General and Specific Strategies Used to Facilitate Locomotor Maneuvers.
People make anticipatory changes in gait patterns prior to initiating a rapid change of direction. How they prepare will change based on their knowledge of the maneuver. To investigate specific and general strategies used to facilitate locomotor maneuvers, we manipulated subjects' ability to anticipate the direction of an upcoming lateral "lane-change" maneuver. To examine specific anticipatory adjustments, we observed the four steps immediately preceding a maneuver that subjects were instructed to perform at a known time in a known direction. We hypothesized that to facilitate a specific change of direction, subjects would proactively decrease margin of stability in the future direction of travel. Our results support this hypothesis: subjects significantly decreased lateral margin of stability by 69% on the side ipsilateral to the maneuver during only the step immediately preceding the maneuver. This gait adaptation may have improved energetic efficiency and simplified the control of the maneuver. To examine general anticipatory adjustments, we observed the two steps immediately preceding the instant when subjects received information about the direction of the maneuver. When the maneuver direction was unknown, we hypothesized that subjects would make general anticipatory adjustments that would improve their ability to actively initiate a maneuver in multiple directions. This second hypothesis was partially supported as subjects increased step width and stance phase hip flexion during these anticipatory steps. These modifications may have improved subjects' ability to generate forces in multiple directions and maintain equilibrium during the onset and execution of the rapid maneuver. However, adapting these general anticipatory strategies likely incurred an additional energetic cost.


Analysis of the viewing zone of the Cambridge autostereoscopic display.
The Cambridge autostereoscopic three-dimensional display is a time-multiplexed device that gives both stereo and movement parallax to the viewer without the need for any special glasses. This analysis derives the size and position of the fully illuminated, and hence useful, viewing zone for a Cambridge display. The viewing zone of such a display is shown to be completely determined by four parameters: the width of the screen, the optimal distance of the viewer from the screen, the width over which an image can be seen across the whole screen at this optimal distance, and the number of views. A display's viewing zone can thus be completely described without reference to the internal implementation of the device. An equation that describes what the eye sees from any position in front of the display is derived. The equations derived can be used in both the analysis and design of this type of time-multiplexed autostereoscopic display.


Molecular characterization and functional analysis of outer membrane vesicles from the antarctic bacterium Pseudomonas syringae suggest a possible response to environmental conditions.
Outer membrane vesicles (OMVs) of Gram-negative bacteria form an important aspect of bacterial physiology as they are involved in various functions essential for their survival. The OMVs of the Antarctic bacterium Pseudomonas syringae Lz4W were isolated, and the proteins and lipids they contain were identified. The matrix-assisted laser desorption/ionization time of flight (MALDI-TOF/TOF) analysis revealed that phosphatidylethanolamines and phosphatidylglycerols are the main lipid components. The proteins of these vesicles were identified by separating them by one-dimensional gel electrophoresis and liquid chromatography coupled to electrospray ionization tandem mass spectrometry (ESI-MS/MS). They are composed of outer membrane and periplasmic proteins according to the subcellular localization predictions by Psortb v.3 and Cello V2.5. The functional annotation and gene ontology of these proteins provided hints for various functions attributed to OMVs and suggested a potential mechanism to respond to the extracellular environmental changes. The OMVs were found to protect the producer organism against the membrane active antibiotics colistin and melittin but not from streptomycin. The 1-N-phenylnapthylamine (NPN)-uptake assay revealed that the OMVs protect the bacterium from membrane active antibiotics by scavenging them and also showed that membrane and protein packing of the OMVs was similar to the parent bacterium. The sequestering depends on the composition and organization of lipids and proteins in the OMVs.


A concreteness judgment of words.
To describe the judgement of the concreteness of a set of 162 Brazilian Portuguese words, prior to the elaboration of a speech recognition test, as well as to verify the influence of variables such as the frequency of occurrence of the words and age and undergraduate program year of the participants on the concreteness ratings. Fifty undergraduate Speech-Language Pathology and Audiology students from a public university rated the concreteness of a set of 162 words using a seven-point scale where the lowest concreteness degree was represented by number one and the highest by number seven. Participants were free to choose any number in the scale. The results showed a tri-modal distribution of values, suggesting the classification of three categories, according to the concreteness rating. The low concreteness category ranged from 1.76 to 3.45; the medium concreteness category, from 3.46 to 4.95; and the high concreteness rating, from 4.96 to 6.70. Positive correlation was found between the concreteness rating and the coefficient of variation, whereby the higher the rating attributed to a word, the lesser variation in the responses. No significant correlation was found between concreteness ratings and the frequency of occurrence of words. The influence of age and undergraduate year was significant for some correlations. Results showed three concreteness categories, and suggest that concreteness can be considered an independent attribute of words, since their frequency of occurrence, as well as participants' age and undergraduate program year did not influence the ratings attributed. The words classified in the high concreteness category were subsequently used for the elaboration of a speech recognition test.


Co-existence of two Yersinia ruckeri biotypes and serotype O1a retrieved from rainbow trout (Oncorhynchus mykiss) farmed in Puno, Peru.
Yersinia ruckeri causes important economic losses for rainbow trout (Oncorhynchus mykiss) farms worldwide. This bacterial disease is likely the most common among trout in Peru; however, no commercial vaccine is available nationally, which is, in part, due to a lack of information on the bacterium. The aim of the current study was to characterize 29 Y. ruckeri isolates sampled from seven cage-reared farms in the Puno Region, the focal point for aquaculture activities in Peru. For this, samples were taken from fish with clinical signs (i.e. haemorrhages, uni- or bilateral exophthalmia, hyphaemia and/or melanosis). Notable among our findings was the existence of both Y. ruckeri biotype 1 (9 isolates) and biotype 2 (20 isolates; negative for sorbitol and Tween 80). The isolates further differed in API profiles 5307100 (21 isolates), 1307100 (4 isolates), 1305100 (2 isolates), 1307120 (1 isolate) and 5305100 (1 isolate), with the main differences being in the tests for lysine decarboxylase, gelatine hydrolysis and D-saccharose fermentation. Despite these differences, all isolates shared identical ERIC-PCR and REP-PCR profiles and belonged to the O1a serotype. Fingerprints were identical to the reference strain CECT 955 (serotype O1a). The information obtained will be used for epidemiological purposes by health authorities and for the development of a vaccine against Y. ruckeri, a prominent request made by fish farmers in Peru.


A nation-wide cross-sectional study of variations in homecare nurses' assessments of informational continuity - the importance of horizontal collaboration and municipal context.
Numerous studies have revealed challenges associated with ensuring informational continuity in municipal care services for older adults with comprehensive, prolonged and complex care needs. Most research is qualitative and on the micro-level. The aim of the current study is to map variation in homecare nurses' assessments of available information in the municipalities' documentation system and investigate the extent to which these assessments are associated with perceived quality of collaborations and with municipal context. We used data from a nationwide web-based survey among 1612 nurses working with older adults (65+) in homecare services in Norway. Responses from individual homecare nurses were linked with municipal-level data from the public registers. Data were analysed with descriptive statistics and multilevel regression analyses. Information on the recipients' medications and medical condition was considered most often available (42.8 and 20.0% responding very often/always), whereas information related to psychosocial needs and future follow-up was perceived less available (4.5 and 6.7% responding very often/always). Homecare nurses' perceptions of the quality of collaboration with the GP and the allotment office were independently and positively associated with assessments of informational continuity (ß =0.86 and ß =0.96). A modest share of the total variation (8%) in assessments of informational continuity was at the structural level of municipality. Small municipalities (< 5000 inhabitants) had, on average, better informational continuity compared to larger municipalities (ß = -0.47). Documentation systems have a limited focus on long-term care needs of older care recipients beyond clinical and medical information. There is a potential for enhanced communication- and care-pathways between GPs, the allotment office and nurses in homecare services. This can support the coordinating role of homecare nurses in ensuring informational continuity for older adults with prolonged and complex care needs and help develop the facilitating role of (electronic) documentation systems.


The effect of whole body vibration on balance, mobility and falls in older adults: a systematic review and meta-analysis.
This systematic review aimed to examine the effect of WBV on balance, mobility and falls among older adults. The databases used included MEDLINE, the Excerpta Medica database, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library Databases of Systematic Reviews, Physiotherapy Evidence Database (PEDro), PubMed, and Science Citation Index (last search in October 2011). Randomized controlled trials that investigated the effect of WBV on balance, mobility or falls in older adults were included in this review. The PEDro score was used to examine the methodological quality of the selected studies. The effect of WBV on balance, mobility and fall-related outcomes were extracted. The data extraction and rating were performed by a researcher and the results were confirmed by the principal investigator. Meta-analysis was done if 3 or more studies measured the same outcome of interest. Among 920 articles screened, fifteen articles (thirteen trials) satisfied the criteria and were included in this review. Methodological quality was good for six of the studies (PEDro score=6-7). Meta-analysis revealed that WBV has a significant treatment effect in Tinetti Total Score (p<0.001), Tinetti Body Balance Score (p=0.010) and Timed-Up-and-Go test (p=0.004). No significant improvement was noted in Tinetti Gait Score after WBV training (p=0.120). The effect of WBV on other balance/mobility outcomes and fall rate remains inconclusive. To conclude, WBV may be effective in improving relatively basic balance ability and mobility among older adults, particularly frailer ones. More good-quality WBV trials are required.


