Gastric myoelectrical activity and its relationship to the development of nausea and vomiting after intensive chemotherapy and autologous stem cell transplantation.
Gastric motor dysfunction may be responsible, in some patients, for the nausea and emesis that occur after high-dose chemotherapy (HDT) and autologous stem cell transplantation (SCT). Because gastric myoelectrical abnormalities may result in nausea and vomiting in other contexts, we sought to define the prevalence of these abnormalities and their relationship to the development of nausea and vomiting in patients undergoing autologous HDT and SCT, and to determine whether electrogastrography (EGG) could serve to detect gastric motor dysfunction in this population. We prospectively studied patients with a variety of malignancies who received standard transplantation doses of chemotherapeutic agents and antiemetics. Gastric emptying scintigraphy was performed before HDT. Gastric myoelectrical activity was assessed before HDT and on days 0, 7, 14, 21, and 28 from SCT using cutaneous EGG electrodes and a portable EGG recorder, and was analyzed by means of a dedicated software program after removal of motion artifact. Symptom assessment was obtained daily from initiation of HDT to 28 days after SCT. A total of 25 patients were studied: 13 women and 12 men, with a median age of 50 yr (range = 32-65 yr). Before HDT, gastric emptying scintigraphy was normal in all patients (median T(1/2) of 50 min [range = 22-75 min]) and only one patient had mild nausea and anorexia. Nausea, emesis, and anorexia occurred in all patients, peaked in severity at day +7 from SCT and, with the exception of anorexia, had returned toward baseline levels by day +28. Fasting dysrhythmias were present in 63% of the studies at baseline. Serial EGG recordings revealed significant slowing of the dominant frequency with a consequent decrease in tachygastria and increase in normogastria and bradygastria as the symptoms peaked in severity with a subsequent return to baseline values at the study's end. The only clinical variable that was predictive of symptom severity was gender. Women had a higher risk of developing anorexia (score > or = 2) at day +14 compared to men (odds ratio = 11.2; 95% CI = 1.7-76.9; p = 0.01). Baseline abnormalities in gastric myoelectrical activity occur frequently in patients who undergo HDT and autologous SCT despite normal gastric emptying scintigraphy and an absence of symptoms. Although slowing of the dominant frequency was seen as symptoms worsened, we failed to identify any EGG parameter at baseline that could predict the severity of nausea, vomiting or anorexia after transplantation.


Some plasma constituents correlate with human cataract location and nuclear colour.
To look for differences in levels of various plasma constituents between pair-matched controls and patients who had cataracts classified by location and appearance of lens opacity and nuclear colour in order to identify systemic risk factors. One thousand patients were taken from the cataract waiting list of a specialist eye hospital. For each patient, a matched control of the same sex and half-decade of age but without cataract was taken from the patient-list of the family doctor of the patient; the control was the next alphabetically after the patient on the doctor's list. At an early morning visit to the homes of both patients and controls, fasting, a team of nurses performed venepunctures and collected information for a questionnaire. Eye examinations were performed by a team of ophthalmologists. Predominantly nuclear cataract was significantly associated with raised plasma alanine aminotransferase and bilirubin, posterior subcapsular cataract with increased calcium and urea, cuneiform with reduced potassium, mature/hypermature with raised potassium and reduced total carbon dioxide. The following were consistently significantly associated with all forms of cataract; diabetes and raised plasma glucose (not in non-diabetics), use of steroid medication, raised levels of cortisol (steroid users excluded), albumin, alkaline phosphatase, gamma-glutamyl transpeptidase, sodium and total protein and reduced levels of cholesterol and albumin/(total protein-albumin) ratio (an approximation for the albumin/globulin ratio). The multivariate analysis indicated that the most important non-specific cataractogenic effects were those of increased total protein, diabetes and use of steroid medication. This and other studies support, broadly, the conclusions that senile or age-related cataract is not merely caused by increasing age and also that various morphological types have different risk factors. The mechanisms underlying the biochemical associations with different patterns of lens opacification and the identification of the ultimate risk factors remain to be elucidated.


Uptake of a team briefing in the operating theatre: a Burkean dramatistic analysis.
Communication among healthcare professionals is a focus for research and policy interventions designed to improve patient safety, but the challenges of changing interprofessional communication patterns are rarely described. We present an analysis of 756 preoperative briefings conducted by general surgery teams (anesthesiologists, nurses, and surgeons) at four urban Canadian hospitals in the context of two research studies conducted between August 2004 and December 2007. We ask the questions: how and why did briefings succeed, how and why did they fail, and what did they mean for different participants? Ethnographic fieldnotes documenting the coordination and performance of team briefings were analyzed using Kenneth Burke's concepts of motive and attitude. The language and behaviour of participants were interpreted as purposive and situated actions which reveal perceptions, beliefs and values. Motives and attitudes varied both within and across sites, professions, individuals, and briefings. They were contingent on the organizational, medical and social scenes in which the briefings took place and on participants' multiple perceived purposes for participating (protecting patient safety, exchanging information, engaging with the team, fulfilling professional commitments, participating in research, and meeting social expectations). Participants' attitudes reflected their recognition (or rejection) of specific purposes, the briefings' perceived effectiveness in serving these purposes, and the briefings' perceived alignment (or conflict) with other priorities. Our findings illustrate the intrinsically rhetorical and variable nature of change.


Assessment of genetic diversity in the sorghum reference set using EST-SSR markers.
Selection and use of genetically diverse genotypes are key factors in any crop breeding program to develop cultivars with a broad genetic base. Molecular markers play a major role in selecting diverse genotypes. In the present study, a reference set representing a wide range of sorghum genetic diversity was screened with 40 EST-SSR markers to validate both the use of these markers for genetic structure analyses and the population structure of this set. Grouping of accessions is identical in distance-based and model-based clustering methods. Genotypes were grouped primarily based on race within the geographic origins. Accessions derived from the African continent contributed 88.6 % of alleles confirming the African origin of sorghum. In total, 360 alleles were detected in the reference set with an average of 9 alleles per marker. The average PIC value was 0.5230 with a range of 0.1379-0.9483. Sub-race, guinea margaritiferum (Gma) from West Africa formed a separate cluster in close proximity to wild accessions suggesting that the Gma group represents an independent domestication event. Guineas from India and Western Africa formed two distinct clusters. Accessions belongs to the kafir race formed the most homogeneous group as observed in earlier studies. This analysis suggests that the EST-SSR markers used in the present study have greater discriminating power than the genomic SSRs. Genetic variance within the subpopulations was very high (71.7 %) suggesting that the germplasm lines included in the set are more diverse. Thus, this reference set representing the global germplasm is an ideal material for the breeding community, serving as a community resource for trait-specific allele mining as well as genome-wide association mapping.


Intestinal vascular endothelial growth factor is decreased in necrotizing enterocolitis.
Decreased intestinal perfusion may contribute to the development of necrotizing enterocolitis (NEC). Vascular endothelial growth factor (VEGF) is an angiogenic protein necessary for the development and maintenance of capillary networks. Whether VEGF is dysregulated in NEC remains unknown. The objective of this study was to determine whether intestinal VEGF expression is altered in a neonatal mouse model of NEC and in human NEC patients. We first assessed changes of intestinal VEGF mRNA and protein in a neonatal mouse NEC model before significant injury occurs. We then examined whether exposure to formula feeding, bacterial inoculation, cold stress and/or intermittent hypoxia affected intestinal VEGF expression. Last, we visualized VEGF protein in intestinal tissues of murine and human NEC and control cases by immunohistochemistry. Intestinal VEGF protein and mRNA were significantly decreased in pups exposed to the NEC protocol compared to controls. Hypoxia, cold stress and commensal bacteria, when administered together, significantly downregulated intestinal VEGF expression, while they had no significant effect when given alone. VEGF was localized to a few single intestinal epithelial cells and some cells of the lamina propria and myenteric plexus. VEGF staining was decreased in murine and human NEC intestines when compared to control tissues. Intestinal VEGF protein is reduced in human and experimental NEC. Decreased VEGF production might contribute to NEC pathogenesis.


Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers.
Here, we investigated the possible predictive value of stromal caveolin-1 (Cav-1) as a candidate biomarker for clinical outcome in triple negative (TN) breast cancer patients. A cohort of 85 TN breast cancer patients was available, with the necessary annotation and nearly 12 years of follow-up data. Our primary outcome of interest in this study was overall survival. Interestingly, TN patients with high-levels of stromal Cav-1 had a good clinical outcome, with >50% of the patients remaining alive during the follow-up period. In contrast, the median survival for TN patients with moderate stromal Cav-1 staining was 33.5 months. Similarly, the median survival for TN patients with absent stromal Cav-1 staining was 25.7 months. A comparison of 5-year survival rates yields a similar pattern. TN patients with high stromal Cav-1 had a good 5-year survival rate, with 75.5% of the patients remaining alive. In contrast, TN patients with moderate or absent stromal Cav-1 levels had progressively worse 5-year survival rates, with 40 and 9.4% of the patients remaining alive. In contrast, in a parallel analysis, the levels of tumor epithelial Cav-1 had no prognostic significance. As such, the prognostic value of Cav-1 immunostaining in TN breast cancer patients is compartment-specific, and selective for an absence of Cav-1 staining in the stromal fibroblast compartment. A recursive-partitioning algorithm was used to assess which factors are most predictive of overall survival in TN breast cancer patients. In this analysis, we included tumor size, histologic grade, whether the patient received surgery, radiotherapy or chemotherapy, CK5/6, EGFR, p53 and Ki67 status, as well as the stromal Cav-1 score. This analysis indicated that stromal loss of Cav-1 expression was the most important prognostic factor for overall survival in TN breast cancer. Virtually identical results were obtained with CK5/6 (+) and/or EGFR (+) TN breast cancer cases, demonstrating that a loss of stromal Cav-1 is also a strong prognostic factor for basal-like breast cancers. Our current findings may have important implications for the close monitoring and treatment stratification of TN and basal-like breast cancer patients.


