrant groups reported the tool lacked explicit consideration of children in their cultural context. Parents discussed the importance of timing and multiple perspectives when interpreting scores from the tool. In summary, this study posed a number of challenges to the use of the Strengths and Difficulties Questionnaire in New Zealand. Further work is required to develop a tool that is culturally appropriate with good content validity.


Iterative Screening Methods for Identification of Chemical Compounds with Specific Values of Various Properties.
Identification of chemical compounds having desirable properties is a central goal of screening campaigns. Iterative screening is a means of surveying a set of compounds, during which their property values are determined and used as feedback for regression models. Quantitative models that assess the relationships between chemical structures and property/activity are repeatedly updated through this type of cycle, and the efficient sampling of compounds for the subsequent test is a key factor in the early identification of target compounds. Nevertheless, methodological approaches to comparisons and to establishing the degree of extrapolation of sampled compounds, including the effects of applicability domains, are still required. In the present study, we conducted a series of virtual experiments to assess the characteristics of different iterative screening methods. Genetic algorithm-based partial least-squares regression, support vector regression, Bayesian optimization with Gaussian Process (GP), and batch-based Bayesian optimization with GP (GP_batch) were all compared, based on the analysis of one million compounds extracted from the ZINC database. Our results show that, irrespective of the diversity of the initial set of compounds, it was possible to identify a compound having the desired property value using the appropriate screening method. However, overall, the GP_batch method was found to be preferable when evaluating properties either which are difficult to predict or for which a key factor is present in the set of molecular descriptors.


Comparisons among survey methodologies to test for abundance and size of a highly targeted fish species.
Three sampling methods for estimating abundance and size of blue cod Parapercis colias were compared inside and outside Kapiti Marine Reserve, New Zealand (40° 49' 31·77('') S; 174° 55' 02·87('') E). Two baited methods, baited underwater video (BUV) and experimental angling (EA), were more efficient and had lower levels of estimate variation than diver-based underwater visual census (UVC). The BUV and EA recorded more fish and of greater size ranges than UVC, and also had fewer zero count replicates. The BUV and EA methodologies revealed highly significant differences in abundance and size of fish between sites (reserve v. non-reserve), whereas UVC revealed no such differences. These results indicate that BUV is likely to be the most accurate, cost-effective and easy to use methodology for the surveying of carnivorous temperate reef fishes for future monitoring. It is noted, however, that new data acquired using the BUV methodology may need to be compared over a calibration period to data acquired using the UVC methodology to ensure that historical data sets derived from UVC still have validity and application for future monitoring activity.


The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors.
We describe the cloning and characterization of a novel fusion protein (termed L19-mIL12), consisting of murine interleukin-12 in single-chain format, sequentially fused to the L19 antibody in tandem diabody format. The fusion protein bound avidly to the cognate antigen (the alternatively spliced EDB domain of fibronectin), retained the activity of the parental cytokine and was able to selectively localize to murine tumors in vivo, as shown by quantitative biodistribution analysis. L19-mIL12 exhibited a potent antitumor activity in immunocompetent mice bearing CT26 carcinomas and WEHI-164 sarcomas, which could be boosted by combination with checkpoint blockade, leading to durable cancer eradication. L19-mIL12 also inhibited tumor growth in mice with Lewis lung carcinoma (LLC), but in this case, cancer cures could not be obtained, both in monotherapy and in combination. A microscopic analysis and a depletion experiment of tumor-infiltrating leukocytes illustrated the contribution of NK cells and CD8+ T cells for the anticancer activity observed in both tumor models. Upon L19-mIL12 treatment, the density of regulatory T cells (Tregs) was strongly increased in LLC, but not in CT26 tumors. A FACS analysis also revealed that the majority of CD8+ T cells in CT26 tumors were specific to the retroviral AH1 antigen.