Membrane-anchored MucR mediates nitrate-dependent regulation of alginate production in Pseudomonas aeruginosa.
Alginates exhibit unique material properties suitable for medical and industrial applications. However, if produced by Pseudomonas aeruginosa, it is an important virulence factor in infection of cystic fibrosis patients. The alginate biosynthesis machinery is activated by c-di-GMP imparted by the inner membrane protein, MucR. Here, it was shown that MucR impairs alginate production in response to nitrate in P. aeruginosa. Subsequent site-specific mutagenesis of MucR revealed that the second MHYT sensor motif (MHYT II, amino acids 121-124) of MucR sensor domain was involved in nitrate sensing. We also showed that both c-di-GMP synthesizing and degrading active sites of MucR were important for alginate production. Although nitrate and deletion of MucR impaired alginate promoter activity and global c-di-GMP levels, alginate yields were not directly correlated with alginate promoter activity or c-di-GMP levels, suggesting that nitrate and MucR modulate alginate production at a post-translational level through a localized pool of c-di-GMP. Nitrate increased pel promoter activity in the mucR mutant while in the same mutant the psl promoter activity was independent of nitrate. Nitrate and deletion of mucR did not impact on swarming motility but impaired attachment to solid surfaces. Nitrate and deletion of mucR promoted the formation of biofilms with increased thickness, cell density, and survival. Overall, this study provided insight into the functional role of MucR with respect to nitrate-mediated regulation of alginate biosynthesis.


Ebf1 controls early cell differentiation in the embryonic striatum.
Ebf1/Olf-1 belongs to a small multigene family encoding closely related helix-loop-helix transcription factors, which have been proposed to play a role in neuronal differentiation. Here we show that Ebf1 controls cell differentiation in the murine embryonic striatum, where it is the only gene of the family to be expressed. Ebf1 targeted disruption affects postmitotic cells that leave the subventricular zone (SVZ) en route to the mantle: they appear to be unable to downregulate genes normally restricted to the SVZ or to activate some mantle-specific genes. These downstream genes encode a variety of regulatory proteins including transcription factors and proteins involved in retinoid signalling as well as adhesion/guidance molecules. These early defects in the SVZ/mantle transition are followed by an increase in cell death, a dramatic reduction in size of the postnatal striatum and defects in navigation and fasciculation of thalamocortical fibres travelling through the striatum. Our data therefore show that Ebf1 plays an essential role in the acquisition of mantle cell molecular identity in the developing striatum and provide information on the genetic hierarchies that govern neuronal differentiation in the ventral telencephalon.


Design of clinical trials in acute kidney injury: a report from an NIDDK workshop--prevention trials.
AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD. No proven effective pharmacologic therapies are currently available for the prevention or treatment of AKI. Advances in addressing this unmet need will require the development of novel therapeutic agents based on precise understanding of key pathophysiological events and the implementation of well designed clinical trials. To address this need, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored the "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" workshop in December 2010. The event brought together representatives from academia, industry, the National Institutes of Health, and the US Food and Drug Administration. We report the discussions of workgroups that developed outlines of clinical trials for the prevention of AKI in two patient populations: patients undergoing elective surgery who are at risk for or who develop AKI, and patients who are at risk for contrast-induced AKI. In both of these populations, primary prevention or secondary therapy can be delivered at an optimal time relative to kidney injury. The workgroups detailed primary and secondary endpoints for studies in these groups, and explored the use of adaptive clinical trial designs for trials of novel preventive strategies to improve outcomes of patients with AKI.


Piggybacking schistosome invasion: similarities are only skin deep.
Schistosomes cause significant morbidity and mortality. In this article, we discuss recent findings regarding how different schistosome species infect and manipulate immune responses in their hosts through the evolution and use of different protease classes. The advent of transgenic schistosomes is explored in relation to the biology of these important molecules.


Plasmin: a possible physiological modulator of the human platelet adenylate cyclase system.
Plasmin was recently reported to inhibit platelet aggregation. We report here on the interaction of plasmin with the adenylate cyclase system of human platelets. Human plasmin caused a dose- and time-dependent increase in adenylate cyclase activity when added to a crude platelet membrane preparation. Both basal and prostaglandin E1-stimulated adenylate cyclase activity doubled in presence of plasmin. This stimulatory activity was shared by papain and alpha-chymotrypsin, but not by thrombin which displayed a slightly inhibitory effect. Plasmin not only stimulated platelet adenylate cyclase activity, but also suppressed the GTP-dependent alpha 2-adrenergic inhibition, thereby producing a five- to six-fold increased activity measured in the presence of adrenaline and GTP. These effects of plasmin on the adenylate cyclase system were suppressed by the addition of the protease inhibitor leupeptin, and of soybean trypsin inhibitor, indicating that proteolysis mediated these effects. We also examined the adenylate cyclase activity in membranes prepared from intact platelets incubated with increasing doses of plasmin. Incubation of platelets with plasmin concentrations as low as 0.25 mg/ml resulted in an irreversible increase in membrane adenylate cyclase activity and suppression of the adrenaline-mediated inhibition of enzyme activity. These results suggest that the proteolytic stimulating effect of plasmin on the platelet adenylate cyclase system may account for the inhibition of platelet aggregation.


Plasma endothelin in normal and diabetic pregnancy.
To examine endothelin-1 (ET-1) concentrations longitudinally throughout pregnancy in healthy and insulin-dependent diabetic women and to evaluate the relationship between ET-1 and big ET-1 in normal pregnancy. Venous blood samples were obtained consecutively in gestational weeks 18, 28, and 38 from 40 healthy women with uneventful pregnancies and 24 pregnant women with IDDM. By radioimmunoassay, plasma ET-1 and big ET-1 were analyzed in the healthy women and plasma ET-1 in the diabetic women. In the diabetic pregnant women, plasma ET-1 levels were significantly higher than in healthy pregnant women during the entire observation period (P < 0.001), but did not change with advancing gestational age. Five of the diabetic, but none of the healthy pregnant women, developed preeclampsia. ET-1 levels did not differ between the diabetic women who developed preeclampsia and those who did not. Plasma ET-1 levels in healthy pregnant women were within the range of those in healthy nonpregnant women and did not change during pregnancy. The big ET-1 levels increased and the ET-1/big ET-1 ratio decreased significantly during the observation period. Plasma ET-1 levels do not change with advancing gestational length. During normal pregnancy, the ET-1/big ET-1 ratio decrease, indicating a suppressed converting enzyme activity or altered clearance of ET-1. Pregnant women with IDDM have markedly elevated ET-1 levels. Although diabetic women with and without preeclampsia did not differ with respect to endothelial dysfunction, as reflected by elevated ET-1 concentration, we cannot exclude that altered endothelial function may be of importance for the increased frequency of preeclampsia in pregnant IDDM patients.


Effects of ozone and other pollutants on the pulmonary function of adult hikers.
This study evaluated the acute effects of ambient ozone (O3), fine particulate matter (PM2.5), and strong aerosol acidity on the pulmonary function of exercising adults. During the summers of 1991 and 1992, volunteers (18-64 years of age) were solicited from hikers on Mt. Washington, New Hampshire. Volunteer nonsmokers with complete covariates (n = 530) had pulmonary function measured before and after their hikes. We calculated each hiker's posthike percentage change in forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), the ratio of these two (FEV1/FVC), forced expiratory flow between 25 and 75% of FVC(FEF25-75%), and peak expiratory flow rate (PEFR). Average O3 exposures ranged from 21 to 74 ppb. After adjustment for age,sex, smoking status (former versus never), history of asthma or wheeze, hours hiked, ambient temperature, and other covariates, there was a 2.6% decline in FEV1 [95% confidence interval (CI), 0.4-4.7; p = 0.02] and a 2.2% decline in FVC (CI, 0.8-3.5; p =0.003) for each 50 ppb increment in mean O3. There were consistent associations of decrements in both FVC (0.4% decline; CI,0.2-0.6, p = 0.001) and PEFR (0.8% decline; CI, 0.01-1.6; p = 0.05) with PM2.5 and of decrements in PEFR (0.4% decline; CI, 0.1-0.7; p = 0.02) with strong aerosol acidity across the interquartile range of these exposures. Hikers with asthma or a history of wheeze (n = 40) had fourfold greater responsiveness to ozone than others. With prolonged outdoor exercise, low-level exposures to O3, PM2.5, and strong aerosol acidity were associated with significant effects on pulmonary function among adults. Hikers with a history of asthma or wheeze had significantly greater air pollution-related changes in pulmonary function.


Impact of genetic variations in C-C chemokine receptors and ligands on infectious diseases.
Chemokine receptors and ligands are crucial for extensive immune response against infectious diseases such as malaria, leishmaniasis, HIV and tuberculosis and a wide variety of other diseases. Role of chemokines are evidenced in the activation and regulation of immune cell migration which is important for immune response against diseases. Outcome of disease is determined by complex interaction among pathogen, host genetic variability and surrounding milieu. Variation in expression or function of chemokines caused by genetic polymorphisms could be associated with attenuated immune responses. Exploration of chemokine genetic polymorphisms in therapeutic response, gene regulation and disease outcome is important. Infectious agents in human host alter the expression of chemokines via epigenetic alterations and thus contribute to disease pathogenesis. Although some fragmentary data are available on chemokine genetic variations and their contribution in diseases, no unequivocal conclusion has been arrived as yet. We therefore, aim to investigate the association of CCR5-CCL5 and CCR2-CCL2 genetic polymorphisms with different infectious diseases, transcriptional regulation of gene, disease severity and response to therapy. Furthermore, the role of epigenetics in genes related to chemokines and infectious disease are also discussed.