Preoperative Noninvasive Cardiac Testing in Older Adults with Hip Fracture: A Multi-Site Study.
For older adults with acute hip fracture, use of preoperative noninvasive cardiac testing may lead to delays in surgery, thereby contributing to worse outcomes. Our study objective was to evaluate the preoperative use of pharmacologic stress testing and transthoracic echocardiogram (TTE) in older adults hospitalized with hip fracture. Retrospective chart review. Seven hospitals (three tertiary, four community) within a large health system. Patients, aged 65 years and older, hospitalized with hip fracture (n = 1,079; mean age = 84.2 years; 75% female; 82% white; 36% married). Data were extracted from electronic medical records. The study evaluated associations between patient factors as well as clinical outcomes (time to surgery [TTS], length of stay [LOS], and in-hospital mortality) and the use of preoperative noninvasive cardiac testing (pharmacologic stress tests or TTE). Descriptive statistics were calculated. Cox regression was performed for both TTS and LOS (evaluated as time-dependent variable); logistic regression was used for in-hospital mortality. Although 34.3% (n = 370) had a preoperative TTE, .7% (n = 8) underwent a nuclear stress test and none had a dobutamine stress echocardiogram. Median TTS was 1.1 days (IQR [interquartile range] = .8-1.8 days), median LOS was 5.3 days (IQR = 4.2-7.2 days), and in-hospital mortality was 3% (n = 32). Patients admitted to the medical service had 3.5 times greater odds of undergoing a TTE compared with those on the orthopedic service (P < .001). Community hospitals had almost three times greater odds of preoperative TTE than tertiary centers (P < .001). In multivariable analysis, preoperative TTE was significantly associated with increased TTS (P < .001). No difference in mortality was found between patients with and without a preoperative TTE. This study highlights the high rate of TTE in preoperative assessment of older adults with acute hip fracture. Given the association between TTE and longer TTS, further studies must clarify the role of preoperative TTE in this population. J Am Geriatr Soc 68:1690-1697, 2020.


Management of the temporomandibular joint after ablative surgery.
Management of the temporomandibular joint in ablative head and neck surgery is controversial with no standardized approach. The aim of the study was to establish risk-based guidelines for the management of the temporomandibular joint after ablative surgery. Analysis of all patients' records receiving ablative surgery involving the temporomandibular joint in the Department of Cranio-Maxillofacial and Oral Surgery, University Hospital of Zürich, from 2001 to 2012, was performed, identifying 15 patients and 14 reconstructive procedures. A literature search was done identifying all relevant literature on current approaches. Applicable cohorts were constructed, and relevant risks were extrapolated. Evaluated studies are not uniform in their reporting with nonhomogeneous patient groups. A diverse approach is used in the management of these patients with complications such as infection, ankylosis, limited mouth opening, plate penetration in the skull base, and plate loosening. Risk factors for complications appear to be radiation, costochondral graft, disk loss, and plate use alone. Clinical data suggest use of a plate with metal condyle reconstructions and previous radiation therapy as potential risks factors. Employing literature evidence and cumulated clinical data, a risk-based flowchart was developed to assist surgical decision making. Risk factors such as radiation, disk preservation, and soft tissue conditions are important complication-associated factors when planning surgery. Free vascularized fibula grafts appear to have the least complications that must be weighed against donor site morbidity.


A trial of the objective structured practical examination in physiology at Melaka Manipal Medical College, India.
A single examination does not fulfill all the functions of assessment. The present study was undertaken to determine the reliability and student satisfaction regarding the objective structured practical examination (OSPE) as a method of assessment of laboratory exercises in physiology before implementing it in the forthcoming university examination. The present study was undertaken in the Department of Physiology of Melaka Manipal Medical College, Manipal Campus, India. During the OSPE, students were made to rotate through 11 stations, of which 8 stations were composed of questions that tested their knowledge and critical thinking and 2 stations were composed of skills that students had to perform before the examiner. One station was kept as the rest station. Performance of the students was assessed by comparing the students' scores in the traditional practical examination (TPE) and OSPE using "Bland-Altman technique." Student perspectives regarding the OSPE were obtained by asking them to respond to a questionnaire. The Bland-Altman plot showed that approximately 63% of the students showed a performance in the scores obtained using the OSPE and TPE within the acceptable limit of 8; 32% of the students scored much above the anticipated difference in the scores, and the rest scored below the anticipated difference in the scores on the OSPE and TPE. Feedback indicated that students were in favor of the OSPE compared with the TPE. Feedback from the students provided scope for improvement before the OSPE was administered for the first time in the forthcoming university examination.


Antipsychotic medication for those with both schizophrenia and learning disability.
Antipsychotic medication is the standard treatment for people with learning disability and schizophrenia. To determine the efficacy of any antipsychotic medication for treating people with a dual diagnosis of learning disability and schizophrenia. Electronic searching of Biological Abstracts, the Cochrane Schizophrenia Group's Register of trials (September 2000), the Cochrane Library (Issue 3 2000), EMBASE, PsycLIT MEDLINE and National Research Register. Unpublished data were sought from pharmaceutical companies. Both authors independently selected the relevant studies from the reports identified in this way. 1. All randomised controlled trials of antipsychotic medication, regardless of dosage, versus a placebo control, of longer than one month's duration. 2. Anyone over 18 years of age with both learning disability and schizophrenia. Learning disability was defined as a measured IQ of 70 or less. Any mode of diagnosis of schizophrenia was acceptable. The two reviewers independently attempted to select and then extract data but it was not possible to do this with the single study that met the inclusion criteria. Only one relevant randomised trial was found by the searches. This study included four people with a dual diagnosis of schizophrenia and learning disability, but results were available for only two. The groups to which the other two people were allocated were unclear. In order to display the data, too many assumptions would have to have been made about these other two people and any results would be uninformative and potentially misleading. Using the methods described the reviewers found no randomised controlled trial evidence to guide the use of antipsychotic medication for those with both learning disability and schizophrenia. Until the urgent need for randomised controlled trials is met, clinical practice will continue to be guided by extrapolation of evidence from randomised controlled trials involving people with schizophrenia but without learning disability and non-randomised trials of those with learning disability and schizophrenia.


Usefulness of biochemical screening of diabetic patients for hemochromatosis.
We assessed the prevalence of previously unrecognized hemochromatosis among patients in whom diabetes mellitus was diagnosed after the age of 30 yr, and we evaluated the positive predictive value of biochemical screening tests for hemochromatosis in diabetic subjects. Thirty-eight of 572 patients screened (6.6%) had a serum ferritin level greater than 324 micrograms/L; 16 patients had normal levels on repeat testing. Four patients' serum ferritin levels fell to less than 400 micrograms/L. Seven of 18 patients with a persistently elevated serum ferritin level did not undergo a liver biopsy because of a recognized cause of hyperferritenemia (carcinoma, alcoholism, or systemic lupus erythematosus). The diagnosis of hemochromatosis seemed certain in 1 of 3 patients who were not biopsied for technical reasons. Of 8 patients biopsied, 2 had hemochromatosis, 4 had fatty liver, 1 had hemosiderosis, and 1 had a chronic inflammatory cell infiltrate with no iron deposition. Of 4 patients with a raised transferrin saturation level, 2 had raised serum ferritin levels and hemochromatosis, 1 had raised serum ferritin and hemosiderosis on liver biopsy, and 1 had a normal transferrin saturation level on repeat testing. Two of 3 cases of hemochromatosis had other clinical markers of the condition. Therefore, routine screening of diabetic patients for hemochromatosis is not necessary, because patients with hemochromatosis will often have other clinical features of the disease. When screening diabetic patients for hemochromatosis, it should be remembered that a persistently raised serum ferritin level has a low positive predictive value (16.6%) and that a normal transferrin saturation level does not exclude the diagnosis.


Assessing cellular efficacy of bromodomain inhibitors using fluorescence recovery after photobleaching.
Acetylation of lysine residues in histone tails plays an important role in the regulation of gene transcription. Bromdomains are the readers of acetylated histone marks, and, consequently, bromodomain-containing proteins have a variety of chromatin-related functions. Moreover, they are increasingly being recognised as important mediators of a wide range of diseases. The first potent and selective bromodomain inhibitors are beginning to be described, but the diverse or unknown functions of bromodomain-containing proteins present challenges to systematically demonstrating cellular efficacy and selectivity for these inhibitors. Here we assess the viability of fluorescence recovery after photobleaching (FRAP) assays as a target agnostic method for the direct visualisation of an on-target effect of bromodomain inhibitors in living cells. Mutation of a conserved asparagine crucial for binding to acetylated lysines in the bromodomains of BRD3, BRD4 and TRIM24 all resulted in reduction of FRAP recovery times, indicating loss of or significantly reduced binding to acetylated chromatin, as did the addition of known inhibitors. Significant differences between wild type and bromodomain mutants for ATAD2, BAZ2A, BRD1, BRD7, GCN5L2, SMARCA2 and ZMYND11 required the addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) to amplify the binding contribution of the bromodomain. Under these conditions, known inhibitors decreased FRAP recovery times back to mutant control levels. Mutation of the bromodomain did not alter FRAP recovery times for full-length CREBBP, even in the presence of SAHA, indicating that other domains are primarily responsible for anchoring CREBBP to chromatin. However, FRAP assays with multimerised CREBBP bromodomains resulted in a good assay to assess the efficacy of bromodomain inhibitors to this target. The bromodomain and extraterminal protein inhibitor PFI-1 was inactive against other bromodomain targets, demonstrating the specificity of the method. Viable FRAP assays were established for 11 representative bromodomain-containing proteins that broadly cover the bromodomain phylogenetic tree. Addition of SAHA can overcome weak binding to chromatin, and the use of tandem bromodomain constructs can eliminate masking effects of other chromatin binding domains. Together, these results demonstrate that FRAP assays offer a potentially pan-bromodomain method for generating cell-based assays, allowing the testing of compounds with respect to cell permeability, on-target efficacy and selectivity.