Inhomogeneities and caustics in the sedimentation of noninertial particles in incompressible flows.
In an incompressible flow, fluid density remains invariant along fluid element trajectories. This implies that the spatial distribution of non-interacting noninertial particles in such flows cannot develop density inhomogeneities beyond those that are already introduced in the initial condition. However, in certain practical situations, density is measured or accumulated on (hyper-) surfaces of dimensionality lower than the full dimensionality of the flow in which the particles move. An example is the observation of particle distributions sedimented on the floor of the ocean. In such cases, even if the initial distribution of noninertial particles is uniform but its support is finite, advection in an incompressible flow will give rise to inhomogeneities in the observed density. In this paper, we analytically derive, in the framework of an initially homogeneous particle sheet sedimenting toward a bottom surface, the relationship between the geometry of the flow and the emerging distribution. From a physical point of view, we identify the two processes that generate inhomogeneities to be the stretching within the sheet and the projection of the deformed sheet onto the target surface. We point out that an extreme form of inhomogeneity, caustics, can develop for sheets. We exemplify our geometrical results with simulations of particle advection in a simple kinematic flow, study the dependence on various parameters involved, and illustrate that the basic mechanisms work similarly if the initial (homogeneous) distribution occupies a more general region of finite extension rather than a sheet.


Binding in agrammatic aphasia: Processing to comprehension.
BACKGROUND: Theories of comprehension deficits in Broca's aphasia have largely been based on the pattern of deficit found with movement constructions. However, some studies have found comprehension deficits with binding constructions, which do not involve movement. AIMS: This study investigates online processing and offline comprehension of binding constructions, such as reflexive (e.g., himself) and pronoun (e.g., him) constructions in unimpaired and aphasic individuals in an attempt to evaluate theories of agrammatic comprehension. METHODS #ENTITYSTARTX00026; PROCEDURES: Participants were eight individuals with agrammatic Broca's aphasia and eight age-matched unimpaired individuals. We used eyetracking to examine online processing of binding constructions while participants listened to stories. Offline comprehension was also tested. OUTCOMES #ENTITYSTARTX00026; RESULTS: The eye movement data showed that individuals with Broca's aphasia were able to automatically process the correct antecedent of reflexives and pronouns. In addition, their syntactic processing of binding was not delayed compared to normal controls. Nevertheless, offline comprehension of both pronouns and reflexives was significantly impaired compared to the control participants. This comprehension failure was reflected in the aphasic participants' eye movements at sentence end, where fixations to the competitor increased. CONCLUSIONS: These data suggest that comprehension difficulties with binding constructions seen in agrammatic aphasic patients are not due to a deficit in automatic syntactic processing or delayed processing. Rather, they point to a possible deficit in lexical integration.


Site-directed mutagenesis on TEM-1 beta-lactamase: role of Glu166 in catalysis and substrate binding.
Class A beta-lactamases are the major cause of bacterial resistance to beta-lactam antibiotics. In these active-site serine hydrolases, glutamic acid 166 has been hypothesized to act as a general acid-base catalyst. Replacing this residue by tyrosine in TEM-1 beta-lactamase yields an enzyme the activity of which is substantially lowered and strongly dependent on pH, thus confirming the alleged role of Glu166 in catalysis. This substitution also resulted in a spectacular change in substrate profile, the mutant enzyme being more active on cephalosporins than on penicillins. In fact, the E166Y enzyme behaves much like a class C enzyme, with high affinity and low hydrolytic activity towards second and third generation cephalosporins. Glu166 therefore seems to play a major part in defining the substrate profile of class A beta-lactamases.


Autoantibody-associated psychiatric syndromes: a systematic literature review resulting in 145 cases.
Autoimmune encephalitis (AE) is an important consideration during the diagnostic work-up of secondary mental disorders. Indeed, isolated psychiatric syndromes have been described in case reports of patients with underlying AE. Therefore, the authors performed a systematic literature review of published cases with AE that have predominant psychiatric/neurocognitive manifestations. The aim of this paper is to present the clinical characteristics of these patients. The authors conducted a systematic Medline search via Ovid, looking for case reports/series of AEs with antineuronal autoantibodies (Abs) against cell surface/intracellular antigens combined with predominant psychiatric/neurocognitive syndromes. The same was done for patients with Hashimoto encephalopathy/SREAT. Only patients with signs of immunological brain involvement or tumors in their diagnostic investigations or improvement under immunomodulatory drugs were included. We identified 145 patients with AE mimicking predominant psychiatric/neurocognitive syndromes. Of these cases, 64% were female, and the mean age among all patients was 43.9 (±22.1) years. Most of the patients had Abs against neuronal cell surface antigens (55%), most frequently against the NMDA-receptor (N = 46). Amnestic/dementia-like (39%) and schizophreniform (34%) syndromes were the most frequently reported. Cerebrospinal fluid changes were found in 78%, electroencephalography abnormalities in 61%, and magnetic resonance imaging pathologies in 51% of the patients. Immunomodulatory treatment was performed in 87% of the cases, and 94% of the patients responded to treatment. Our findings indicate that AEs can mimic predominant psychiatric and neurocognitive disorders, such as schizophreniform psychoses or neurodegenerative dementia, and that affected patients can be treated successfully with immunomodulatory drugs.