A 3-year physical activity intervention program increases the gain in bone mineral and bone width in prepubertal girls but not boys: the prospective copenhagen school child interventions study (CoSCIS).
The aim of this study was to evaluate the effect of increasing the amount of time spent in physical education classes on bone mineral accrual and gain in bone size in prepubertal Danish children. A total of 135 boys and 108 girls, aged 6-8 years, were included in a school-based curriculum intervention program where the usual time spent in physical education classes was doubled to four classes (180 min) per week. The control group comprised age-matched children (62 boys and 76 girls) recruited from a separate community who completed the usual Danish school curriculum of physical activity (90 min/week). Dual-energy X-ray absorptiometry was used to evaluate bone mineral content (BMC; g), bone mineral density (g/cm(2)), and bone width at the calcaneus and distal forearm before and after 3 years of intervention. Anthropometrics and Tanner stages were evaluated on the same occasions. General physical activity was measured with an accelerometer worn for 4 days. In girls, the intervention group had a 12.5% increase (P = 0.04) in distal forearm BMC and a 13.2% increase (P = 0.005) in distal forearm scanned area compared with girls in the control group. No differences were found between the intervention and control groups in boys. Increasing the frequency of physical education classes for prepubertal children is associated with a higher accrual of bone mineral and higher gain in bone size after 3 years in girls but not in boys.


Psychotic-like experiences and disordered eating in the English general population.
There are no studies on psychotic-like experiences (PLEs) and disordered eating in the general population. We aimed to assess this association in the English adult population. Data from the 2007 Adult Psychiatric Morbidity Survey (APMS) were analyzed. This was a nationally representative survey comprising 7403 English adults aged ≥16 years. The Psychosis Screening Questionnaire was used to identify the past 12-month occurrence of five forms of psychotic symptoms. Questions from the five-item SCOFF screening instrument were used to identify those with eating disorder (ED) symptoms and possible ED in the past year. The prevalence of any PLE was 5.1% (female) and 5.4% (male), while that of possible ED was 9.0% (female) and 3.5% (male). After adjustment for potential confounders, possible ED was associated with hypomania/mania in females (OR=3.23 95%CI=1.002-10.39), strange experiences [females (OR=1.85 95%CI=1.07-3.20) and males (OR=3.54 95%CI=1.65-7.57)], and any PLE in males (OR=3.44 95%CI=1.85-6.39). An interaction analysis revealed that the association was stronger among males for: auditory hallucinations and uncontrolled eating; and any PLE with uncontrolled eating, food dominance, and possible ED. Clinical practitioners should be aware that PLEs and disordered eating behavior often coexist. When one condition is detected, screening for the other may be advisable, especially among males.


Comparative genomics of European avian pathogenic E. Coli (APEC).
Avian pathogenic Escherichia coli (APEC) causes colibacillosis, which results in significant economic losses to the poultry industry worldwide. However, the diversity between isolates remains poorly understood. Here, a total of 272 APEC isolates collected from the United Kingdom (UK), Italy and Germany were characterised using multiplex polymerase chain reactions (PCRs) targeting 22 equally weighted factors covering virulence genes, R-type and phylogroup. Following these analysis, 95 of the selected strains were further analysed using Whole Genome Sequencing (WGS). The most prevalent phylogroups were B2 (47%) and A1 (22%), although there were national differences with Germany presenting group B2 (35.3%), Italy presenting group A1 (53.3%) and UK presenting group B2 (56.1%) as the most prevalent. R-type R1 was the most frequent type (55%) among APEC, but multiple R-types were also frequent (26.8%). Following compilation of all the PCR data which covered a total of 15 virulence genes, it was possible to build a similarity tree using each PCR result unweighted to produce 9 distinct groups. The average number of virulence genes was 6-8 per isolate, but no positive association was found between phylogroup and number or type of virulence genes. A total of 95 isolates representing each of these 9 groupings were genome sequenced and analysed for in silico serotype, Multilocus Sequence Typing (MLST), and antimicrobial resistance (AMR). The UK isolates showed the greatest variability in terms of serotype and MLST compared with German and Italian isolates, whereas the lowest prevalence of AMR was found for German isolates. Similarity trees were compiled using sequencing data and notably single nucleotide polymorphism data generated ten distinct geno-groups. The frequency of geno-groups across Europe comprised 26.3% belonging to Group 8 representing serogroups O2, O4, O18 and MLST types ST95, ST140, ST141, ST428, ST1618 and others, 18.9% belonging to Group 1 (serogroups O78 and MLST types ST23, ST2230), 15.8% belonging to Group 10 (serogroups O8, O45, O91, O125ab and variable MLST types), 14.7% belonging to Group 7 (serogroups O4, O24, O35, O53, O161 and MLST type ST117) and 13.7% belonging to Group 9 (serogroups O1, O16, O181 and others and MLST types ST10, ST48 and others). The other groups (2, 3, 4, 5 and 6) each contained relatively few strains. However, for some of the genogroups (e.g. groups 6 and 7) partial overlap with SNPs grouping and PCR grouping (matching PCR groups 8 (13 isolates on 22) and 1 (14 isolates on 16) were observable). However, it was not possible to obtain a clear correlation between genogroups and unweighted PCR groupings. This may be due to the genome plasticity of E. coli that enables strains to carry the same virulence factors even if the overall genotype is substantially different. The conclusion to be drawn from the lack of correlations is that firstly, APEC are very diverse and secondly, it is not possible to rely on any one or more basic molecular or phenotypic tests to define APEC with clarity, reaffirming the need for whole genome analysis approaches which we describe here. This study highlights the presence of previously unreported serotypes and MLSTs for APEC in Europe. Moreover, it is a first step on a cautious reconsideration of the merits of classical identification criteria such as R typing, phylogrouping and serotyping.


Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women.
Little is known in human immunodeficiency virus (HIV)-positive women about how the combination of plasma HIV RNA level and CD4+ T-cell count is associated with the natural history of human papillomavirus (HPV) infection or about HPV reactivation--whether it occurs and with what frequency in HIV-positive women. HIV-positive (n = 1848) and -negative (n = 514) women were assessed at semiannual visits (total person-years = 5661) for cervicovaginal HPV with polymerase chain reaction assays and for squamous intraepithelial lesions (SILs) by Pap smear. We studied the prevalent detection of HPV and SILs with generalized estimating equations and the incident detection and persistence of HPV and SILs with multivariable Cox models. All statistical tests were two-sided. We observed a strong interaction between the associations of CD4+ and plasma HIV RNA strata with both prevalent (P(interaction) = .002) and incident (P(interaction) = .001) detection of HPV. Indeed, the hazard ratio for incident HPV detection peaked between 4.0 and 5.0, with either a CD4+ count of less than 200 cells per mm3 or an HIV RNA level of more than 100,000 copies per mL. Although incident HPV detection in all women was associated with the number of recent sex partners (P(trend)<.001), 22% of sexually inactive HIV-positive women with a CD4+ count of less than 200 cells/mm3 also had at least one incidentally detected HPV type. The association between CD4+/HIV RNA strata and HPV persistence was statistically significantly smaller (P<.001) than for incident HPV detection. SIL prevalence, incident detection, and persistence had similar associations with CD4+/HIV RNA strata as HPV (above). In HIV-positive women, plasma HIV RNA level and CD4+ count in combination appear to have a strong and statistically interactive association with incident detection of HPV, some of which may reflect HPV reactivation (e.g., in sexually inactive women). The more moderate association between HIV coinfection and HPV persistence could partly explain why cervical cancer rates have not reached more epidemic proportions in HIV-positive women.


Immunoregulatory cytokines and chronic tonsillitis.
The purposes of the present study were to determine the distribution of cells producing cytokines: tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in different morphological sections of tonsils in patients with tonsillar hypertrophy (TH) and recurrent tonsillitis (RT), to analyze the level of production of these cytokines in TH and RT and evaluate the potential of peripheral blood lymphocytes for production of interferon-γ (IFN-γ) and interleukin 4 (IL-4). Analyzed materials consisted of the tonsils after tonsillectomy and blood taken from patients right before tonsillectomy (study group) and blood taken from healthy donors (control group).We used histological and immunohistochemical method, morphometric methods for the quantification of TNF-α and IL- 6 producing cells and immunological methods for determining the concentration of IFN-γ and IL-4. Most of TNF-α producing cells are settled in the subepithelial region (55%). Numerical density of TNF-α producing cells in the crypt epithelium, subepithelial and interfollicular region was significantly higher in RT compared with TH. The concentration of IFN-γ is three times higher in RT then in TH. After the stimulation of peripheral blood lymphocytes in culture there was no significant increase in concentrations of IL- 4. The index of stimulation of IFN-γ was the highest in the RT, and of IL- 4 in TH. The production of Th1-type cytokines (TNF-α and IFN-γ) is higher in RT compared with TH. In both forms of tonsillitis, production of Th1-type cytokines is higher in relation to the production of Th2-type cytokines (IL-6 and IL-4).


Structure and reactivity of hydroxypropylphosphonic acid epoxidase in fosfomycin biosynthesis by a cation- and flavin-dependent mechanism.
The biosynthesis of fosfomycin, an oxirane antibiotic in clinical use, involves a unique epoxidation catalyzed by (S)-2-hydroxypropylphosphonic acid epoxidase (HPPE). The reaction is essentially dehydrogenation of a secondary alcohol. A high-resolution crystallographic analysis reveals that the HPPE subunit displays a two-domain combination. The C-terminal or catalytic domain has the cupin fold that binds a divalent cation, whereas the N-terminal domain carries a helix-turn-helix motif with putative DNA-binding helices positioned 34 A apart. The structure of HPPE serves as a model for numerous proteins, of ill-defined function, predicted to be transcription factors but carrying a cupin domain at the C terminus. Structure-reactivity analyses reveal conformational changes near the catalytic center driven by the presence or absence of ligand, that HPPE is a Zn(2+)/Fe(2+)-dependent epoxidase, proof that flavin mononucleotide is required for catalysis, and allow us to propose a simple mechanism that is compatible with previous experimental data. The participation of the redox inert Zn(2+) in the mechanism is surprising and indicates that Lewis acid properties of the metal ions are sufficient to polarize the substrate and, aided by flavin mononucleotide reduction, facilitate the epoxidation.