Myocardial tissue phase mapping with cine phase-contrast mr imaging: regional wall motion analysis in healthy volunteers.
To establish prospectively a database of normal three-dimensional systolic and diastolic endocardial and epicardial velocity values for all myocardial segments in healthy volunteers by using cine phase-contrast velocity magnetic resonance imaging, also called tissue phase mapping (TPM). The study was approved by the institutional ethics committee and was conducted according to principles of the Declaration of Helsinki; each subject provided informed written consent. Ninety-six healthy volunteers (57 [59%] men, 39 [41%] women; mean age, 38 years +/- 12 [standard deviation]) underwent cardiac phase-contrast imaging with a black blood segmented k-space gradient-echo sequence for the analysis of three-dimensional myocardial velocity with high spatial resolution at 1.5 T on basal, midventricular, and apical short-axis views. Eighteen consecutive volunteers were imaged twice to determine interstudy reproducibility, and intra- and interobserver variability values were analyzed. Systolic and diastolic velocity curves were analyzed for peak velocity and time to peak velocity in the radial, circumferential, and longitudinal directions, as well as for torsion rate and longitudinal strain rate. Mixed-effects models with a random intercept for volunteers were used to test differences among the three ventricular sections and the transmural, endocardial, and epicardial parameters. TPM enabled reproducible assessment of myocardial velocity with small intra- and interobserver variability values. Systolic peak radial velocity was lowest at the apical level (P < .001); diastolic peak radial velocity was similar at all three myocardial levels (P = .73). As viewed from the apex, a relative counterclockwise rotation during systole was followed by a relative clockwise rotation of the apex against the base. Diastolic and systolic peak longitudinal velocity values decreased from base to apex (P < .001). A gradient between endocardium and epicardium was observed for radial velocity values, with greater endocardial velocity values (P < .001). TPM is a reproducible comprehensive modality for assessment of regional wall motion, and intra- and interobserver variability values are low.


Anti-CD8 conjugated nanoparticles to target mammalian cells expressing CD8.
This work aimed at the development of targeted drug delivery systems using nanoparticles fused with antibodies. The antibody anti-human CD8 was coupled onto PLGA nanoparticles, and the ability of these particles to specifically target cells expressing CD8 was studied. The obtained particles were found to be of spherical shape exhibiting a size between 350 and 600 nm. In vitro experiments with different cellular cultures (TE671, CHO and HEK293) using unmodified nanoparticles containing rhodamine have shown that particles were present on their surface within 48 h of incubation. In vitro tests using anti-CD8 conjugated nanoparticles in CHO cell cultures indicated that all transfected cells which express CD8 show these particles on their surface within 1h of incubation. These results demonstrated that, in a shorter time, the produced particles can target cells expressing CD8 on their surface which offers the ability to reduce drug side effects. The antibody-coupled nanoparticles represent a promising approach to improve the efficacy of active targeting for lymphoblastic leukaemia therapy.


Human invariant NKT cell subsets differentially promote differentiation, antibody production, and T cell stimulation by B cells in vitro.
Invariant NK T (iNKT) cells can provide help for B cell activation and Ab production. Because B cells are also capable of cytokine production, Ag presentation, and T cell activation, we hypothesized that iNKT cells will also influence these activities. Furthermore, subsets of iNKT cells based on CD4 and CD8 expression that have distinct functional activities may differentially affect B cell functions. We investigated the effects of coculturing expanded human CD4(+), CD8α(+), and CD4(-)CD8α(-) double-negative (DN) iNKT cells with autologous peripheral B cells in vitro. All iNKT cell subsets induced IgM, IgA, and IgG release by B cells without needing the iNKT cell agonist ligand α-galactosylceramide. Additionally, CD4(+) iNKT cells induced expansions of cells with phenotypes of regulatory B cells. When cocultured with α-galactosylceramide-pulsed B cells, CD4(+) and DN iNKT cells secreted Th1 and Th2 cytokines but at 10-1000-fold lower levels than when cultured with dendritic cells. CD4(+) iNKT cells reciprocally induced IL-4 and IL-10 production by B cells. DN iNKT cells expressed the cytotoxic degranulation marker CD107a upon exposure to B cells. Remarkably, whereas iNKT cell subsets could induce CD40 and CD86 expression by B cells, iNKT cell-matured B cells were unable to drive proliferation of autologous and alloreactive conventional T cells, as seen with B cells cultured in the absence of iNKT cells. Therefore, human CD4(+), CD8α(+), and DN iNKT cells can differentially promote and regulate the induction of Ab and T cell responses by B cells.


Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring.
Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high-throughput fragment-based docking of a diversity set of approximately 40,000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC(50)=2-5 microM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium- and high-throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.


The development of error correction strategies in young children's manipulative play.
The focus of this study was the strategies used by young children between 18 and 42 months for correcting the errors they made as they attempted to nest a set of 5 seriated cups. In the process of combining the cups, the children committed numerous errors (such as putting a cup that was too large on a smaller cup), and they tried to correct the majority of those errors. Detailed examination of the children's correction attempts revealed that the strategies they used changed substantially with age, becoming increasingly more flexible and involving more extensive restructuring of the relations among the cups. Earlier correction attempts tended to focus on a single, nonfitting cup or on a single relation between 2 cups. Later-appearing strategies involved the coordination of relations involving several cups. The same trend toward increasing flexibility of thought and action also appeared in the procedures the children used to combine the cups. This study thus documents a finely graded series of cognitively significant changes in children's constructive activity during a period that has been poorly differentiated by cognitive developmental research. In so doing, it demonstrates the usefulness for problem-solving research of analyzing how subjects go about trying to rectify their own mistakes.


Non-occupational postexposure prophylaxis for HIV: a systematic review.
To review the evidence on the clinical effectiveness and cost-effectiveness of non-occupational postexposure prophylaxis (PEP) for HIV. Eleven electronic databases were searched from inception to December 2007. Selected studies were assessed, subjected to data extraction using a standard template and quality assessment using published criteria. Studies were synthesised using a narrative approach with full tabulation of results from all included studies. One clinical effectiveness study meeting the inclusion criteria was identified, a cohort study of PEP in a high-risk HIV-negative homosexual male cohort in Brazil. The quality of the study was generally weak. Seroincidence in the cohort as a whole (2.9 per 100 person-years) was very similar to that expected in this population (3.1 per 100 person-years, p > 0.97), despite the seroconversion to HIV being 1/68 in the PEP group and 10/132 in the group not receiving PEP. High-risk sexual activities declined over time for both PEP and non-PEP users. Four economic evaluations met the inclusion criteria of the review. The methodological quality of the studies was mixed. The studies are constrained by a lack of published data on the clinical effectiveness of PEP after non-occupational exposure, with effectiveness data derived from one study of occupational PEP. Their generalisability to the UK is not clear. Results suggest that PEP following non-occupational exposure to HIV was cost saving for men who have unprotected receptive anal intercourse with men, whether the source partner is known to be HIV positive or not; heterosexuals after unprotected receptive anal intercourse; and intravenous drug users sharing needles with a known HIV-positive person. PEP following non-occupational exposure to HIV was cost-effective for all male-male intercourse (unprotected receptive and insertive anal intercourse, unprotected receptive oral sex, and 'other') and was possibly cost-effective for intravenous drug users and high-risk women. Four additional studies were identified giving further information about adverse events associated with PEP after non-occupational exposure to HIV. The majority of participants experienced adverse events with the most common being nausea and fatigue. Rates were generally higher in participants receiving triple therapy than in participants receiving dual therapy. Completion of PEP therapy was variable, ranging from 24% to 78% of participants depending on type of therapy. Toxicity was the main reason for discontinuation of treatment. It is not possible to draw conclusions on the clinical effectiveness of non-occupational PEP for HIV because of the limited evidence available. The review of cost-effectiveness suggests that non-occupational PEP may be cost-effective, especially in certain population subgroups; however, the assumptions made and data sources used in the cost-effectiveness studies mean that their results should be used with caution.


Analysing published global Ebola Virus Disease research using social network analysis.
The 2014/2015 West African Ebola Virus Disease (EVD) outbreak attracted global attention. Numerous opinions claimed that the global response was impaired, in part because, the EVD research was neglected, although quantitative or qualitative studies did not exist. Our objective was to analyse how the EVD research landscape evolved by exploring the existing research network and its communities before and during the outbreak in West Africa. Social network analysis (SNA) was used to analyse collaborations between institutions named by co-authors as affiliations in publications on EVD. Bibliometric data of publications on EVD between 1976 and 2015 was collected from Thomson Reuters' Web of Science Core Collection (WoS). Freely available software was used for network analysis at a global-level and for 10-year periods. The networks are presented as undirected-weighted graphs. Rankings by degree and betweenness were calculated to identify central and powerful network positions; modularity function was used to identify research communities. Overall 4,587 publications were identified, of which 2,528 were original research articles. Those yielded 1,644 authors' affiliated institutions and 9,907 connections for co-authorship network construction. The majority of institutions were from the USA, Canada and Europe. Collaborations with research partners on the African continent did exist, but less frequently. Around six highly connected organisations in the network were identified with powerful and broker positions. Network characteristics varied widely among the 10-year periods and evolved from 30 to 1,489 institutions and 60 to 9,176 connections respectively. Most influential actors are from public or governmental institutions whereas private sector actors, in particular the pharmaceutical industry, are largely absent. Research output on EVD has increased over time and surged during the 2014/2015 outbreak. The overall EVD research network is organised around a few key actors, signalling a concentration of expertise but leaving room for increased cooperation with other institutions especially from affected countries. Finding innovative ways to maintain support for these pivotal actors while steering the global EVD research network towards an agenda driven by agreed, prioritized needs and finding ways to better integrate currently peripheral and newer expertise may accelerate the translation of research into the development of necessary live saving products for EVD ahead of the next outbreak.