Influence of preoperative treatment and surgical operation on immune function of patients with esophageal carcinoma.
Multiple immunological parameters, including total lymphocyte count, lymphocyte subpopulations (CD2+, CD19+, CD3+, CD4+ and CD8+), phytohemagglutinin (PHA) response, and natural killer (NK) activity, were measured in 66 patients with previously untreated esophageal carcinoma. The influence of preoperative treatment and/or surgical operation on the immune function were evaluated in 40 patients. The PHA response and NK activity of the patients with esophageal carcinoma were 229 +/- 103 S.I.% and 18.5 +/- 11.9% lysis, respectively, and were significantly depressed as compared with the control. The CD4+/CD8+ ratio, PHA response, and NK activity in stage IV were also significantly depressed compared to that in stages I-III. Preoperative treatment induced significant reductions in the total lymphocyte count (1,994 +/- 644 to 670 +/- 274/mm3), PHA response (219 +/- 77 to 159 +/- 59 S.I.%), and NK activity (19.7 +/- 13.2 to 11.1 +/- 10.3% lysis) as well as a significant gradual decrease in the CD4+/CD8+ ratio (2.09 +/- 1.42 to 0.69 +/- 0.48), while the surgical operation significantly influenced only the total lymphocyte count. This study demonstrates that preoperative treatment induces a more pronounced influence on the immune function than surgical operation alone, in patients with esophageal carcinoma in which the immune function is disturbed prior to these treatments.


Cancellation of scheduled procedures as a mechanism to generate hospital bed surge capacity-a pilot study.
The ability to generate hospital beds in response to a mass-casualty incident is an essential component of public health preparedness. Although many acute care hospitals' emergency response plans include some provision for delaying or cancelling elective procedures in the event of an inpatient surge, no standardized method for implementing and quantifying the impact of this strategy exists in the literature. The aim of this study was to develop a methodology to prospectively emergency plan for implementing a strategy of delaying procedures and quantifying the potential impact of this strategy on creating hospital bed capacity. This is a pilot study. A categorization methodology was devised and applied retrospectively to all scheduled procedures during four one-week periods chosen by convenience. The categorization scheme grouped procedures into four categories: (A) procedures with no impact on inpatient capacity; (B) procedures that could be delayed indefinitely; (C) procedures that could be delayed by one week; and (D) procedures that could not be delayed. The categorization scheme was applied by two research assistants and an emergency medicine resident. All three raters categorized the first 100 cases to allow for calculation of inter-rater reliability. Maximal hospital bed capacity was defined as the 95th percentile weekday occupancy, as this is more representative of functional bed capacity than is the number of licensed beds. The main outcome was the number of hospital beds that could be created by postponing procedures in categories B and C. Maximal hospital bed capacity was 816 beds. Mean occupancy during weekdays was 759 versus 694 on weekends. By postponing Group B and C procedures, a mean of 60 beds (51 general medical/surgical and nine intensive care unit (ICU)) could be created on weekdays, and four beds (three general medical/surgical and one ICU) on weekends. This represents 7.3% and 0.49% of maximal hospital bed capacity and ICU capacity, respectively. In the event that sustained surge is needed, delaying all category B and C procedures for one week would lead to the generation of 1,235 hospital-bed days. Inter-rater reliability was high (kappa = 0.74) indicating good agreement between all three raters. For the institution studied, the strategy of delaying scheduled procedures could generate inpatient capacity with maximal impact during weekdays and little impact on weekends. Future research is needed to validate the categorization scheme and increase the ability to predict inpatient surge capacity across various hospital types and sizes.