OK432-activated human dendritic cells kill tumor cells via CD40/CD40 ligand interactions.
In vivo, dendritic cells (DC) are programmed to orchestrate innate and adaptive immunity in response to pathogen-derived "danger" signals. Under particular circumstances, DC can also be directly cytotoxic against tumor cells, potentially allowing them to release tumor associated Ags from dying cells and then prime antitumor immunity against them. In this study, we describe the innate characteristics of DC (OK-DC) generated in vitro after exposure of immature human myeloid-derived DC to OK432, a penicillin-inactivated and lyophilized preparation of Streptococcus pyrogenes. OK-DC produced proinflammatory cytokines, stimulated autologous T cell proliferation and IFN-gamma secretion, expressed CCR7, and migrated in response to MIP-3beta. Moreover, OK-DC displayed strong, specific cytotoxicity toward tumor cell targets. This cytotoxicity was associated with novel, OK432-induced up-regulation of CD40L on the cell surface of OK-DC, and was absolutely dependent on expression of CD40 on the tumor targets. These data demonstrate that maturation of human DC with OK432, an adjuvant suitable for clinical use, induces direct tumor cell killing by DC, and describes a novel CD40/CD40L-mediated mechanism for specific DC antitumor cytotoxicity.


Optic nerve invasion of uveal melanoma.
The aim of the study was to identify the histopathological characteristics associated with the invasion of the optic nerve of uveal melanoma and to evaluate the association between invasion of the optic nerve and survival. In order to achieve this, all uveal melanomas with optic nerve invasion in Denmark between 1942 and 2001 were reviewed (n=157). Histopathological characteristics and depth of optic nerve invasion were recorded. The material was compared with a control material from the same period consisting of 85 cases randomly drawn from all choroidal/ciliary body melanomas without optic nerve invasion. Prelaminar/laminar optic nerve invasion was in multivariate analysis associated with focal retinal invasion, neovascularization of the chamber angle, and scleral invasion. Postlaminar invasion was further associated with non-spindle cell type and rupture of the inner limiting membrane of the retina. The optic nerve was invaded in four different ways: 1) by tumor extension from the neuroretina through the lamina cribrosa; 2) by direct extension into the optic nerve head between Bruch's membrane and the border tissue of Elschnig; 3) by direct invasion through the border tissue of Elschnig; and 4) in one case a tumor spread along the inner limiting membrane to the optic nerve through the lamina cribrosa. Invasion of the optic nerve had no impact on all-cause mortality or melanoma-related mortality in multivariate analyses. The majority of melanomas invading the optic nerve are large juxtapapillary tumors invading the optic nerve because of simple proximity to the nerve. A neurotropic subtype invades the optic nerve and retina in a diffuse fashion unrelated to tumor size or location.


Abnormal response to negative feedback in depression.
Recent studies have suggested that subjects with depression suffer a diagnosis-specific motivational deficit, characterized by an abnormal response to negative feedback that endures beyond clinical recovery. Furthermore, it has been suggested that negative feedback may motivate non-depressed controls, but not depressed patients, to improve their performance in neuropsychological tests. We describe two studies. The first compared performance on the simultaneous and delayed match to sample (SDMS) task from the CANTAB neuropsychological test battery, in 20 patients with severe depression with 20 with acute schizophrenia, 40 with chronic schizophrenia and 40 healthy controls. The second examined the performance of depressed patients with diurnal variation in symptoms and cognitive function. All patients groups showed impairments on the simultaneous and delayed match to sample task compared to controls. Depressed patients did not show an abnormal response to negative feedback. Controls did not show a motivational effect of negative feedback. Depressed patients with diurnal variation showed no variation in their response to perceived failure. There was no evidence of abnormal response to negative feedback in any patient group using the 'runs test' or of a motivational effect in controls. Conditional probability analysis was not independent of the total number of errors made in the SDMS task. Further studies are suggested to examine whether an abnormal response to negative feedback characterizes particular subgroups of patients suffering from depression.


Negative information: both presence and absence of spatial pattern elements guide rats' spatial choices.
Rats learn the spatial pattern in which hidden caches of food are located. Once the pattern is learned, finding one or more baited locations provides (positive) information about the remaining baited locations. In the present experiment, we examined whether negative information (the absence of food in a location) would also be used in locating the remaining baited locations. Rats were tested in an apparatus containing a matrix of vertical poles, on top of which food could be hidden. At the beginning of the trial, the location of the baited poles was unpredictable, but the poles were always arranged in a linear pattern. The rats learned the pattern and used both positive and negative information in locating baited poles.


Arrhythmia during diagnostic cardiac catheterization in pediatric patients with congenital heart disease.
Diagnostic and interventional cardiac catheterization procedures for congenital heart diseases (CHD) are becoming increasingly more popular, and arrhythmia is a well-known complication. This study was an evaluation of the incidence and causative agents of arrhythmia and the subsequent treatment strategies applied during cardiac catheterization. The catheterization data of all of the patients who underwent diagnostic cardiac catheterization for CHD between January 2012 and 2018 at a single center were examined retrospectively. A total of 1316 children underwent diagnostic cardiac catheterization due to CHD. The median age and body weight was 18 months (6 days-21 years) and 9.9 kg (2.2-135 kg), respectively. Patients with ventricular septal defect (281 patients) and those with tetralogy of Fallot (257 patients) represented 2 major groups of the study population. In 93 (7%) patients, arrhythmia developed during cardiac catheterization. Among them, there were 58 (62%) cases of bradyarrhythmia and 35 (38%) cases of tachyarrhythmia. Arrhythmia was classified as low, high, or major, according to the adverse event severity score; the rates were 2.7%, 4.3%, and 1.2%, respectively. In 36 (39%) patients, there was no need for therapy, whereas 57 (61%) required treatment to eliminate the arrhythmia. Treatment modalities included catheter manipulation in 15, pharmacological therapy in 24, and cardioversion in 3 patients. Eleven patients required cardiopulmonary resuscitation. Temporary pacemaker implantation was required in 2 patients, while 2 others underwent permanent pacemaker implantation secondary to catheterization-related arrhythmia. There were no cases of mortality secondary to catheterization-related arrhythmia. Diagnostic cardiac catheterization in CHD may result in various types of cardiac arrhythmias. The proper management of arrhythmias may reduce morbidity and mortality related to cardiac catheterization.


Ancient Echinostome Eggs Discovered in Archaeological Strata Specimens from a Baekje Capital Ruins of South Korea.
Echinostomiasis is prevalent in southeastern as well as northeastern Asian countries. This endemicity notwithstanding, no echinostome egg has as yet been reported by paleoparasitological studies conducted in Asian countries. Recently we analyzed geological-strata specimens retrieved from the ancient capital city of the Baekje Kingdom to uncover clues to the possible prevalence of echinostomiasis among contemporaneous populations of Korea. By means of archaeoparasitological technique, we found ancient Isthmiophora hortensis eggs in the specimens, thus revealing for the first time that ancient Korean people experienced isthmiophoriasis. Our report can be considered to have effectively broadened the spatial and temporal scope of research on echinostomiasis in human history.


Socioeconomic status in childhood and C reactive protein in adulthood: a systematic review and meta-analysis.
Inflammation plays a central role in cardiometabolic disease and may represent a mechanism linking low socioeconomic status (SES) in early life and adverse cardiometabolic health outcomes in later life. Accumulating evidence suggests an association between childhood SES and adult inflammation, but findings have been inconsistent. We conducted a systematic review and meta-analysis of observational studies to quantify the association between childhood (age <18 years) SES and the inflammatory marker C reactive protein (CRP) in adulthood. Studies were identified in Medline and Embase databases, and by reviewing the bibliographies of articles published from 1946 to December 2015. Study-specific estimates were combined into meta-analyses using random-effects models. 15 of 21 eligible studies (n=43 629) were ultimately included in two separate meta-analyses. Compared with those from the most advantaged families, participants from the least advantaged families had 25% higher CRP levels (ratio change in geometric mean CRP: 1.25; 95% CI 1.19 to 1.32) in minimally adjusted analyses. This finding was attenuated by the inclusion of adult body mass index (BMI) in adjusted models, suggesting BMI has a strong mediating role in CRP levels. We observed an inverse association between childhood SES and adulthood CRP, potentially mediated through BMI. Investigating how childhood SES is associated with childhood BMI and CRP would provide insight into the effective timing of social and clinical interventions to prevent cardiometabolic disease.


A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma.
We have previously reported on the ex vivo generation of cytotoxic effector cells, termed cytokine-induced killer (CIK) cells, that have both in vitro and in vivo antitumor activity in murine models. We now report on our efforts for the large-scale expansion of CIK cells and also present preliminary results from a phase I clinical trial. Nine patients with advanced Hodgkin disease (n = 7) and non-Hodgkin lymphoma (n = 2), all of whom had relapsed after an autologous transplantation, were treated with escalating doses of CIK cells (3 patients at each dose level of 1 x 10(9) , 5 x 10(9) , or 1 x 10(10) cells). The CIK cells were produced by culturing unselected cells from steady-state apheresis products with interferon gamma, OKT3, and interleukin 2. After 21 days in culture, with the addition of fresh media and interleukin 2 every 3 to 4 days, the median culture was 97% viable (range, 61%-100%), 98% CD3 + (range, 66%-99%), 76% CD8 + (range, 27%-96%), 23% CD4 + (range, 6%-78%), 20% CD3 + CD56 + (range, 8%-58%), and <1% CD16 + 56 + (range, 0.2%-7.7%). The CD3 + CD56 + cells have previously been shown to exhibit the most cytotoxic activity. The absolute number of CD3 + CD56 + cells typically expanded 290-fold (range, 3- to 4000-fold) under these culture conditions. In vitro cytotoxic activity was measured against a human B-cell tumor line (OCI-Ly8). At a 40:1 effector-target cell ratio, CIK cells killed 32% (range, 2%-69%) of the target cells. A total of 21 infusions were administered to 9 patients. The number of CIK cells infused ranged from 1.0 x 10(9) to 1.0 x 10(10) per treatment. Toxicity was minimal, and there were no immediate adverse reactions to the infusions. Two patients had partial responses, and 2 patients had stabilization of disease: 1 for more than 18 months. Considering that these were heavily pretreated patients with advanced hematologic malignancies, we believe that CIK cells expanded in this fashion may have utility for the treatment of high-risk patients with evidence of minimal residual disease after autologous transplantation.