Congestion road tax and physical activity.
Large-scale policy and environmental changes, such as congestion road taxes, may be a way to promote active transportation. This study aimed to examine the potential effect of a congestion road tax on physical activity. Baseline data were collected during October-November 2003, follow-up data in May 2006, and analysis was performed in September 2008. The short self-administered version of the International Physical Activity Questionnaire was used to assess physical activity. Data from those with access to motorized vehicles in the Stockholm region (n=165), where the tax was in place, were compared with those from the Göteborg/Malmö regions (n=138). Within each region before and during the road tax implementation, the data were analyzed for differences in time spent at different intensity levels of physical activity, in addition to sitting, as well as for changes in reported time in overall (weighted) physical activity. There were no significant differences in the magnitude of the changes of the intensity levels of physical activity, weighted overall physical activity, or sitting, between Stockholm and Göteborg/Malmö. Among those exposed to the congestion road tax and with access to motorized vehicles, an increase in moderate physical activity (p=0.036); overall physical activity (p=0.015); and a reduction in time spent sitting (p=0.009) was observed. No differences were observed among those unexposed. The results from this study on the influence of a congestion road tax on levels of physical activity, though inconclusive, suggest that policy changes such as a congestion road tax might promote improvements in physical activity levels in individuals with motorized vehicles.


Multimodal Affective State Assessment Using fNIRS + EEG and Spontaneous Facial Expression.
Human facial expressions are regarded as a vital indicator of one's emotion and intention, and even reveal the state of health and wellbeing. Emotional states have been associated with information processing within and between subcortical and cortical areas of the brain, including the amygdala and prefrontal cortex. In this study, we evaluated the relationship between spontaneous human facial affective expressions and multi-modal brain activity measured via non-invasive and wearable sensors: functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) signals. The affective states of twelve male participants detected via fNIRS, EEG, and spontaneous facial expressions were investigated in response to both image-content stimuli and video-content stimuli. We propose a method to jointly evaluate fNIRS and EEG signals for affective state detection (emotional valence as positive or negative). Experimental results reveal a strong correlation between spontaneous facial affective expressions and the perceived emotional valence. Moreover, the affective states were estimated by the fNIRS, EEG, and fNIRS + EEG brain activity measurements. We show that the proposed EEG + fNIRS hybrid method outperforms fNIRS-only and EEG-only approaches. Our findings indicate that the dynamic (video-content based) stimuli triggers a larger affective response than the static (image-content based) stimuli. These findings also suggest joint utilization of facial expression and wearable neuroimaging, fNIRS, and EEG, for improved emotional analysis and affective brain-computer interface applications.


Clinical evaluation and management strategy for sexual dysfunction in men and women.
The optimal approach for identification and evaluation of the sexual problems in men and women in primary care or general medicine practice has not been consensed. To provide recommendations/guidelines concerning state-of-the-art knowledge for clinical evaluation and management strategies in the evaluation and treatment of sexual dysfunction in men and women, emphasizing evidence-based medicine and a patient-centered framework. An International Consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a 2-year period. Concerning the Clinical Evaluation and Management Strategies Committee, there were 12 experts from five countries. Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation and debate. Three concepts underlie sexual medicine management: (i) adoption of a patient-centered framework for evaluation and treatment; (ii) application of the principles of evidence-based medicine in diagnostic and treatment planning; and (iii) use of a unified management approach in men and women. When taken together, these three principles provide a balanced and integrated approach to sexual dysfunction management. Common algorithms for diagnosis and management of men and women with sexual dysfunction, brief sexual symptom checklists, basics in history and physical examination, indications for specialized referral and development of a follow-up strategy are presented. More research is needed in understanding the role of evidence-based and patient-centered medicine in the clinical evaluation and management strategies of men and women with sexual dysfunction.


In vivo imaging of trypanosomes for a better assessment of host-parasite relationships and drug efficacy.
The advances in microscopy combined to the invaluable progress carried by the utilization of molecular, immunological or immunochemical markers and the implementation of more powerful imaging technologies have yielded great improvements to the knowledge of the interaction between microorganisms and their hosts, notably a better understanding of the establishment of infectious processes. Still today, the intricacies of the dialog between parasites, cells and tissues remain limited. Some improvements have been attained with the stable integration and expression of the green fluorescence protein or firefly luciferase and other reporter genes, which have allowed to better approach the monitoring of gene expression and protein localization in vivo, in situ and in real time. Aiming at better exploring the well-established models of murine infections with the characterized strains of Trypanosoma cruzi and Trypanosoma vivax, we revisited in the present report the state of the art about the tools for the imaging of Trypanosomatids in vitro and in vivo and show the latest transgenic parasites that we have engineered in our laboratory using conventional transfection methods. The targeting of trypanosomes presented in this study is a promising tool for approaching the biology of parasite interactions with host cells, the progression of the diseases they trigger and the screening of new drugs in vivo or in vitro.


A large accumulation of metallic foreign bodies in the stomach.
A routine x-ray examination showed a fishhook lodged in the esophagus of an asymptomatic 68-year-old man. Further examination revealed multiple foreign objects in his stomach. In all, 82 metallic objects were removed endoscopically. The authors believe that this is the largest accumulation of foreign objects to be removed by this procedure and that endoscopy, properly performed, is a safe and effective alternative to laparotomy. However, surgery remains a safer procedure in some situations.


Infant stepping: a method to study the sensory control of human walking.
1. Stepping responses were studied in infants between the ages of 10 days and 10 months while they were supported to step on a slowly moving treadmill belt. Surface electromyography (EMG) from muscles in the lower limb, force exerted by the feet on the treadmill belt, and the motion of the lower limbs were recorded. 2. Two groups of infants were studied, those who had a small amount of daily practice in stepping and those who did not. Practice resulted in a dramatic increase in the incidence of stepping recorded in the laboratory, particularly for the periods between 1 and 6 months of age. 3. The majority of infants showed clear alternation between the flexor and extensor muscles during walking, regardless of age. Co-contraction between flexors and extensors, estimated by the overlap in area between rectified and smoothed EMG from a muscle pair, was greater for some muscle groups in the infant compared with the adult. 4. Practice resulted in a significantly lower co-contraction index for the tibialis anterior- quadriceps muscle pair. Practice did not affect the mean step cycle duration. 5. Infants of all ages could step at a range of treadmill speeds by adjusting their step cycle duration. The relationship between the treadmill speed and cycle duration was well fitted by a power function, similar to those reported for intact cats and adult humans. The change in step cycle duration resulted almost entirely from a change in the extensor burst duration, whereas the flexor burst duration remained constant. 6. Airstepping could be elicited in some infants. The cycle durations for airstepping were close to the shortest cycles recorded on the treadmill. 7. In conclusion, the system for generating rhythmic, alternating activity of the lower limbs for stepping is clearly developed by birth. The stepping is sustained and regular, particularly if stepping practice is incorporated briefly each day. The infant population provides a good subject pool for studying the afferent control of walking in the human, before cerebral influences are fully developed. The characteristics and maturity of the system remain to be determined.


Correlates of Perceived Social Support in Chinese Adult Child Caregivers of Parent Stroke Survivors.
Prevalence of stroke and traditional filial responsibility involve adult children in caregiving to their parent stroke survivors in China. Support resources are insufficient because of the shrinking size of family and the underdeveloped support system. The aim of this study was to identify the correlates of perceived social support among adult child caregivers of parent stroke survivors in China. A cross-sectional correlational design was used in this study. A nonproportional quota sample of 126 adult child caregivers was recruited from Zhejiang Province, China. Data were collected at either the hospital stroke units or the respondents' homes using structured questionnaires of caregiving dyadic demographics and caregiving characteristics, 14-item Activities of Daily Living, 15-item Mutuality Scale, and 12-item Multidimensional Scale of Perceived Social Support. SPSS 17.0 was used for analysis. Caregivers' mutuality, education, full employment or being retired, monthly income, having a co-carer, and having a father as the care receiver were significantly positively associated with caregivers' perceived social support. However, mutuality was not significantly associated with caregivers' perceived social support after the other factors were adjusted. Adult child caregivers with higher levels of mutuality, education, or monthly income; who are fully employed or are retired; who have a co-carer; or who are caring for a father perceived more social support. Nursing strategies and social policies need to be directed to enhance caregiver mutuality and support caregiving efforts.


Gamma Knife radiosurgery for facial nerve schwannomas: a multicenter study.
Facial nerve schwannomas (FNSs) are rare intracranial tumors, and the optimal management of these tumors remains unclear. Resection can be undertaken, but the tumor's intimate association with the facial nerve makes resection with neurological preservation quite challenging. Stereotactic radiosurgery (SRS) has been used to treat FNSs, and this study evaluates the outcome of this approach. At 8 medical centers participating in the North American Gamma Knife Consortium (NAGKC), 42 patients undergoing SRS for an FNS were identified, and clinical and radiographic data were obtained for these cases. Males outnumbered females at a ratio of 1.2:1, and the patients' median age was 48 years (range 11-76 years). Prior resection was performed in 36% of cases. The mean tumor volume was 1.8 cm(3), and a mean margin dose of 12.5 Gy (range 11-15 Gy) was delivered to the tumor. At a median follow-up of 28 months, tumor control was achieved in 36 (90%) of the 40 patients with reliable radiographic follow-up. Actuarial tumor control was 97%, 97%, 97%, and 90% at 1, 2, 3, and 5 years postradiosurgery. Preoperative facial nerve function was preserved in 38 of 42 patients, with 60% of evaluable patients having House-Brackmann scores of 1 or 2 at last follow-up. Treated patients with a House-Brackmann score of 1 to 3 were more likely to demonstrate this level of facial nerve function at last evaluation (OR 6.09, 95% CI 1.7-22.0, p = 0.006). Avoidance of temporary or permanent neurological symptoms was more likely to be achieved in patients who received a tumor margin dose of 12.5 Gy or less (log-rank test, p = 0.024) delivered to a tumor of ≤ 1 cm(3) in volume (log-rank test, p = 0.01). Stereotactic radiosurgery resulted in tumor control and neurological preservation in most FNS patients. When the tumor is smaller and the patient exhibits favorable normal facial nerve function, SRS portends a better result. The authors believe that early, upfront SRS may be the treatment of choice for small FNSs, but it is an effective salvage treatment for residual/recurrent tumor that remain or progress after resection.