Structured and unstructured abstracts in journal articles: a review.
Abstracts in journals are important paragraphs in review or original articles, which help one to decide if such articles are worth reading. The layout and the content of abstracts have undergone tremendous changes over the years from traditional, unstructured to structured, informative format. Many journal editors abroad are moving fast with time in the adoption of the innovation, allowing only articles with structured abstracts to appear in their journals. Journals in Africa especially in Nigeria are lagging behind in this respect. This review article examines the relative advantage of structured abstracts over unstructured abstracts as documented by various reports on the subject and makes a recommendation for structuring abstracts in articles appearing in Nigerian Journals.


Sequence identity in an early chorion multigene family is the result of localized gene conversion.
The multigene families that encode the chorion (eggshell) of the silk moth, Bombyx mori, are closely linked on one chromosome. We report here the isolation and characterization of two segments, totaling 102 kb of genomic DNA, containing the genes expressed during the early period of choriogenesis. Most of these early genes can be divided into two multigene families, ErA and ErB, organized into five divergently transcribed ErA/ErB gene pairs. Nucleotide sequence identity in the major coding regions of the ErA genes was 96%, while nucleotide sequence identity for the ErB major coding regions was only 63%. Selection pressure on the encoded proteins cannot explain this difference in the level of sequence conservation between the ErA and ErB gene families, since when only fourfold redundant codon positions are considered, the divergence within the ErA genes is 8%, while the divergence within the ErB genes (corrected for multiple substitutions at the same site) is 110%. The high sequence identity of the ErA major exons can be explained by sequence exchange events similar to gene conversion localized to the major exon of the ErA genes. These gene conversions are correlated with the presence of clustered copies of the nucleotide sequence GGXGGX, encoding paired glycine residues. This sequence has previously been correlated with gradients of gene conversion that extend throughout the coding and noncoding regions of the High-cysteine (Hc) chorion genes of B. mori. We suggest that the difference in the extent of the conversion tracts in these gene families reflects a tendency for these recombination events to become localized over time to the protein encoding regions of the major exons.


Two-versus three-dimensional regions of interest for quantifying SPECT-CT images.
The aim of this study was to investigate the relationship of quantitative parameters between the two-dimensional region of interest (ROI) and the three-dimensional volume of interest (VOI) for accumulation of radiopharmaceutical. Single-photon emission computed tomography combined with computed tomography (SPECT/CT) images of the NEMA/IEC phantom were acquired. The ROIs and VOIs were automatically set to the sphere and background in the phantom. We defined as two-dimensional analysis (2D analysis) that which used ROIs set on the center section of the sphere, and as three-dimensional analysis (3D analysis) that which used VOIs set on the center of gravity of the sphere. Dose linearity (DL), the recovery coefficient (RC), the contrast-to-noise ratio (CNR), and standardized uptake value (SUV) were evaluated. Each index value was compared between both analyses. DL was almost 1 under both conditions. RC showed a similar tendency with 2D and 3D analyses. The CNR for 3D analysis was smaller than for 2D analysis. The maximum SUV was almost equal with both analyses. The mean SUV with 3D analysis was underestimated by 4.83% on average compared with 2D analysis. For the same accumulation, a difference may occur in the quantitative index between 2 and 3D analyses. In particular, the quantitative parameters based on the average value tends to be smaller with 3D analysis than 2D analysis. The quantitative parameters in 2D analysis showed dependence upon the cross section used for setting the ROI, whereas 3D analysis showed less dependence on the position of the VOI.


Salivary fluoride concentrations in children with various systemic fluoride exposures.
Parotid ductal saliva fluoride concentrations were determined as an indication of baseline plasma fluoride levels in three groups of children. Group I had been exposed to drinking water containing less than 0.1 ppm F and had not received fluoride supplements. Group II had consumed optimally fluoridated water (1 ppm) since infancy. Group III had consumed water with less than 0.1 ppm F but had received a daily fluoride supplement for at least two years. The mean salivary fluoride concentrations in Groups II and III were significantly higher than Group I, but were not significantly different from each other. The findings suggest that peak plasma fluoride concentrations achieved following a daily fluoride supplement dose are higher than previously thought.