Impact of Personality on Cognitive Aging: A Prospective Cohort Study.
The aim of this study was to assess the association between personality factors and age-related longitudinal cognitive performance, and explore interactions of stress-proneness with apolipoprotein E (APOE) ɛ4, a prevalent risk factor for Alzheimer's disease (AD). A total of 510 neuropsychiatrically healthy residents of Maricopa County recruited through media ads (mean age 57.6±10.6 years; 70% women; mean education 15.8±2.4 years; 213 APOE ɛ4 carriers) had neuropsychological testing every 2 years (mean duration follow-up 9.1±4.4 years), and the complete Neuroticism Extraversion Openness Personality Inventory-Revised. Several tests were administered within each of the following cognitive domains: memory, executive skills, language, visuospatial skills, and general cognition. Primary effects on cognitive trajectories and APOE ɛ4 interactions were ascertained with quadratic models. With personality factors treated as continuous variables, Neuroticism was associated with greater decline, and Conscientiousness associated with reduced decline consistently across tests in memory and executive domains. With personality factors trichotomized, the associations of Neuroticism and Conscientiousness were again highly consistent across tests within memory and to a lesser degree executive domains. While age-related memory decline was greater in APOE ɛ4 carriers as a group than ɛ4 noncarriers, verbal memory decline was mitigated in ɛ4 carriers with higher Conscientiousness, and visuospatial perception and memory decline was mitigated in ɛ4 carriers with higher Openness. Neuroticism and Conscientiousness were associated with changes in longitudinal performances on tests sensitive to memory and executive skills. APOE interactions were less consistent. Our findings are consistent with previous studies that have suggested that personality factors, particularly Neuroticism and Conscientiousness are associated with cognitive aging patterns. (JINS, 2016, 22, 765-776).


Myocardial perfusion is a useful screening test for the evaluation of cardiovascular risk in patients undergoing simultaneous pancreas kidney transplantation.
Cardiovascular disease is the leading cause of death in simultaneous pancreas kidney transplantation (SPKT) patients. SPKT is increasingly being undertaken to manage patients with advanced diabetic nephropathy and type 1 diabetes mellitus. Traditionally, invasive angiography has been used as a tool to diagnose significant coronary disease and inform decision making with regard to coronary revascularization prior to transplantation. In our retrospective analysis of 167 consecutive patients who underwent SPKT in our center, we show that using myocardial perfusion scintigraphy (MPS) as the first-line screening tool is highly sensitive without exposing the patient to undue investigative procedural risks (or an unacceptably high false-negative rate) and it provides 1-year cardiovascular outcomes that are comparable with those of patients managed via the more traditional but riskier invasive route.


Evolutionary stability of mutualism: interspecific population regulation as an evolutionarily stable strategy.
Interspecific mutualisms are often vulnerable to instability because low benefit : cost ratios can rapidly lead to extinction or to the conversion of mutualism to parasite-host or predator-prey interactions. We hypothesize that the evolutionary stability of mutualism can depend on how benefits and costs to one mutualist vary with the population density of its partner, and that stability can be maintained if a mutualist can influence demographic rates and regulate the population density of its partner. We test this hypothesis in a model of mutualism with key features of senita cactus (Pachycereus schottii)-senita moth (Upiga virescens) interactions, in which benefits of pollination and costs of larval seed consumption to plant fitness depend on pollinator density. We show that plants can maximize their fitness by allocating resources to the production of excess flowers at the expense of fruit. Fruit abortion resulting from excess flower production reduces pre-adult survival of the pollinating seed-consumer, and maintains its density beneath a threshold that would destabilize the mutualism. Such a strategy of excess flower production and fruit abortion is convergent and evolutionarily stable against invasion by cheater plants that produce few flowers and abort few to no fruit. This novel mechanism of achieving evolutionarily stable mutualism, namely interspecific population regulation, is qualitatively different from other mechanisms invoking partner choice or selective rewards, and may be a general process that helps to preserve mutualistic interactions in nature.


Differential shock transmission response of the human body to impact severity and lower limb posture.
The shocks imparted to the foot during locomotion may lead to joint-degenerative diseases and jeopardize the visual-vestibular functions. The body relies upon several mechanisms and structures that have unique viscoelastic properties for shock attenuation. The purpose of the present study was to determine whether impact severity and initial knee angle (IKA) could alter the shock transmission characteristics of the body. Impacts were administered to the right foot of 38 subjects with a human pendulum device. Combinations of velocities (0.9, 1.05 and 1.2 m s-1) and surfaces (soft and hard foams) served to manipulate impact severity in the first experiment. Three IKA (0, 20 and 40 degrees) were examined in the second experiment. Transmission between shank and head was characterized by measuring the shock at these sites with miniature accelerometers. Velocity and surface had no effect on the frequency profile of shock transmission suggesting a consistent response of the body to impact severity. Shank shock power spectrum features accounted for the lower shock ratio (head/shank) measured under the hard surface condition. IKA flexion caused considerable reduction in effective axial stiffness of the body (EASB), 28.7-7.9 kNm-1, which improved shock attenuation. The high correlation (r = 0.97) between EASB and shock ratio underscored the importance of EASB to shock attenuation. The present findings provide valuable information for the development of strategies aimed at protecting the joints, articular cartilage, spine and head against locomotor shock.


Incidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci.
There is limited evidence on how the risk of breast cancer and its subtypes depend on low-penetrance susceptibility loci, individually or in combination. To analyze breast cancer risk, overall and by tumor subtype, in relation to 14 individual single-nucleotide polymorphisms (SNPs) previously linked to the disease, and in relation to a polygenic risk score. Study of 10,306 women with breast cancer (mean age at diagnosis, 58 years) and 10,393 women without breast cancer who in 2005-2008 provided blood samples for genotyping in a large prospective study of UK women; and meta-analysis of these results and of other published results. Estimated per-allele odds ratio (OR) for individual SNPs, and cumulative incidence of breast cancer to age 70 years in relation to a polygenic risk score based on the 4, 7, or 10 SNPs most strongly associated with risk. Odds ratios for breast cancer were greatest for FGFR2-rs2981582 and TNRC9-rs3803662 and, for these 2 SNPs, were significantly greater for estrogen receptor (ER)-positive than for ER-negative disease, both in our data and in meta-analyses of all published data (pooled per-allele ORs [95% confidence intervals] for ER-positive vs ER-negative disease: 1.30 [1.26-1.33] vs 1.05 [1.01-1.10] for FGFR2; interaction P < .001; and 1.24 [1.21-1.28] vs 1.12 [1.07-1.17] for TNRC9; interaction P < .001). The next strongest association was for 2q-rs13387042, for which the per-allele OR was significantly greater for bilateral than unilateral disease (1.39 [1.21-1.60] vs 1.15 [1.11-1.20]; interaction P = .008) and for lobular than ductal tumors (1.35 [1.23-1.49] vs 1.10 [1.05-1.15]; interaction P < .001). The estimated cumulative incidence (95% confidence interval) of breast cancer to age 70 years among women in the top and bottom fifths of a polygenic risk score based on 7 SNPs was 8.8% (8.3%-9.4%) and 4.4% (4.2%-4.8%), respectively. For ER-positive disease the corresponding risks were 7.4% (6.9%-8.0%) and 3.4% (3.1%-3.8%), respectively; while for ER-negative disease they were 1.4% (1.2%-1.6%) and 1.0% (0.8%-1.2%). The findings did not differ materially according to the number of SNPs included in the polygenic risk model. The polygenic risk score was substantially more predictive of ER-positive than of ER-negative breast cancer, particularly for absolute risk.


Young children's food in Liverpool day-care settings: a qualitative study of pre-school nutrition policy and practice.
To explore nutrition and food provision in pre-school nurseries in order to develop interventions to promote healthy eating in early years settings, especially across deprived communities. An ethnographic approach was used combining participant observation with semi-structured interviews. Research participants were selected purposively using convenience sampling. Community pre-school nurseries. Nursery managers (n 9), cooks (n 6), staff (n 12), parents (n 12) and children at six nurseries (four private and two attached to children's centres) in Liverpool, UK. Private nurseries had minimal access to information and guidelines. Most nurseries did not have a specific healthy eating policy but used menu planning to maintain a focus on healthy eating. No staff had training in healthy eating for children under the age of 5 years. However, enthusiasm and interest were widespread. The level and depth of communication between the nursery and parents was important. Meal times can be an important means of developing social skills and achieving Early Years Foundation Stage competencies. Nurseries are genuinely interested in providing appropriate healthy food for under-5s but require support. This includes: improved mechanisms for effective communication between all government levels as well as with nurseries; and funded training for cooks and managers in menu planning, cost-effective food sourcing and food preparation. Interventions to support healthy eating habits in young children developed at the area level need to be counterbalanced by continued appropriate national-level public health initiatives to address socio-economic differences.


Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group.
- Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. - To provide updated, practical guidelines for the pathologic diagnosis of MM. - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks. - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.


Health crises due to infectious and communicable diseases : European preparedness and response tools in an international context.
The combination of changes in eating habits, ways of living, globalisation, extensive travelling and the migration of millions of people around the world may be contributing to increased health risks. Certainly, health crises today are proving highly complex. More and more people are travelling and may carry with them unexpected virus vectors such as mosquitoes. Preparedness is challenging and there is a need for action plans to safeguard the growing at-risk population. Health crises can potentially affect a large proportion of the population and may lead to a significant increase in mortality or to an abnormally high death rate. This should be integrated into the general concept of national and international surveillance in order to provide a prepared response in the event of crisis. This paper provides an inventory of the relevant laws, guidelines and tools in Europe (and to a lesser degree, beyond), and proposes answers to the health crisis problems associated with infectious and communicable diseases. In crisis management, communication is an important factor to consider. This paper can serve as a tool for people involved in crisis preparedness.