Deletion of the varicella-zoster virus large subunit of ribonucleotide reductase impairs growth of virus in vitro.
Cells infected with varicella-zoster virus (VZV) express a viral ribonucleotide reductase which is distinct from that present in uninfected cells. VZV open reading frames 18 and 19 (ORF18 and ORF19) are homologous to the herpes simplex virus type 1 genes encoding the small and large subunits of ribonucleotide reductase, respectively. We generated recombinant VZV by transfecting cultured cells with four overlapping cosmid DNAs. To construct a virus lacking ribonucleotide reductase, we deleted 97% of VZV ORF19 from one of the cosmids. Transfection of this cosmid with the other parental cosmids yielded a VZV mutant with a 2.3-kbp deletion confirmed by Southern blot analysis. Virus-specific ribonucleotide reductase activity was not detected in cells infected with VZV lacking ORF19. Infection of melanoma cells with ORF19-deleted VZV resulted in plaques smaller than those produced by infection with the parental VZV. The mutant virus also exhibited a growth rate slightly slower than that of the parental virus. Chemical inhibition of the VZV ribonucleotide reductase has been shown to potentiate the anti-VZV activity of acyclovir. Similarly, the concentration of acyclovir required to inhibit plaque formation by 50% was threefold lower for the VZV ribonucleotide reductase deletion mutants than for parental virus. We conclude that the VZV ribonucleotide reductase large subunit is not essential for virus infection in vitro; however, deletion of the gene impairs the growth of VZV in cell culture and renders the virus more susceptible to inhibition by acyclovir.


Biomimetic cilia arrays generate simultaneous pumping and mixing regimes.
Living systems employ cilia to control and to sense the flow of fluids for many purposes, such as pumping, locomotion, feeding, and tissue morphogenesis. Beyond their use in biology, functional arrays of artificial cilia have been envisaged as a potential biomimetic strategy for inducing fluid flow and mixing in lab-on-a-chip devices. Here we report on fluid transport produced by magnetically actuated arrays of biomimetic cilia whose size approaches that of their biological counterparts, a scale at which advection and diffusion compete to determine mass transport. Our biomimetic cilia recreate the beat shape of embryonic nodal cilia, simultaneously generating two sharply segregated regimes of fluid flow: Above the cilia tips their motion causes directed, long-range fluid transport, whereas below the tips we show that the cilia beat generates an enhanced diffusivity capable of producing increased mixing rates. These two distinct types of flow occur simultaneously and are separated in space by less than 5 microm, approximately 20% of the biomimetic cilium length. While this suggests that our system may have applications as a versatile microfluidics device, we also focus on the biological implications of our findings. Our statistical analysis of particle transport identifying an enhanced diffusion regime provides novel evidence for the existence of mixing in ciliated systems, and we demonstrate that the directed transport regime is Poiseuille-Couette flow, the first analytical model consistent with biological measurements of fluid flow in the embryonic node.


An innovative method for counting females of soybean cyst nematode with fluorescence imaging technology.
Use of resistant cultivars is one of the major tactics for combating soybean cyst nematode, Heterodera glycines Ichinohe, which is the most destructive pathogen affecting soybean seed production. However, developing new H. glycines-resistant soybean cultivars is a very labor-intensive process, partially due to the lack of a quick method for counting the H. glycines females that develop on soybean roots. We have developed a fluorescence image-based system for counting females on excised seedling roots cultured on nutrient media in petri dishes. In this system, the females fluoresced when exposed to a wavelength of 570 nm. The fluorescent images were captured with a digital camera, transferred to a computer, and displayed on a monitor. The image of an entire sample was viewed at once, and the fluorescing females were counted manually. This system significantly improved the efficiency and accuracy of counting females developed on cultured seedling roots compared to a microscope counting method. The potential for applications in the screening of nematode-resistant crops is discussed.


Lessons from structural genomics.
A decade of structural genomics, the large-scale determination of protein structures, has generated a wealth of data and many important lessons for structural biology and for future large-scale projects. These lessons include a confirmation that it is possible to construct large-scale facilities that can determine the structures of a hundred or more proteins per year, that these structures can be of high quality, and that these structures can have an important impact. Technology development has played a critical role in structural genomics, the difficulties at each step of determining a structure of a particular protein can be quantified, and validation of technologies is nearly as important as the technologies themselves. Finally, rapid deposition of data in public databases has increased the impact and usefulness of the data and international cooperation has advanced the field and improved data sharing.


Functional brain imaging of cognitive dysfunction in Parkinson's disease.
Multiple factors are involved in the development of cognitive impairment in Parkinson's disease (PD) and related disorders. Notably, several underlying factors, such as monoaminergic dysfunction, Lewy body pathology, Alzheimer disease-like pathology and cerebrovascular disease are implied in the PD pathophysiology of cognitive impairment. The mesocortical dopaminergic system is associated with executive functions which are frequently affected in PD and are influenced by local levodopa concentration, dopamine metabolism and baseline performance status. The ventral striatum and frontal cortex are associated with impulse control disorders reported in PD patients treated with dopamine replacement therapy. Cholinergic impairment in PD plays a cardinal role in the development of dementia. Acetylcholinesterase positron emission tomography demonstrates that posterior brain areas are related to cognitive decline in PD patients. Amyloid radiotracer illustrates that patients with PD with severe cognitive impairment were prone to accompanied cortical amyloid deposition. Metabolism/perfusion change associated with cognitive impairment in PD, so-called PD related cognitive pattern, is characterised by reduced frontoparietal activity and is an effective way to differentiate and monitor cognitive function of individual PD patients. Cognitive impairment in PD cannot be explained by a single mechanism and is entangled by multiple factors. Imaging studies can unravel each pathological domain, further shed light on the interrelation between different pathomechanisms, not only in PD but also in other dementia related disorders, and thereby integrate its interpretation to apply to therapeutics in individual patients.


Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model.
Hirschsprung disease (HSCR, MIM #142623) is a multigenic neurocristopathy (neural crest disorder) characterized by absence of enteric ganglia in a variable portion of the distal colon. Subsets of HSCR individuals also present with neural crest-derived melanocyte deficiencies (Hirschsprung-Waardenburg, HSCR-WS, MIM #277580). Murine models have been instrumental in the identification and analysis of HSCR disease genes. These include mice with deficiencies of endothelin B receptor (Ednrb(s-l); refs 1,2) endothelin 3 (Edn3(ls): refs 1,3) the tyrosine kinase receptor cRet and glial-derived neurotrophic factor. Another mouse model of HSCR disease, Dom, arose spontaneously at the Jackson Laboratory. While Dom/+ heterozygous mice display regional deficiencies of neural crest-derived enteric ganglia in the distal colon, Dom/Dom homozygous animals are embryonic lethal. We have determined that premature termination of Sox10, a member of the SRY-like HMG box family of transcription factors, is responsible for absence of the neural crest derivatives in Dom mice. We demonstrate expression of Sox10 in normal neural crest cells, disrupted expression of both Sox10 and the HSCR disease gene Ednrb in Dom mutant embryos, and loss of neural crest derivatives due to apoptosis. Our studies suggest that Sox10 is essential for proper peripheral nervous system development. We propose SOX10 as a candidate disease gene for individuals with HSCR whose disease does not have an identified genetic origin.


Surgical Management of Complex Syndromic Craniosynostosis: Experience With a Rare Genetic Variant.
Patients with syndromic craniosynostosis (CS) can present with both intracranial and extracranial manifestations. Extracranial features include proptosis, exorbitism, and midface hypoplasia. Intracranial manifestations can include elevated intracranial pressure (ICP), brainstem compression, foramen magnum stenosis or jugular foramen hypoplasia with resultant venous hypertension and anomalous drainage. While fronto-orbital advancement, cranial vault remodeling, and posterior fossa decompression are standard surgical approaches to normalizing orbito-cranial volume and morphology, associated hydrocephalus, anomalous venous drainage, and tonsillar herniation often affect the timing, safety, and selection of corrective interventions. The surgical decision-making to circumvent venous emissaries, effectively time treatment of hydrocephalus, and address posterior versus anterior pathology primarily has not been widely described in the literature, and is important in the development of guidelines in these complex cases. In this report, we describe the surgical management of a patient with Jackson-Weiss syndrome presenting with delayed, but rapidly progressive bilateral lambdoid CS, severe proptosis, midface hypoplasia, elevated ICP, hydrocephalus, tonsillar ectopia, and severe venous hypertension with anomalous drainage. We review the literature related to management of complex synostosis and present our surgical decision-making in the setting of complex syndromic synostosis to aid in the formation of guidelines toward approaching these cases.


Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer†.
Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m(2) i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m(2) i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity. Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred. The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group. NCT00499603.