Developing a stone database for clinical practice.
Our objective was to design an intranet-based database to streamline stone patient management and data collection. The system developers used a rapid development approach that removed the need for laborious and unnecessary documentation, instead focusing on producing a rapid prototype that could then be altered iteratively. By using open source development software and website best practice, the development cost was kept very low in comparison with traditional clinical applications. Information about each patient episode can be entered via a user-friendly interface. The bespoke electronic stone database removes the need for handwritten notes, dictation, and typing. From the database, files may be automatically generated for clinic letters, operation notes. and letters to family doctors. These may be printed or e-mailed from the database. Data may be easily exported for audits, coding, and research. Data collection remains central to medical practice, to improve patient safety, to analyze medical and surgical outcomes, and to evaluate emerging treatments. Establishing prospective data collection is crucial to this process. In the current era, we have the opportunity to embrace available technology to facilitate this process. The database template could be modified for use in other clinics. The database that we have designed helps to provide a modern and efficient clinical stone service.


Remote heart function monitoring: role of the CardioMEMS HF System.
Heart failure is a pandemic condition that is challenging cardiology today. The primary economical and social burden of this syndrome is hospitalization rate whose costs represent the highest ones within the entire healthcare management. Remote monitoring of physiological data, obtained through self-reporting via telephone calls or, automatically, using external devices is a potential novel approach to implement management of patients with heart failure and reduce hospitalization rates. Relatively large but, sometimes, contradicting information exists about the efficacy of remote monitoring via different noninvasive approaches to reduce the economical and social burden of heart failure management. This leaves still partly unaddressed this critical issue and generates the need for new approaches. In this context, the CardioMEMS device that can chronically monitor pulmonary pressures from a small microchip inserted transvenously in the pulmonary artery seems to represent an innovative tool to challenge hospitalization rates. Consecutive analyses from the CHAMPION study had indeed documented the efficacy of the CardioMEMS in the remote monitoring of the pulmonary circulation status of patients with heart failure and in providing adequate information to optimally manage such patients with the final result of a significant hospitalization rate reduction. The striking information here is that this appears to be true in patients with preserved left ventricular ejection fraction also. Overall, the reports from the CHAMPION study encourage the use of CardioMEMS but larger populations are needed to definitively prove its value.


Expanding disaster mental health response: a conceptual training framework for public health professionals.
The available research literature suggests that in disasters, individuals presenting acutely with psychologically-related complaints tend to outnumber those presenting with physical symptoms directly stemming from the injury-causing agent or event. This acute "mental health surge" can rapidly overwhelm existing community mental health resources, especially in the context of terrorism. Training professionals from outside the traditional mental health workforce in basic psychological crisis intervention may promote more efficient use of mental health services through a gatekeeper process of early intervention and appropriate referrals to mental health specialists. With their experience in patient and client services at the community level, public health professionals represent a cohort well-suited for training in and delivery of acute mental health services in disasters. In this paper, we outline a conceptual model and rationale for training public health professionals in basic crisis-oriented mental health functions (psychological first aid) in order to augment community-based mental health services for affected populations in a disaster.


Designing and application of a new medical instrument sterilization system using reactive oxygen species.
The aim of this study is to design and test a new medical sterilization system as an alternative to the techniques used in the sterilization of medical instruments. The designed system, which uses a new oxygen molecule allotrope (NOMA) in the reactive oxygen species, is developed as an alternative to the sterilization systems using other gases. The test was conducted on 12 different materials, each having a surface of 2 cm2, sterilized under 120 °C at 1 atm pressure for 20 min in the NUVE-OT 4060 sterilizer, and all surfaces were contaminated with a biological indicator Geobacillus stearothermophilus cultured in an incubator at 37 °C. Test samples in sterile Petri dishes were placed in a desiccator, and a sample was taken at 30-, 45-, and 60-min test periods and were placed on an agar medium and put in a Memmert incubator IN75 at 37 °C; in the controls conducted following 16-18 h of incubation period, no bacterial growth was observed in the newly designed system tested with gram positive bacilli; moreover, it was observed that the new system was 100% effective in sterilizing the microbes as no growth was observed on the samples. Within the scope of this study, a faster, low-cost, low-temperature, residue-free, and human and environmental friendly system was developed and tested for sterilization of medical devices compared to existing sterilization methods using NOMA.