Scattering from a cylindrical reflector: modified theory of physical optics solution.
The problem of scattering from a perfectly conducting cylindrical reflector is examined with the method of the modified theory of physical optics. In this technique the physical optics currents are modified by using a variable unit vector on the scatterer's surface. These current components are obtained for the reflector, which is fed by an offset electric line source. The scattering integral is expressed by using these currents and evaluated asymptotically with the stationary phase method. The results are compared numerically by using physical optics theory, geometrical optics diffraction theory, and the exact solution of the Helmholtz equation. It is found that the modified theory of physical optics scattering field equations agrees with the geometrical optics diffraction theory and the exact solution of the Helmholtz equation.


Prediction of peptides binding to MHC class I and II alleles by temporal motif mining.
MHC (Major Histocompatibility Complex) is a key player in the immune response of most vertebrates. The computational prediction of whether a given antigenic peptide will bind to a specific MHC allele is important in the development of vaccines for emerging pathogens, the creation of possibilities for controlling immune response, and for the applications of immunotherapy. One of the problems that make this computational prediction difficult is the detection of the binding core region in peptides, coupled with the presence of bulges and loops causing variations in the total sequence length. Most machine learning methods require the sequences to be of the same length to successfully discover the binding motifs, ignoring the length variance in both motif mining and prediction steps. In order to overcome this limitation, we propose the use of time-based motif mining methods that work position-independently. The prediction method was tested on a benchmark set of 28 different alleles for MHC class I and 27 different alleles for MHC class II. The obtained results are comparable to the state of the art methods for both MHC classes, surpassing the published results for some alleles. The average prediction AUC values are 0.897 for class I, and 0.858 for class II. Temporal motif mining using partial periodic patterns can capture information about the sequences well enough to predict the binding of the peptides and is comparable to state of the art methods in the literature. Unlike neural networks or matrix based predictors, our proposed method does not depend on peptide length and can work with both short and long fragments. This advantage allows better use of the available training data and the prediction of peptides of uncommon lengths.


Electron transfer in human cytochrome P450 reductase.
Cytochrome P450 reductase (CPR) is a diflavin enzyme responsible for electron donation to mammalian cytochrome P450 enzymes in the endoplasmic reticulum. Dissection of the enzyme into functional domains and studies by site-directed mutagenesis have enabled detailed characterization of the mechanism of electron transfer using stopped-flow and equilibrium-perturbation methods, and redox potentiometry. These studies and the mechanism of electron transfer in CPR are reported herein.


The integration hypothesis of human language evolution and the nature of contemporary languages.
How human language arose is a mystery in the evolution of Homo sapiens. Miyagawa et al. (2013) put forward a proposal, which we will call the Integration Hypothesis of human language evolution, that holds that human language is composed of two components, E for expressive, and L for lexical. Each component has an antecedent in nature: E as found, for example, in birdsong, and L in, for example, the alarm calls of monkeys. E and L integrated uniquely in humans to give rise to language. A challenge to the Integration Hypothesis is that while these non-human systems are finite-state in nature, human language is known to require characterization by a non-finite state grammar. Our claim is that E and L, taken separately, are in fact finite-state; when a grammatical process crosses the boundary between E and L, it gives rise to the non-finite state character of human language. We provide empirical evidence for the Integration Hypothesis by showing that certain processes found in contemporary languages that have been characterized as non-finite state in nature can in fact be shown to be finite-state. We also speculate on how human language actually arose in evolution through the lens of the Integration Hypothesis.


Environmental drivers of coral reef carbonate production and bioerosion: a multi-scale analysis.
The resilience of coral reefs depends on the balance between reef growth and reef breakdown, and their responses to changing environmental conditions. Across the 2500-km Hawaiian Archipelago, we quantified rates of carbonate production, bioerosion, and net accretion at regional, island, site, and within-site spatial scales and tested how these rates respond to environmental conditions across different spatial scales. Overall, there were four major outcomes from this study: (1) bioerosion rates were generally higher in the populated Main Hawaiian Islands (MHI) than the remote, protected Northwestern Hawaiian Islands (NWHI), while carbonate production rates did not vary significantly between the two regions; (2) variability in carbonate production, bioerosion, and net accretion rates was greatest at the smallest within-reef spatial scale; (3) carbonate production and bioerosion rates were associated with distinct sets of environmental parameters; and (4) the strongest correlates of carbonate production, bioerosion, and net accretion rates were different between the MHI region and the NWHI region: in the MHI, the dominant correlates were percent cover of macroalgae and herbivorous fish biomass for carbonate production and bioerosion, respectively, whereas in the NWHI, the top correlates were total alkalinity and benthic cover. This study highlights the need to understand accretion and erosion processes as well as local environmental conditions to predict net coral reef responses to future environmental changes.


First Plant Cell Atlas symposium report.
The Plant Cell Atlas (PCA) community hosted a virtual symposium on December 9 and 10, 2021 on single cell and spatial omics technologies. The conference gathered almost 500 academic, industry, and government leaders to identify the needs and directions of the PCA community and to explore how establishing a data synthesis center would address these needs and accelerate progress. This report details the presentations and discussions focused on the possibility of a data synthesis center for a PCA and the expected impacts of such a center on advancing science and technology globally. Community discussions focused on topics such as data analysis tools and annotation standards; computational expertise and cyber-infrastructure; modes of community organization and engagement; methods for ensuring a broad reach in the PCA community; recruitment, training, and nurturing of new talent; and the overall impact of the PCA initiative. These targeted discussions facilitated dialogue among the participants to gauge whether PCA might be a vehicle for formulating a data synthesis center. The conversations also explored how online tools can be leveraged to help broaden the reach of the PCA (i.e., online contests, virtual networking, and social media stakeholder engagement) and decrease costs of conducting research (e.g., virtual REU opportunities). Major recommendations for the future of the PCA included establishing standards, creating dashboards for easy and intuitive access to data, and engaging with a broad community of stakeholders. The discussions also identified the following as being essential to the PCA's success: identifying homologous cell-type markers and their biocuration, publishing datasets and computational pipelines, utilizing online tools for communication (such as Slack), and user-friendly data visualization and data sharing. In conclusion, the development of a data synthesis center will help the PCA community achieve these goals by providing a centralized repository for existing and new data, a platform for sharing tools, and new analytical approaches through collaborative, multidisciplinary efforts. A data synthesis center will help the PCA reach milestones, such as community-supported data evaluation metrics, accelerating plant research necessary for human and environmental health.


Use of Benefit Enhancement Strategies among 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Users: Associations with Mystical, Challenging, and Enduring Effects.
5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a potent, fast-acting psychedelic. Anecdotal reports from 5-MeO-DMT users suggest that they employ a variety of benefit enhancement (BE) strategies aimed to increase positive effects and decrease any potential challenging effects of the substance, but no empirical study has investigated this claim. We examined the prevalence of BE strategy use using secondary data from a survey of 5-MeO-DMT users (n = 515; Mage = 35.4, SD = 11.7; Male = 79%; White/Caucasian = 86%). Results indicated that BE strategy use was common in this sample. As a secondary aim, we assessed whether the use of BE strategies was associated with acute subjective (i.e., mystical-type, challenging) and persisting effects of 5-MeO-DMT among a subset of respondents who reported using 5-MeO-DMT once in their lifetime (n = 116). Results showed that the use of several BE strategies were associated with significantly more intense mystical-type effects and enduring beliefs about the personal meaning and spiritual significance of their experience, and some BE strategies were associated with less intense or challenging experiences. Data suggests that BE strategies are commonly used, and that the use of BE strategies may be associated with increases in positive mystical-type and enduring effects. The causal influence of BE strategies on acute/persisting effects of 5-MeO-DMT should be examined in longitudinal research.


One and four layer acellular bladder matrix for fascial tissue reconstruction.
To determine whether the use of multiple layers of acellular bladder matrix (ABM) is more suitable for the treatment of abdominal wall hernia than a single layered ABM. The feasibility, biocompatibility and mechanical properties of both materials were assessed and compared. Biocompatibility testing was performed on 4 and 1 layered ABM. The matrices were used to repair an abdominal hernia model in 24 rabbits. The animals were followed for up to 3 months. Immediately after euthanasia, the implant site was inspected and samples were retrieved for histology, scanning electron microscopy and biomechanical studies. Both acellular biomaterials demonstrated excellent biocompatibility. At the time of retrieval, there was no evidence of infection. The matrices demonstrated biomechanical properties comparable to native tissue. Three hernias (25%) were found in the single layer ABM group and only 1 hernia (8%) was found in the 4 layer ABM group. Histologically, the matrix structure was intact and the cell density within the matrices decreased with time. The dominant cell type present within the matrices shifted from lymphocytes to fibroblasts over time. Both ABMs maintained adequate strength over time when used for hernia repair, and there was an extremely low incidence of adhesion formation. The single layer ABM showed enhanced cellular integration, while the 4 layer ABM reduced hernia formation. Either of these matrices may be useful as an off-the-shelf biomaterial for patients requiring fascial repair.