Characterization of a novel extended-spectrum beta-lactamase from Pseudomonas aeruginosa.
A clinical isolate of Pseudomonas aeruginosa RNL-1 showed resistance to extended-spectrum cephalosporins which was inhibited by clavulanic acid. Although this strain contained three plasmids ca. 80, 20, and 4 kb long, the resistance could not be transferred by mating-out assays with P. aeruginosa or Escherichia coli. Cloning of a 2.1-kb Sau3A fragment from P. aeruginosa RNL-1 into plasmid pACYC184 produced pPZ1, a recombinant plasmid that encodes a beta-lactamase. This beta-lactamase (PER-1) had a relative molecular mass of 29 kDa and a pI of 5.4 and was biosynthesized by P. aeruginosa RNL-1 along with a likely cephalosporinase with a pI of 8.7. PER-1 showed a broad substrate profile by hydrolyzing benzylpenicillin, amoxicillin, ticarcillin cephalothin, cefoperazone, cefuroxime, HR 221, ceftriaxone, ceftazidime, and (moderately) aztreonam but not oxacillin, imipenem, or cephamycins. Vmax values for extended-spectrum cephalosporins were uncommonly high, and the affinity of the enzyme for most compounds was relatively low (i.e., high Km). PER-1 activity was inhibited by clavulanic acid, sulbactam, imipenem, and cephamycins but not by EDTA. A 1.1-kb SnaBI fragment from pPZ1 failed to hybridize with plasmids that encode TEM-, SHV-, OXA-, or CARB/PSE-type beta-lactamase or with the ampC gene of P. aeruginosa. However, the same probe appeared to hybridize with chromosomal but not plasmid DNA from P. aeruginosa RNL-1. This study reports the properties of a novel extended-spectrum beta-lactamase in P. aeruginosa which may not be derived by point mutations from previously known enzymes of this species.


Etiology of reactive arthritis in Pan paniscus, P. troglodytes troglodytes, and P. troglodytes schweinfurthii.
The character of arthritis has not received the same attention in Pan paniscus as it has in P. troglodytes. Reactive arthritis (a form of spondyloarthropathy) in the latter has been considered to be either a sexually transmitted or an infectious-agent diarrhea-related disorder. The unique sexual promiscuity of P. paniscus enables us to distinguish between those hypotheses. The macerated skeletons of 139 adult P. paniscus, P. troglodytes troglodytes, and P. troglodytes schweinfurthii were macroscopically analyzed for osseous and articular pathologies. The sex of the animal was recorded at the time of acquisition. Twenty-one percent of the P. paniscus, 28% of the P. t. troglodytes, and 27% of the P. t. schweinfurthii specimens had peripheral and central joint erosive disease characteristic of spondyloarthropathy. Subchondral pauciarticular distribution and reactive new bone clearly distinguish this disease from rheumatoid arthritis, osteoarthritis, and direct bone/joint infection. The fact that P. paniscus and P. t. troglodytes were similar in terms of disease frequency makes the notion of sexual transmission unlikely. While the frequencies of spondyloarthropathy were indistinguishable among all species/subspecies studied, the patterns of joint involvement were disparate. The Pan paniscus and P. t. troglodytes home ranges are geographically separate. We assessed possible habitat factors (e.g., exposure to specific infectious agents of diarrhea) by comparing P. paniscus and P. t. troglodytes with P. t. schweinfurthii. The latter shared similar patterns and habitats (separated by the Congo River) with P. paniscus. The explanation offered for habitat-specific patterns is differential bacterial exposure-most likely Shigella or Yersinia in P. paniscus and P. t. schweinfurthii.


Novel optical techniques for detecting and classifying toxic dinoflagellate Karenia brevis blooms using satellite imagery.
Karenia brevis (K. brevis) blooms are of great interest and have been commonly reported throughout the Gulf of Mexico. In this study we propose a detection technique for blooms with low backscatter characteristics, which we name the Red Band Difference (RBD) technique, coupled with a selective K. brevis bloom classification technique, which we name the K. brevis Bloom Index (KBBI). These techniques take advantage of the relatively high solar induced chlorophyll fluorescence and low backscattering of K. brevis blooms. The techniques are applied to the detection and classification of K. brevis blooms from Moderate Resolution Imaging Spectroradiometer (MODIS) ocean color measurements off the Gulf of Mexico. To assess the efficacy of the techniques for detection and classification, simulations, including chlorophyll fluorescence (assuming 0.75% quantum yield) based on K. brevis blooms and non-K. brevis blooms conditions were performed. These show that effective bloom detection from satellite measurements requires a threshold of RBD>0.15W/m(2)/microm/sr, corresponding to about 5mg/m(3) of chlorophyll. Blooms can be detected at lower concentration by lowering the RBD threshold but false positives may increase. The classification technique is found most effective for thresholds of RBD>0.15W/m(2)/microm/sr and KBBI>0.3*RBD. The techniques were applied and shown to be effective for well documented blooms of K. brevis in the Gulf of Mexico and compared to other detection techniques, including FLH approaches. Impacts of different atmospheric corrections on results were also examined.


The response of spinal cord ependymomas to bevacizumab in patients with neurofibromatosis Type 2.
OBJECTIVE People with neurofibromatosis Type 2 (NF2) have a genetic predisposition to nervous system tumors. NF2-associated schwannomas stabilize or decrease in size in over half of the patients while they are receiving bevacizumab. NF2 patients treated with bevacizumab for rapidly growing schwannoma were retrospectively reviewed with regard to ependymoma prevalence and response to treatment. METHODS The records of 95 NF2 patients receiving bevacizumab were retrospectively reviewed with regard to spinal ependymoma prevalence and behavior. The maximum longitudinal extent (MLE) of the ependymoma and associated intratumoral or juxtatumoral cysts were measured on serial images. Neurological changes and patient function were reviewed and correlated with radiological changes. RESULTS Forty-one of 95 patients were found to have ependymomas (median age 26 years; range 11-53 years). Thirty-two patients with a total of 71 ependymomas had scans appropriate for serial assessment with a mean follow-up of 24 months (range 3-57 months). Ependymomas without cystic components showed minimal change in MLE. Twelve patients had ependymomas with cystic components or syringes. In these patients, reductions in MLE were observed, particularly due to decreases in the cystic components of the ependymoma. Clinical improvement was seen in 7 patients, who all had cystic ependymomas. CONCLUSIONS Bevacizumab treatment in NF2 patients with spinal cord ependymomas results in a decrease in the size of intratumoral and juxtatumoral cysts as well as adjacent-cord syringes and a decrease in cord edema. This may provide clinical benefit in some patients, although the changes do not meet the current criteria for radiological tumor response.


Interaction with human plasminogen system turns on proteolytic activity in Streptococcus agalactiae and enhances its virulence in a mouse model.
Interactions of several microbial pathogens with the plasminogen system increase their invasive potential. In this study, we show that Streptococcus agalactiae binds human plasminogen which can be subsequently activated to plasmin, thus generating a proteolytic bacterium. S. agalactiae binds plasminogen via the direct pathway, using plasminogen receptors, and via the indirect pathway through fibrinogen receptors. The glyceraldehyde-3-phosphate dehydrogenase is one of the S. agalactiae proteins that bind plasminogen. Presence of exogenous activators such as uPA and tPA are required to activate bound plasminogen. Results from competitive inhibition assays indicate that binding is partially mediated through the lysine binding sites of plasminogen. Following plasminogen binding and activation, S. agalactiae is able to degrade in vitro fibronectin, one of the host extracellular matrix proteins. Moreover, incubation of S. agalactiae with either plasminogen alone, or plasminogen plus fibrinogen, in the presence of tPA enhanced its virulence in C57BL/6 mice, suggesting that acquisition of plasmin-like activity by the bacteria increase their invasiveness.


Marine sponges (Porifera: Demospongiae) from the Gulf of México, new records and redescription of Erylus trisphaerus (de Laubenfels, 1953).
Marine sponges usually constitute the most diverse group of the benthic community in coral reefs. Although they are reasonably well studied at the northern Gulf of Mexico (GMx), the southern GMx is poorly known and lacks records from many major reef systems that lie off the Mexican coast. The present taxonomic study is the first sponge account from Alacranes reef, the largest coral reef system in the GMx, and from the shallow reef banks of Sisal, both in the northwest Yucatan Peninsula. The 19 species herein described represent the first sponge fauna records from these reefs. Among these, seven species represent new record for GMx: Erylus formosus, Cliona flavifodina, Spirastrella aff. mollis, Strongylacidon bermuda, Topsentia bahamensis, Agelas tubulata and Chelonaplysilla aff. erecta. Twelve species are new records for the Southern GMx: Erylus trisphaerus, Cliona amplicavata, Chondrilla caribensis, Halichondria lutea, Hymeniacidon caerulea, Axinella corrugata, Dragmacidon reticulatum, Chalinula molitba, Amphimedon caribica, A. complanata, Hyatella cavernosa and Dysidea variabilis. Additionally, a redescription of Erylus trisphaerus is presented which had not been reviewed since its original description in 1953 off Western Florida, except that it was listed for north La Habana, Cuba.


Physical therapy is effective for patients with osteoarthritis of the knee: a randomized controlled clinical trial.
To assess the effectiveness of physical therapy, given either as an individually attended treatment or in a small group format, in terms of pain, physical function, and health related quality of life for patients with osteoarthritis (OA) of the knee. After 2 baseline assessments, 126 patients were randomized into one of 3 allocation arms: individual treatments (n = 43), small group format program (n = 40), and waiting list control (n = 43). After reassessment at 8 weeks, patients allocated to waiting list control were randomized into one of the 2 active treatment arms. Assessments included both self-report measures (WOMAC, SF-36) and objective measures of physical performance (gait analysis and muscle strength). Both physical therapy treatment allocations resulted in significant improvements in pain, physical function, and health related quality of life above the control group (standardized response mean 0.36 to 0.65). Improvements in the self-report measures were substantiated by significant correlated improvements in knee extensor strength and fast walking speed (rho 0.36-0.42). There were no significant differences in effectiveness between the 2 physical therapy allocations for any of the measured outcomes. Improvements gained were maintained for at least 2 months. Responsiveness to treatment was modified by loss of medial joint space width, the interaction being significant for physical function, gait, and knee extensor strength. Physical therapy, either as an individually delivered treatment or in a small group format, is an effective intervention for patients with knee OA. Responsiveness to this 8 week intervention was modified by loss of medial joint space width.