Collective motion diminishes, but variation between groups emerges, through time in fish shoals.
Despite extensive interest in the dynamic interactions between individuals that drive collective motion in animal groups, the dynamics of collective motion over longer time frames are understudied. Using three-spined sticklebacks, Gasterosteus aculeatus, randomly assigned to 12 shoals of eight fish, we tested how six key traits of collective motion changed over shorter (within trials) and longer (between days) timescales under controlled laboratory conditions. Over both timescales, groups became less social with reduced cohesion, polarization, group speed and information transfer. There was consistent inter-group variation (i.e. collective personality variation) for all collective motion parameters, but groups also differed in how their collective motion changed over days in their cohesion, polarization, group speed and information transfer. This magnified differences between groups, suggesting that over time the 'typical' collective motion cannot be easily characterized. Future studies are needed to understand whether such between-group differences in changes over time are adaptive and represent improvements in group performance or are suboptimal but represent a compromise between individuals in their preferences for the characteristics of collective behaviour.


Stark-effect experiments on photochemical holes in chromoproteins: protoporphyrin IX-substituted myoglobin.
We performed comparative Stark-effect experiments on spectral holes in a protein and a glass sample. The protein was protoporphyrin IX-substituted myoglobin in a glycerol/water solvent. The glass sample was a protoporphyrin IX-doped mixture of dimethylformamide/glycerol. As expected, in both cases the spectral holes varied linearly with the electric field. Yet, whereas in the protein the holes showed a clear splitting, they showed no splitting in the glass sample, irrespective of the chosen polarization of the laser. In both samples the hole broadened in the applied field. The magnitude of the broadening was about the same in both cases. The following conclusions were drawn. The absence of a splitting in the glass signals an effective global inversion symmetry of the chromophore, despite its low symmetry group. The dipole moment changes are random. In the protein the inversion symmetry is broken through the spatial correlation of the protein building blocks, leading to a molecular frame-fixed dipole moment difference and, hence, to the observed splitting. Despite these symmetry-breaking properties, the local structural randomness is of the same magnitude in the glass and in the protein, as is obvious from the broadening. The distinct difference in the Stark pattern shows that the range of the relevant chromophore interactions is confined to typical dimensions of the protein.


Identification of Functional MKK3/6 and MEK1/2 Homologs from Echinococcus granulosus and Investigation of Protoscolecidal Activity of Mitogen-Activated Protein Kinase Signaling Pathway Inhibitors In Vitro and In Vivo.
Cystic echinococcosis is a zoonosis caused by the larval stage of Echinococcus granulosussensu lato There is an urgent need to develop new drugs for the treatment of this disease. In this study, we identified two new members of mitogen-activated protein kinase (MAPK) cascades, MKK3/6 and MEK1/2 homologs (termed EgMKK1 and EgMKK2, respectively), from E. granulosussensu stricto Both EgMKK1 and EgMKK2 were expressed at the larval stages. As shown by yeast two-hybrid and coimmunoprecipitation analyses, EgMKK1 interacted with the previously identified Egp38 protein but not with EgERK. EgMKK2, on the other hand, interacted with EgERK. In addition, EgMKK1 and EgMKK2 displayed kinase activity toward the substrate myelin basic protein. When sorafenib tosylate, PD184352, or U0126-ethanol (EtOH) was added to the medium for in vitro culture of E. granulosus protoscoleces (PSCs) or cysts, an inhibitory and cytolytic effect was observed via suppressed phosphorylation of EgMKKs and EgERK. Nonviability of PSCs treated with sorafenib tosylate or U0126-EtOH, and not with PD184352, was confirmed through bioassays, i.e., inoculation of treated and untreated protoscoleces into mice. In vivo treatment of E. granulosussensu stricto-infected mice with sorafenib tosylate or U0126-EtOH for 4 weeks demonstrated a reduction in parasite weight, but the results did not show a significant difference. In conclusion, the MAPK cascades were identified as new targets for drug development, and E. granulosus was efficiently inhibited by their inhibitors in vitro The translation of these findings into in vivo efficacy requires further adjustment of treatment regimens using sorafenib tosylate or, possibly, other kinase inhibitors.