Age at Exposure to Arsenic in Water and Mortality 30-40 Years After Exposure Cessation.
Arsenic in drinking water is known to cause cancer and noncancer diseases, but little is known about its association with age at exposure. Here, we investigated age at arsenic exposure and mortality in Antofagasta, Chile, 30-40 years after a distinct period of very high water arsenic concentrations (1958-1970). We calculated standardized mortality ratios (SMRs) comparing Antofagasta with the rest of Chile for 2001-2010 by sex and age at potential first exposure. A remarkable relationship with age at first exposure was found for bronchiectasis, with increased risk in adults 30-40 years after exposure being confined to those who were in utero (SMR = 11.7, 95% confidence interval (CI): 4.3, 25.4) or aged 1-10 years (SMR = 5.4, 95% CI: 1.1, 15.8) during the high-exposure period. Increased SMRs for lung, bladder, and laryngeal cancer were evident for exposures starting at all ages, but the highest SMRs were for exposures beginning at birth (for bladder cancer, SMR = 16.0 (95% CI: 10.3, 23.8); for laryngeal cancer, SMR = 6.8 (95% CI: 2.2, 15.8); for lung cancer, SMR = 3.8 (95% CI: 2.9, 4.9)). These findings suggest that interventions targeting early-life arsenic exposure could have major impacts in reducing long-term mortality due to arsenic 30-40 years after exposure ends.


Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein-DNA complexes.
Fanconi anemia (FA) is a genetic disease characterized by congenital abnormalities, bone marrow failure, and susceptibility to leukemia and other cancers. FANCJ, one of 13 genes linked to FA, encodes a DNA helicase proposed to operate in homologous recombination repair and replicational stress response. The pathogenic FANCJ-A349P amino acid substitution resides immediately adjacent to a highly conserved cysteine of the iron-sulfur domain. Given the genetic linkage of the FANCJ-A349P allele to FA, we investigated the effect of this particular mutation on the biochemical and cellular functions of the FANCJ protein. Purified recombinant FANCJ-A349P protein had reduced iron and was defective in coupling adenosine triphosphate (ATP) hydrolysis and translocase activity to unwinding forked duplex or G-quadruplex DNA substrates or disrupting protein-DNA complexes. The FANCJ-A349P allele failed to rescue cisplatin or telomestatin sensitivity of a FA-J null cell line as detected by cell survival or γ-H2AX foci formation. Furthermore, expression of FANCJ-A349P in a wild-type background exerted a dominant-negative effect, indicating that the mutant protein interferes with normal DNA metabolism. The ability of FANCJ to use the energy from ATP hydrolysis to produce the force required to unwind DNA or destabilize protein bound to DNA is required for its role in DNA repair.


Comparison of chronic occupational upper extremity versus lumbar disorders for differential disability-related outcomes and predictor variables.
To systematically evaluate if an interdisciplinary functional restoration program (FRP), shown to be a viable treatment option for patients with chronic disabling occupational lumbar disorders, is as effective in treating chronic disabling occupational upper extremity disorders. Participants were 2484 consecutive patients with either arm or lumbar disorders admitted to an FRP. Analyses compared demographic, psychosocial, and work-related factors, and 1-year post-rehabilitation socioeconomic outcomes. Socioeconomic outcomes showed that work-return and work-retention rates after successful completion of the FRP did not differ between the two groups, or among the upper extremity subgroups. FRP is equally effective for patients with chronic upper extremity or lumbar spine disorders, regardless of the injury type, site in the upper extremity, or the disparity in injury-specific and psychosocial factors identified before treatment.


A population-based study of survival among elderly persons diagnosed with colorectal cancer: does race matter if all are insured? (United States).
Racial disparities in colorectal cancer (CRC) outcomes exist. Insurance coverage might impact access to care and thus processes and outcomes of care. We examined the effect of race on CRC outcomes in a population-based study of elderly Tennesseeans who had identical healthcare coverage - simultaneous enrollment in both Medicaid and Medicare. The study cohort consisted of all persons dually enrolled in both Tennessee Medicaid and Medicare who were hospitalized with an incident CRC between 1984 and 1994 and whose medical records were available for review. Information confirming the diagnosis and staging was obtained by review of hospital records. Administrative data from the Tennessee Medicaid database identified important medical co-morbidities and determined which patients received chemotherapy and radiotherapy. We ascertained vital status though 2001 by a search of state and national death certificates using the National Death Index. 697 white patients and 272 black patients were identified with incident CRC. Blacks were slightly less likely to be diagnosed with localized disease than whites (45.2% versus 56.1%, p < 0.01). In a Cox-regression model that controlled for stage and co-morbidities, there was no racial difference in overall mortality (HR for blacks 0.95, 95% CI: 0.81-1.11). Blacks were less likely to have surgery (86% versus 91%, p = 0.02). Chemotherapy (for stage III or greater) or radiation therapy for rectal cancer was not used as frequently as expected in this elderly population. In this population-based study of elderly Tennesseans covered by both Medicaid and Medicare, there were no significant differences in outcomes, raising the possibility that 'equal coverage*rsquo; leads to more equal outcomes.


Computer reminders to implement preventive care guidelines for hospitalized patients.
Hospitalizations are an opportunity to provide preventive care. To determine if computer reminders, which we have shown to be effective in our ambulatory care setting, increasing the provision of inpatient preventive care. Randomized, controlled trial on the general medicine inpatient service of an urban, university-affiliated public hospital. Study subjects were 78 house staff rotating on the 6 general medicine services. The intervention was reminders to physicians printed on daily rounds reports about preventive care for which their patients were eligible, and suggested orders for preventive care provided through the physicians' workstations. The preventive care guidelines were derived from the US Preventive Care Task Force recommendations. Compliance with preventive care guidelines and house staff attitudes toward providing preventive care to hospitalized patients were the main outcome measures. No significant differences were seen between intervention and control physicians in compliance with preventive care guidelines in the aggregate or when individual preventive care actions individual preventive care actions were analyzed. This was true even though most physicians endorsed providing most kinds of preventive care for hospitalized patients. Despite past success in increasing preventive care in the outpatient setting, we were unable, using a moderately intensive intervention, to increase the provision of preventive care during hospitalizations. The physicians providing care during the hospitalization were not the patients' primary care physicians, which proved to be an important barrier. More intensive interventions, or more direct linkages between inpatient and outpatient care providers, may be required to overcome this resistance.


[Comparison of performance of dairy herds that were or were not vaccinated with a bovine herpes virus 1 marker vaccine in 1998].
This study analysed the effects of the use of bovine herpesvirus 1 (BHV1) marker vaccine on the performance of dairy cattle. In Spring of 1999, vaccination of 12 herds with the BHV1 marker vaccine resulted in severe animal health problems and mortality. The vaccines used on these farms were all from a batch that appeared to be contaminated with bovine virus diarrhoea virus type 2. This led to a general call to farmers and veterinary practitioners to report side-effects of this vaccine. As a result, more than 7000 farmers reported symptoms. The information was obtained by means of a questionnaire; there was no control group. To determine the effects of the use of the marker vaccine, it was necessary to perform a study based on objectively acquired information. The information collected by the Royal Dutch Cattle Syndicate and the office of Identification and Registration was complied into herd indices on production, udder health, reproduction, and culling. Two groups of dairy farms that had used the BHV1 marker vaccine (attenuated and inactivated vaccine) were compared with farms that were certified BHV1-free. The analyses were performed based on intra-herd comparisons, meaning that per herd each index calculated over a certain period of time after the use of the marker vaccine was compared to a similar period of time prior to the use of the marker vaccine. A total of 144 comparisons were made. Seven comparisons were statistically significant. In two comparisons, the results were in favour of the BHV1-free farms and in five comparisons, the result were in favour of the vaccinated farms. Thus use of the BHV1 marker vaccine could not be proven to affect herd performance. The sensitivity of the tests was very high, so with a high level of probability even very small differences in indices between groups would have been detected.


A chronic increase of corticosterone age-dependently reduces systemic DNA damage from oxidation in rats.
Stress and depression are associated with an acceleration of brain and bodily aging; effects which have been attributed to chronic elevations of glucocorticoids. We tested the hypothesis that a three week administration of stress-associated levels of corticosterone (CORT, the principal rodent glucocorticoid) would increase systemic and CNS DNA and RNA damage from oxidation; a phenomenon known to be centrally involved in the aging process. We also hypothesized that older individuals would be more sensitive to this effect and that the chronic CORT administration would exacerbate age-related memory decline. Young and old male Sprague-Dawley rats were non-invasively administered CORT by voluntary ingestion of nut paste containing either CORT (25mg/kg) or vehicle for a total of 22 days. CORT increased the 24h urinary excretion of the hormone to the levels previously observed after experimental psychological stress and caused a downregulation of the glucocorticoid receptor in the CA1 area of the hippocampus. Contrary to our hypothesis, 24h excretion of 8-oxodG/8-oxoGuo (markers of DNA/RNA damage from oxidation) was reduced in CORT-treated young animals, whereas old animals showed no significant differences. In old animals, CORT caused a borderline significant reduction of RNA oxidation in CNS, which was paralleled by a normalization of performance in an object location memory test. To our knowledge, this is the first demonstration that chronic stress-associated levels of CORT can reduce nucleic acid damage from oxidation. These findings contradict the notion of elevated CORT as a mediator of the accelerated aging observed in stress and depression.