Long-Term Outcome after Joint Bleeds in Von Willebrand Disease Compared to Haemophilia A: A Post Hoc Analysis.
Long-term outcome after joint bleeds in von Willebrand disease (VWD) (von Willebrand factor activity ≤ 30 IU/dL) could differ from moderate or severe haemophilia A (HA) (factor VIII [FVIII] 1-5 IU/dL or FVIII < 1 IU/dL). We performed a post hoc analysis on Haemophilia Joint Health Score (HJHS, 0-124), X-ray Pettersson scores (PS, 0-13/joint) and the Haemophilia Activities List (HAL, 0-100), using multivariable regression to adjust for age (rate ratio [RR] or odds ratio [OR] [95% confidence interval]). We included 48 VWD (median age, 47 years, type 3 VWD, n = 19), 39 moderate HA (median, 39 years) and 59 severe HA patients (median, 25 years) with documented joint bleeds. VWD patients suffered repeated bleeding (lifetime > 5/joint) less often than moderate and severe HA patients (52% vs. 77% vs. 98%). HJHS and PS in VWD were similar to moderate HA (median HJHS 5 vs. 6, RR 0.9 [0.5-1.4] and PS > 3 of ≥ 1 joint OR 0.3 [0.1-1.4]), but better than in severe HA patients (median HJHS 5 vs. 9, RR 1.8 [1.1-2.9]; PS > 3 in any joint OR 0.1 [0.0-0.3]). Self-reported limitations in activities were comparable across VWD, moderate HA (HAL score < 95: 67% vs. 49%; OR 1.4 [0.5-3.6]) and young adults with severe HA (67% vs. 48%; OR 1.7 [0.7-4.4]). Despite fewer joint bleeds, joint outcome after joint bleeds was similar in VWD and moderate HA patients. Type 3 VWD patients had worst joint outcome, comparable to younger intensively treated severe HA patients. Limitations in activities occurred as often in VWD as in both moderate and severe HA.


Hypothermia in trauma.
The human core temperature is maintained by highly controlled regulatory mechanisms that balance heat production and heat loss. When this balance is interrupted, there are consequences for human physiology that are not yet fully understood. Extremes of temperature have a physiological impact on human cells. In some instances, such as cardiac arrest, traumatic brain injury, and organ transplantation, controlled hypothermia can be physiologically beneficial, but hypothermia in traumatic injury is distinctly different. In trauma, hypothermia often begins at the time of injury as a result of increased heat loss by conduction and convection due to exposure and reduced heat production due to decreased motor activity.


SU-E-J-109: Accurate Contour Transfer Between Different Image Modalities Using a Hybrid Deformable Image Registration and Fuzzy Connected Image Segmentation Method.
To develop and evaluate a tool that can improve the accuracy of contour transfer between different image modalities under challenging conditions of low image contrast and large image deformation, comparing to a few commonly used methods, for radiation treatment planning. The software tool includes the following steps and functionalities: (1) accepting input of images of different modalities, (2) converting existing contours on reference images (e.g., MRI) into delineated volumes and adjusting the intensity within the volumes to match target images (e.g., CT) intensity distribution for enhanced similarity metric, (3) registering reference and target images using appropriate deformable registration algorithms (e.g., B-spline, demons) and generate deformed contours, (4) mapping the deformed volumes on target images, calculating mean, variance, and center of mass as the initialization parameters for consecutive fuzzy connectedness (FC) image segmentation on target images, (5) generate affinity map from FC segmentation, (6) achieving final contours by modifying the deformed contours using the affinity map with a gradient distance weighting algorithm. The tool was tested with the CT and MR images of four pancreatic cancer patients acquired at the same respiration phase to minimize motion distortion. Dice's Coefficient was calculated against direct delineation on target image. Contours generated by various methods, including rigid transfer, auto-segmentation, deformable only transfer and proposed method, were compared. Fuzzy connected image segmentation needs careful parameter initialization and user involvement. Automatic contour transfer by multi-modality deformable registration leads up to 10% of accuracy improvement over the rigid transfer. Two extra proposed steps of adjusting intensity distribution and modifying the deformed contour with affinity map improve the transfer accuracy further to 14% averagely. Deformable image registration aided by contrast adjustment and fuzzy connectedness segmentation improves the contour transfer accuracy between multi-modality images, particularly with large deformation and low image contrast.


Association between urinary vascular endothelial growth factor excretion and chronic kidney disease in hyperthyroid cats.
Many hyperthyroid cats develop azotaemic chronic kidney disease (aCKD) following treatment, which has led to the hypothesis that hyperthyroidism might be detrimental to renal function. Renin-angiotensin-aldosterone system (RAAS) activation occurs in hyperthyroidism, which could cause peri-tubular hypoxia, tubular damage and the development of aCKD. Urinary vascular endothelial growth factor:creatinine ratio (VEGFCR) is postulated to be a marker of tubular hypoxia. VEGFCR was correlated with plasma renin activity (PRA) and compared between hyperthyroid cats that did and did not develop aCKD following treatment (pre-azotaemic and non-azotaemic groups respectively). PRA was positively correlated with VEGFCR (rs = 0.382; P = 0.028); however, pre-azotaemic hyperthyroid cats had significantly lower VEGFCR than non-azotaemic cats at baseline (median 122.3 fg/g versus 167.0 fg/g; P < 0.001). RAAS activation in hyperthyroidism is associated with increased VEGFCR; however, increased VEGFCR was not correlated with the development of aCKD. Therefore, tubular hypoxia may not be a mechanism for renal damage in hyperthyroid cats.


Enhanced biofilm and extracellular matrix production by chronic carriage versus acute isolates of Salmonella Typhi.
Salmonella Typhi is the primary causative agent of typhoid fever; an acute systemic infection that leads to chronic carriage in 3-5% of individuals. Chronic carriers are asymptomatic, difficult to treat and serve as reservoirs for typhoid outbreaks. Understanding the factors that contribute to chronic carriage is key to development of novel therapies to effectively resolve typhoid fever. Herein, although we observed no distinct clustering of chronic carriage isolates via phylogenetic analysis, we demonstrated that chronic isolates were phenotypically distinct from acute infection isolates. Chronic carriage isolates formed significantly thicker biofilms with greater biomass that correlated with significantly higher relative levels of extracellular DNA (eDNA) and DNABII proteins than biofilms formed by acute infection isolates. Importantly, extracellular DNABII proteins include integration host factor (IHF) and histone-like protein (HU) that are critical to the structural integrity of bacterial biofilms. In this study, we demonstrated that the biofilm formed by a chronic carriage isolate in vitro, was susceptible to disruption by a specific antibody against DNABII proteins, a successful first step in the development of a therapeutic to resolve chronic carriage.


Backbone dynamics of the 18.5 kDa isoform of myelin basic protein reveals transient alpha-helices and a calmodulin-binding site.
The 18.5 kDa isoform of myelin basic protein (MBP) is the predominant form in adult human central nervous system myelin. It is an intrinsically disordered protein that functions both in membrane adhesion, and as a linker connecting the oligodendrocyte membrane to the underlying cytoskeleton; its specific interactions with calmodulin and SH3-domain containing proteins suggest further multifunctionality in signaling. Here, we have used multidimensional heteronuclear nuclear magnetic resonance spectroscopy to study the conformational dependence on environment of the protein in aqueous solution (100 mM KCl) and in a membrane-mimetic solvent (30% TFE-d(2)), particularly to analyze its secondary structure using chemical shift indexing, and to investigate its backbone dynamics using (15)N spin relaxation measurements. Collectively, the data revealed three major segments of the protein with a propensity toward alpha-helicity that was stabilized by membrane-mimetic conditions: T33-D46, V83-T92, and T142-L154 (murine 18.5 kDa sequence numbering). All of these regions corresponded with bioinformatics predictions of ordered secondary structure. The V83-T92 region comprises a primary immunodominant epitope that had previously been shown by site-directed spin labeling and electron paramagnetic resonance spectroscopy to be alpha-helical in membrane-reconstituted systems. The T142-L154 segment overlapped with a predicted calmodulin-binding site. Chemical shift perturbation experiments using labeled MBP and unlabeled calmodulin demonstrated a dramatic conformational change in MBP upon association of the two proteins, and were consistent with the C-terminal segment of MBP being the primary binding site for calmodulin.


SU-E-T-490: Comparison of XVMC Monte Carlo Dose Calculations with Eclipse AAA Calculations for RapidArc Plans.
The consistency between the AAA and XVMC algorithm in the treatment planning for RapidArc is investigated. While the majority of the radiation field is blocked by the MLC system, multiple small dose islands with MLC opened only slightly can be observed in one control point. This raises questions on how accurate the clinically used AAA algorithm in Eclipse is able to calculate RapidArc dose distributions. The fast Monte Carlo Code XVMC was used as a benchmark to test the AAA algorithm. RadpidArc plans of 25 patients were calculated with AAA and XVMC. The patient cohort consisted of 4 different cancer sites (H&N, upper abdominal, lung, prostate). Dose distributions, PTV and OAR coverage were compared looking at the PTV mean dose Dmean, the volume V95% of the PTV receiving 95% of the prescribed dose, the dose D95% delivered to 95% of the PTV Volume, the percentage PTV mean dose with respect to the prescribed dose Dmean/prescr and OAR mean dose. The recalculation of RapidArc plans yielded good agreement of both calculation algorithms for treatment plans of all four cancer sites. PTV mean dose differences of AAA and XVMC were found to be in between -0.11% and 4.89% of the prescribed dose. The mean dose difference found was 0.48±0.77 Gy. Local dose differences were found when comparing dose distributions in regions of big mass density differences and in high dose regions. One head and neck plan and one prostate plan revealed significant differences in PTV coverage (ΔDmean=3.25 Gy) and OAR mean dose (prostate mean dose -13.71 Gy) respectively. The vast majority of treatment plans calculated with the AAA algorithm were found to agree within the expected and acceptable tolerances compared to XVMC results. Nevertheless in some cases dose differences were observed that could be of clinical significance. This work was funded by a Varian grant. Wolfram Laub is working in the physics group of CMS.