Ethmoid bone sandwich grafting for caudal septal defects.
To evaluate a new technique for correction of severe caudal septal defects. For all patients, preoperative photographs were graded with regard to the severity of caudal septal defects. Preoperatively, nasal airway breathing surveys were conducted and nasal tip projection (NTP) measurements were recorded. The caudal septal defects were then repaired with use of the ethmoid bone sandwich grafting technique. Photographs, NTP measurements, and an airway survey were then repeated 6 and 12 months postoperatively. Preoperative and postoperative assessments were compared and analyzed. Lateral nasal roentgenograms were obtained in five of 10 patients to assess resorption of the bone grafts. Complications were noted if present. Urban medical center. Ten volunteers with severe caudal septal defects causing both cosmetic and functional problems. All patients had undergone at least one previous submucous resection. Durability and degree of correction, maintenance of NTP, airway improvement, and morbidity. After 1 year, all patients maintained satisfactory correction of their caudal septal defect based on postoperative photographic grading and physical examination findings. The NTP was maintained in eight of 10 patients. Two patients experienced loss of NTP after 1 year that was not present 6 months postoperatively. Average airway improvement was 126.7% after 1 year. Postoperative roentgenograms showed only minor (< 10%) bone graft resorption. The only complication was a granuloma. The ethmoid bone sandwich grafting technique corrected severe caudal septal deviations while maintaining or strengthening structural support of the caudal septal strut without loss of NTP, airway compromise, or morbidity.


Evaluating the implementation of team nursing in a clinical setting.
Evaluating changes in the delivery of nursing care is vital to the acceptance of such changes, by both the staff and the profession as a whole. This article describes the evaluation of a change to team nursing in a clinical setting.


Differential regulation of action potential firing in adult murine thalamocortical neurons by Kv3.2, Kv1, and SK potassium and N-type calcium channels.
Sensory signals of widely differing dynamic range and intensity are transformed into a common firing rate code by thalamocortical neurons. While a great deal is known about the ionic currents, far less is known about the specific channel subtypes regulating thalamic firing rates. We hypothesized that different K(+) and Ca(2+) channel subtypes control different stimulus-response curve properties. To define the channels, we measured firing rate while pharmacologically or genetically modulating specific channel subtypes. Inhibiting Kv3.2 K(+) channels strongly suppressed maximum firing rate by impairing membrane potential repolarization, while playing no role in the firing response to threshold stimuli. By contrast, inhibiting Kv1 channels with alpha-dendrotoxin or maurotoxin strongly increased firing rates to threshold stimuli by reducing the membrane potential where action potentials fire (V(th)). Inhibiting SK Ca(2+)-activated K(+) channels with apamin robustly increased gain (slope of the stimulus-response curve) and maximum firing rate, with minimum effects on threshold responses. Inhibiting N-type Ca(2+) channels with omega-conotoxin GVIA or omega-conotoxin MVIIC partially mimicked apamin, while inhibiting L-type and P/Q-type Ca(2+) channels had small or no effects. EPSC-like current injections closely mimicked the results from tonic currents. Our results show that Kv3.2, Kv1, SK potassium and N-type calcium channels strongly regulate thalamic relay neuron sensory transmission and that each channel subtype controls a different stimulus-response curve property. Differential regulation of threshold, gain and maximum firing rate may help vary the stimulus-response properties across and within thalamic nuclei, normalize responses to diverse sensory inputs, and underlie sensory perception disorders.


Improved sensitivity of proton MR to oxygen-17 as a contrast agent using fast imaging: detection in brain.
The potential utility of H2(17)O as a contrast agent has been demonstrated in biological solutions and isolated tissues but its use has been impaired by the need to run heavily T2-weighted spin-echo images. By choosing an appropriate steady-state free precession experiment sensitive to T1/T2, we have improved the available contrast-to-noise per unit time by more than a factor of 5. This allows easy measurement of the proton effects for concentrations as low as 0.4% H2(17)O in less than 1 min. Injection into small animals produces a marked reduction in the overall image intensity. Consecutive imaging at the rate of one every 52 s has been used to follow the rate of change in brain image intensity immediately after injection.