Maltreatment of Strongyloides infection: case series and worldwide physicians-in-training survey.
Strongyloidiasis infects hundreds of millions of people worldwide and is an important cause of mortality from intestinal helminth infection in developed countries. The persistence of infection, increasing international travel, lack of familiarity by health care providers, and potential for iatrogenic hyperinfection all make strongyloidiasis an important emerging infection. Two studies were performed. A retrospective chart review of Strongyloides stercoralis cases identified through microbiology laboratory records from 1993-2002 was conducted. Subsequently, 363 resident physicians in 15 training programs worldwide were queried with a case scenario of strongyloidiasis, presenting an immigrant with wheezing and eosinophilia. The evaluation focused on resident recognition and diagnostic recommendations. In 151 strongyloidiasis cases, stool ova and parasite sensitivity is poor (51%), and eosinophilia (>5% or >400 cells/microL) commonly present (84%). Diagnosis averaged 56 months (intra-quartile range: 4-72 months) after immigration. Presenting complaints were nonspecific, although 10% presented with wheezing. Hyperinfection occurred in 5 patients prescribed corticosteroids, with 2 deaths. Treatment errors occurred more often among providers unfamiliar with immigrant health (relative risk of error: 8.4; 95% confidence interval, 3.4-21.0; P <.001). When presented with a hypothetical case scenario, US physicians-in-training had poor recognition (9%) of the need for parasite screening and frequently advocated empiric corticosteroids (23%). International trainees had superior recognition at 56% (P <.001). Among US trainees, 41% were unable to choose any parasite causing pulmonary symptoms. Strongyloidiasis is present in US patients. Diagnostic consideration should occur with appropriate exposure, nonspecific symptoms including wheezing, or eosinophilia (>5% relative or >400 eosinophils/microL). US residents' helminth knowledge is limited and places immigrants in iatrogenic danger. Information about Strongyloides should be included in US training and continuing medical education programs.


Nutritional intervention and quality of life in palliative care patients.
Quality of life measures can be used by health professionals to assess effectiveness of nutritional interventions administered to palliative care patients. Stabilizing, maintaining and attempting to increase weight in palliative care patients through the support of oral feeding, and provision of artificial feeding, has been shown to mediate the metabolic and physical wasting effects of the disease process and improve general comfort. A quality of life instrument is a multi-dimensional questionnaire that health professionals can use to measure domains relating to physical, psychological and social aspects of living, and health and disease outcomes. There are three instruments specifically designed to assess quality of life in patients receiving palliative care. These are: The Palliative Care Quality of life Instrument, The Assessment of Quality of Life at the End of Life (AQEL), and The Spitzer Quality of Life Index (SQLI). General use quality of life measures are multifaceted; however, for use with palliative care patients, they have added dimensions of spirituality, existential issues (purpose and meaning of life), family members' perceptions of quality of care, symptom control and family support. Use of quality of life scales provides health professionals and organizations with an ideal measure for planning, targeting and evaluating health interventions.


Quantitative measurement of alpha 6 beta 1 and alpha 6 beta 4 integrin internalization under cross-linking conditions: a possible role for alpha 6 cytoplasmic domains.
In epithelial cells integrins are segregated on discrete domains of the plasma membrane. Redistribution may also occur during migration or differentiation. However, little is known about the mechanisms that control such redistribution. Receptor internalization may be a part of one such mechanism. We developed a quantitative assay and measured internalization of two epithelial integrin heterodimers, alpha 6 beta 1 and alpha 6 beta 4, induced by cross-linking with specific antibodies. alpha 6 beta 1 is a receptor for EHS laminin, while alpha 6 beta 4 is a receptor for a component of the basement membrane. alpha 6 beta 4 plays an important role in the establishment of hemidesmosomes, and becomes redistributed on the epithelial cell surface when cells are in a migratory phase. We report that alpha 6 beta 4 is efficiently internalized in human keratinocytes. More than 25% of cell surface alpha 6 beta 4 was internalized at 30 minutes, after cross-linking with A9, an anti-beta 4 monoclonal antibody. alpha 6 beta 1 is also internalized, in melanoma and teratocarcinoma cells, with maximum values of 20% of total receptors expressed at the cell surface. No significant difference was observed between the alpha 6 isoforms A and B in these assays. To determine whether alpha 6 cytoplasmic domains could influence integrin endocytosis, we prepared chimeric constructs with the extracellular domain of a reporter protein (CD8), and the cytoplasmic domains of either alpha 6 A or alpha 6 B. Both alpha 6 cytoplasmic domains but not a control cytoplasmic domain promoted internalization of the chimeric proteins, after cross-linking with antibody. Internalization of alpha 6 integrins may have a role in redistributing these receptors at the cell surface. Furthermore, the cytoplasmic domains of alpha 6 may be involved in regulating integrin internalization.


Transcriptomic and macroevolutionary evidence for phenotypic uncoupling between frog life history phases.
Anuran amphibians undergo major morphological transitions during development, but the contribution of their markedly different life-history phases to macroevolution has rarely been analysed. Here we generate testable predictions for coupling versus uncoupling of phenotypic evolution of tadpole and adult life-history phases, and for the underlying expression of genes related to morphological feature formation. We test these predictions by combining evidence from gene expression in two distantly related frogs, Xenopus laevis and Mantidactylus betsileanus, with patterns of morphological evolution in the entire radiation of Madagascan mantellid frogs. Genes linked to morphological structure formation are expressed in a highly phase-specific pattern, suggesting uncoupling of phenotypic evolution across life-history phases. This gene expression pattern agrees with uncoupled rates of trait evolution among life-history phases in the mantellids, which we show to have undergone an adaptive radiation. Our results validate a prevalence of uncoupling in the evolution of tadpole and adult phenotypes of frogs.


Intervening to reduce the future burden of occupational cancer in britain: what could work?
In Britain, 14 carcinogenic agents and occupational circumstances currently account for 86% of estimated occupation attributable cancer. The future burden associated with these carcinogens has been forecast, using attributable fractions for forecast scenarios representing patterns of past and predicted future exposure, and exposure levels representing the introduction of new occupational exposure limits, increased levels of compliance with these limits and other reductions in worker exposure. Without intervention, occupational attributable cancers are forecast to remain at more than 10,000 by 2060. With modest intervention over 2,600, or with stricter interventions more than 8,200 cancers could be avoided by 2060 although because of long latency no impact will be seen until at least 10 years after intervention. Effective interventions assessed in this study include reducing workplace exposure limits and improving compliance with these limits. Cancers associated with asbestos, diesel engine exhaust, polycyclic aromatic hydrocarbons, work as a painter, radon, and solar radiation are forecast to continue, with construction remaining the prime industry of concern. Although exposure levels to the established carcinogens are falling, workers are remaining exposed at low levels at which there is still a cancer risk, although the aging population also contributes to rising cancer numbers, These forecasts can be used to assess the relative costs to society of different occupational carcinogenic agents, and the relative merits and savings associated with alternative intervention strategies. The methods are adaptable for different data circumstances, other types of interventions and could be extended to environmental carcinogens and other chronic diseases.


Effect of the Uganda Newborn Study on care-seeking and care practices: a cluster-randomised controlled trial.
Care for women and babies before, during, and after the time of birth is a sensitive measure of the functionality of any health system. Engaging communities in preventing newborn deaths is a promising strategy to achieve further progress in child survival in sub-Saharan Africa. To assess the effect of a home visit strategy combined with health facility strengthening on uptake of newborn care-seeking, practices and services, and to link the results to national policy and scale-up in Uganda. The Uganda Newborn Study (UNEST) was a two-arm cluster-randomised controlled trial in rural eastern Uganda. In intervention villages volunteer community health workers (CHWs) were trained to identify pregnant women and make five home visits (two during pregnancy and three in the first week after birth) to offer preventive and promotive care and counselling, with extra visits for sick and small newborns to assess and refer. Health facility strengthening was done in all facilities to improve quality of care. Primary outcomes were coverage of key essential newborn care behaviours (breastfeeding, thermal care, and cord care). Analyses were by intention to treat. This study is registered as a clinical trial, number ISRCTN50321130. The intervention significantly improved essential newborn care practices, although many interventions saw major increases in both arms over the study period. Immediate breastfeeding after birth and exclusive breastfeeding were significantly higher in the intervention arm compared to the control arm (72.6% vs. 66.0%; p=0.016 and 81.8% vs. 75.9%, p=0.042, respectively). Skin-to-skin care immediately after birth and cord cutting with a clean instrument were marginally higher in the intervention arm versus the control arm (80.7% vs. 72.2%; p=0.071 and 88.1% vs. 84.4%; p=0.023, respectively). Half (49.6%) of the mothers in the intervention arm waited more than 24 hours to bathe the baby, compared to 35.5% in the control arm (p<0.001). Dry umbilical cord care was also significantly higher in intervention areas (63.9% vs. 53.1%, p<0.001). There was no difference in care-seeking for newborn illness, which was high (around 95%) in both arms. Skilled attendance at delivery increased in both the intervention (by 21%) and control arms (by 19%) between baseline and endline, but there was no significant difference in coverage across arms at endline (79.6% vs. 78.9%; p=0.717). Home visits were pro-poor, with more women in the poorest quintile visited by a CHW compared to families in the least poor quintile, and more women who delivered at home visited by a CHW after birth (73.6%) compared to those who delivered in a hospital or health facility (59.7%) (p<0.001). CHWs visited 62.8% of women and newborns in the first week after birth, with 40.2% receiving a visit on the critical first day of life. Consistent with results from other community newborn care studies, volunteer CHWs can be effective in changing long-standing practices around newborn care. The home visit strategy may provide greater benefit to poorer families. However, CHW strategies require strong linkages with and concurrent improvement of quality through health system strengthening, especially in settings with high and increasing demand for facility-based services.


Probing shear-induced rearrangements in Fourier space. I. Dynamic light scattering.
Understanding the microscopic origin of the rheological behavior of soft matter is a long-lasting endeavour. While early efforts concentrated mainly on the relationship between rheology and structure, current research focuses on the role of microscopic dynamics. We present in two companion papers a thorough discussion of how Fourier space-based methods may be coupled to rheology to shed light on the relationship between the microscopic dynamics and the mechanical response of soft systems. In this first companion paper, we report a theoretical, numerical and experimental investigation of dynamic light scattering coupled to rheology. While in ideal solids and simple viscous fluids the displacement field under a shear deformation is purely affine, additional non-affine displacements arise in many situations of great interest, for example in elastically heterogeneous materials or due to plastic rearrangements. We show how affine and non-affine displacements can be separately resolved by dynamic light scattering, and discuss in detail the effect of several non-idealities in typical experiments.