How to use replicate weights in health survey analysis using the National Nutrition and Physical Activity Survey as an example.
To conduct nutrition-related analyses on large-scale health surveys, two aspects of the survey must be incorporated into the analysis: the sampling weights and the sample design; a practice which is not always observed. The present paper compares three analyses: (1) unweighted; (2) weighted but not accounting for the complex sample design; and (3) weighted and accounting for the complex design using replicate weights. Descriptive statistics are computed and a logistic regression investigation of being overweight/obese is conducted using Stata. Cross-sectional health survey with complex sample design where replicate weights are supplied rather than the variables containing sample design information. Responding adults from the National Nutrition and Physical Activity Survey (NNPAS) part of the Australian Health Survey (2011-2013). Unweighted analysis produces biased estimates and incorrect estimates of se. Adjusting for the sampling weights gives unbiased estimates but incorrect se estimates. Incorporating both the sampling weights and the sample design results in unbiased estimates and the correct se estimates. This can affect interpretation; for example, the incorrect estimate of the OR for being a current smoker in the unweighted analysis was 1·20 (95 % CI 1·06, 1·37), t= 2·89, P = 0·004, suggesting a statistically significant relationship with being overweight/obese. When the sampling weights and complex sample design are correctly incorporated, the results are no longer statistically significant: OR = 1·06 (95 % CI 0·89, 1·27), t = 0·71, P = 0·480. Correct incorporation of the sampling weights and sample design is crucial for valid inference from survey data.


Competition between hydrogen bonds and van der Waals forces in intermolecular structure formation of protonated branched-chain alcohol clusters.
To investigate the influence of bulky alkyl groups on hydrogen-bonded (H-bonded) network structures of alcohols, infrared (IR) spectra of protonated clusters of 2-propanol (2-PrOH) and tert-butyl alcohol (t-BuOH) were observed in the OH and CH stretch regions. In addition, by varying the tag species, the temperature dependence profile of the isomer population of H+(t-BuOH)n was revealed. An extensive search for stable isomers was performed using dispersion-corrected density functional theory methods, and temperature-dependent IR spectral simulations were done on the basis of the harmonic superposition approximation. The computational results qualitatively agreed with the observed size and temperature dependence of the H-bonded network structures of these protonated bulky alcohol clusters. However, the difficulty in the quantitative evaluation of dispersion was also demonstrated. It was shown that H+(2-PrOH)n (n = 4-7) have essentially the same network structures as the protonated normal alcohol clusters studied so far. On the other hand, H+(t-BuOH)n (n = 4-8) showed a clear preference for the smaller-membered ring structures, that is very different from the preference of the protonated normal alcohol clusters. The origin of the different structure preferences was discussed in terms of the steric effect and dispersion.


A qualitative and quantitative analysis of the New Zealand media portrayal of Down syndrome.
There are only a small number of studies that systematically explore the tensions between the global shift to universal screening and the media representations of the people with Down syndrome. This paper contributes to the literature by analyzing the New Zealand media coverage of this topic. To describe the content and quality of selected New Zealand media references to Down syndrome in light of the claim by New Zealand support group Saving Downs of state supported eugenics via universal screening. Quantitative content analysis was conducted of 140 relevant New Zealand articles (from 2001 to 2011) and qualitative critical discourse analysis of 18 relevant articles (from 2009 to 2011) selected from television, magazine and newspaper. The content analysis showed no strong directional reporting although the quality of life for people with Down syndrome was represented as slightly negative. Most articles focused on issues of society, government and care rather than genetics. The qualitative analysis identified themes around quality of life, information and bias, preparedness, eugenics, the visualness of disability and the need for public debate around genetic screening and testing. The New Zealand print media coverage of these issues has been relatively balanced. Recent mixed media coverage of the topic is critical, complex and socially inclusive of people with Down syndrome.


Long-term effectiveness of pulmonary rehabilitation in patients with chronic airway obstruction.
The aim of this study was to evaluate the long-term outcome of an outpatient pulmonary rehabilitation programme (PRP) in patients with chronic airway obstruction (CAO). In 61 CAO patients (35 asthmatics and 26 chronic obstructive pulmonary disease (COPD)) lung and respiratory muscle function, exercise tolerance (by symptom limited cycloergometer and walking tests), dyspnoea (Borg scale, visual analogue scale (VAS), baseline and transitional dyspnoea index (BDI and TDI, respectively)) and quality of life (St George's Respiratory Questionnaire (SGRQ)) were assessed at baseline (to), at discharge (t1) and 12 months postdischarge (t2). Preprogramme and post-programme hospital admissions and exacerbations of disease were also recorded. In comparison with baseline, no significant change was observed in lung function tests in either diagnostic group, either at t1 or at t2. In both groups improvements in respiratory muscle strength, exercise tolerance, Borg scale and VAS reported at t1 were partially reduced at t2. Analysis of variance showed that these changes over time were similar in the two groups. Mean values of SGRQ and BDI/TDI improved at t1, and, unlike exercise tolerance, did not worsen at t2. However, a clinically relevant difference in SGRQ between t2 and to was reported only in 56% of asthmatics and 52% of COPD patients. Compared with the preceding 2 yrs, in the year following PRP, hospital admissions and disease exacerbations decreased significantly in both diagnostic groups. Regardless of diagnosis, patients with chronic airway obstruction who underwent an outpatient pulmonary rehabilitation programme maintained an improved quality of life 12 months postdischarge despite a partial loss of the improvement in exercise tolerance.


[Biogeography, origin, and distribution of triatominae domiciliarity in Brazil. Revista de Saúde Pública, 14(3):265-99, 1980].
An association is established between the Brazilian geographical pattern of the domiciliarity of the triatominae bugs and open lands characterized by natural savanna vegetation or artificial, man-made landscapes. The Brazilian open lands involved are the "caatingas'' and "cerrados", both wholly included in Brazilian territory, while the mixed Southern subtropical prairies belong to systems extending bevond national boundary lines. The other open lands are anthropic-lands opened mainly by the destruction of primitive forests of the tropical Atlantic system. Attempts were made to subject the four synanthropic species of epidemiological importance to model paleoecologic refuges and endemic centers. Triatoma sordida, Triatoma brasiliensis, and Triatoma pseudomaculata seem to have their endemic centers in the "cerrados" and "caatinga", while the Panstrongylus megistus may have originated in the tropical Atlantic forest system. The Triatoma infestans, however, seem to have originated in Bolivia, then were spread to large dispersal regions by man. Thus it can be assumed that domiciliarity is arrived at through an opportunistic mechanism stimulated by shelter and food availability factors. Once established, domiciliarity favors the species survival and dispersal, and this is of particular interest to control and surveillance programs because it increases the probability of the triatominae's success in synanthropic specialization. The present intense anthropic activities in the Amazonian system will lead to even greater expansion into the open lands; consequently, a triatominae domiciliarity spread can be expected, due to either autochthonous or man-introduced populations. A public health problem will then arise in a region where it has, heretofore, been unknown.


International migration as a determinant of emergency caesarean.
High caesarean rates are of concern given associated risks. International migrant women (women born abroad) represent a substantial proportion of women giving birth in high-income countries (HICs) and face social conditions that may exacerbate childbearing health risks. Among migrant women, emergency rather than planned caesareans, tend to be more prevalent. This method of delivery can be stressful, physically harmful and result in an overall negative birth experience. Research establishing evidence of risk factors for emergency caesareans in migrants is insufficient. (1) Describe potential pathways (with a focus on modifiable factors) by which migration, using internationally recommended migration indicators: country of birth, length of time in country, fluency in receiving-country language, migration classification and ethnicity, may lead to emergency caesarean; and (2) propose a framework to guide future research for understanding "potentially preventable" emergency caesareans in migrant women living in HICs. "Potentially preventable" emergency caesareans in migrant women are likely due to several modifiable, interrelated factors pre-pregnancy, during pregnancy and during labour. Migration itself is a determinant and also shapes other determinants. Complications and ineffective labour progress and/or foetal distress and ultimately the decision to perform an emergency caesarean may be the result of poor health (i.e., physiological effects), lack of support and disempowerment (i.e., psychological effects) and sub-optimal care. Understanding the direct and indirect effects of migration on emergency caesarean is crucial so that targeted strategies can be developed and implemented for reducing unnecessary caesareans in this vulnerable population.


Insect ryanodine receptors: molecular targets for novel pest control chemicals.
Ryanodine receptors (RyRs) are a distinct class of ligand-gated calcium channels controlling the release of calcium from intracellular stores. They are located on the sarcoplasmic reticulum of muscle and the endoplasmic reticulum of neurons and many other cell types. Ryanodine, a plant alkaloid and an important ligand used to characterize and purify the receptor, has served as a natural botanical insecticide, but attempts to generate synthetic commercial analogues of ryanodine have proved unsuccessful. Recently two classes of synthetic chemicals have emerged resulting in commercial insecticides that target insect RyRs. The phthalic acid diamide class has yielded flubendiamide, the first synthetic ryanodine receptor insecticide to be commercialized. Shortly after the discovery of the phthalic diamides, the anthranilic diamides were discovered. This class has produced the insecticides Rynaxypyr and Cyazypyr. Here we review the structure and functions of insect RyRs and address the modes of action of phthalic acid diamides and anthranilic diamides on insect ryanodine receptors. Particularly intersting is the inherent selectivity both chemical classes exhibit for insect RyRs over their mammalian counterparts. The future prospects for RyRs as a commercially-validated target site for insect control chemicals are also considered.