Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group.
The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression.


Economic evaluation of multisystemic therapy for young people at risk for continuing criminal activity in the UK.
To evaluate whether multisystemic therapy (MST) is more cost-effective than statutory interventions that are currently available for young offenders in England. A cost-offset evaluation of MST based on data from a randomised controlled trial conducted in North London, England, comparing MST with usual services provided by two youth offending teams (YOT). Service costs were compared to cost savings in terms of rates of criminal re-offending. 108 adolescents, aged 11-17 years, were randomly allocated to MST+YOT (n = 56) or YOT alone (n = 52). Reductions in offending were evident in both groups, but were higher in the MST+YOT group. At 18-month follow-up, the MST+YOT group cost less in terms of criminal activity (£9,425 versus £11,715, p = 0.456). The MST+YOT group were significantly cheaper in terms of YOT services than the YOT group (£3,402 versus £4,619, p = 0.006), but more expensive including the cost of MST, although not significantly so (£5,687 versus £4,619, p = 0.195). The net benefit per young person for the 18-month follow-up was estimated to be £1,222 (95% CI -£5,838 to £8,283). The results reported in this study support the finding that MST+YOT has scope for cost-savings when compared to YOT alone. However, the limitations of the study in terms of method of economic evaluation, outcome measures used and data quality support the need for further research.


A preliminary study on the association of single nucleotide polymorphisms of interleukin 4 (IL4), IL13, IL4 receptor alpha (IL4Rα) & Toll-like receptor 4 (TLR4) genes with asthma in Indian adults.
Interleukin 4 (IL4) and IL13 genes are believed to be responsible for inflammation of the airways in asthmatics. These share a common receptor component called IL4Rα which is another potentially important candidate gene linked to asthma phenotypes. Another gene Toll-like receptor 4 (TLR4) might affect the incidence or progression of asthma through the expression of proinflammatory genes. Several single nucleotide polymorphisms (SNPs) in IL4, IL13, IL4Rα and TLR4 have been reported to be linked to asthma or related phenotypes in several ethnic populations using linkage studies and association studies. However, the results have not been consistent. We investigated five SNPs (C-589T and C-33T of IL4, G+2044A of IL13, A+1902G of IL4Rα, and A+896G of TLR4) in patients with adult onset asthma to evaluate their role in manifestation and severity of asthma. Adult (>18 yr of age) patients with asthma (n=100) and healthy controls (n=50) were included in the study. Genotyping was performed using sequenom MassARRAY technology. The mutant alleles of the C-589T and C-33T SNPs in the promoter region of IL4 were present in 4 per cent patients with asthma but absent from the control group suggesting that the variations in IL4 may contribute to asthma occurrence. The SNPs of other genes were seen in both controls and patients. The results suggest the possible association between the genetic distribution of C-589T and C-33T SNPs of IL4 with asthma in Indian adults.


The status of immunity against the hepatitis B virus among vaccinated hemodialysis patients: a single center report from Iran.
Patients on maintenance hemodialysis (HD) are very susceptible to infection with the hepatitis B virus (HBV). Repeated contact with factors that aid in transmission of this virus, is conceivably a reason for the high prevalence of HBV infection in patients on HD. Suppressed immunity also probably plays a role. The present study attempts to determine the level of immunity against the HBV among patients on HD at the Urmia University of Medical Sciences, Iran. A total of 141 patients were enrolled in the study and comprised of 76 males and 65 females. Their mean age was 45 years. Data such as the age, gender, blood transfusion(s) received and renal transplantation background, were collected from their medical records in order to identify the risk factors. The hepatitis B surface antibody (HBsAb) levels in the serum was measured in these patients using enzyme-linked immunosorbent assay (ELISA). Based on the levels of HBsAb, the study subjects were classified as non-immune (less than 10 IU/L), which included 56 patients (39.71%); moderately immune (between 10 and 100 IU/L) comprising 65 patients (46.09%) and fully immune (more than 100 IU/L) seen in 20 patients (14.18%). Our results suggest that the current status of vaccination of patients on maintenance HD, against hepatitis B is not satisfactory. Better training should be imparted to the relevant staff members. Also, timely kidney transplantation and avoiding blood transfusions, as far as possible, is recommended.


The Role of Medial Frontal Cortex in Action Anticipation in Professional Badminton Players.
Some studies show that the medial frontal cortex is associated with more skilled action anticipation, while similar findings are not observed in some other studies, possibly due to the stimuli employed and the participants used as the control group. In addition, no studies have investigated whether there is any functional connectivity between the medial frontal cortex and other brain regions in more skilled action anticipation. Therefore, the present study aimed to re-investigate how the medial frontal cortex is involved in more skilled action anticipation by circumventing the limitations of previous research and to investigate that the medial frontal cortex functionally connected with other brain regions involved in action processing in more skilled action anticipation. To this end, professional badminton players and novices were asked to anticipate the landing position of the shuttlecock while watching badminton match videos or to judge the gender of the players in the matches. The video clips ended right at the point that the shuttlecock and the racket came into contact to reduce the effect of information about the trajectory of the shuttlecock. Novices who lacked training and watching experience were recruited for the control group to reduce the effect of sport-related experience on the medial frontal cortex. Blood oxygenation level-dependent activation was assessed by means of functional magnetic resonance imaging. Compared to novices, badminton players exhibited stronger activation in the left medial frontal cortex during action anticipation and greater functional connectivity between left medial frontal cortex and some other brain regions (e.g., right posterior cingulate cortex). Therefore, the present study supports the position that the medial frontal cortex plays a role in more skilled action anticipation and that there is a specific brain network for more skilled action anticipation that involves right posterior cingulate cortex, right fusiform gyrus, right inferior parietal lobule, left insula and particularly, and left medial frontal cortex.


Associations between hyponatraemia, volume depletion and the risk of falls in US hospitalised patients: a case-control study.
We aimed to determine if abnormal laboratory values which may indicate volume depletion are associated with increased odds of experiencing a hospital-acquired fall. Matched case-control study. Four hospitals located in the Southeast USA. Data from 699 adult fallers and 1189 matched controls (non-fallers) were collected via chart review from 2005 to 2010. Controls were matched to cases by nursing unit, time of fall and length of stay. The primary exposures included serum sodium, blood urea nitrogen (BUN), creatinine, BUN/creatinine ratio and haematocrit. Conditional logistic regression with m:n matching was used to determine adjusted and unadjusted ORs. Serum sodium levels were strongly associated with falls. In models controlling for demographic and other fall risk factors, patients with serum sodium levels of 125 mEq/L or less were associated with increased odds of experiencing a fall as compared with those with serum sodium levels of greater than 134 mEq/L (adjusted OR (aOR)=5.08, 95% CI 1.43 to 18.08). Conversely, elevated BUN, creatinine and elevated BUN/creatinine ratios were not associated with increased odds of experiencing a fall (aOR=0.64, 95% CI 0.49 to 0.84; aOR=0.70, 95% CI 0.54 to 0.92 and aOR=0.77, 95% CI 0.58 to 1.04, respectively.) CONCLUSIONS: Laboratory indices that may indicate volume depletion appear to be unrelated to falls. However, hyponatraemia does appear to be a risk factor for falls, and those with serum sodium levels below 126 mEq/L are at especially high risk. It may be that other deficits associated with hyponatraemia, like altered mental status, are associated with risk of experiencing a hospital-acquired fall. These results indicate that abnormal laboratory values, like low sodium, can be useful for identifying hospitalised patients at risk of falling. Therefore, further investigation into abnormal laboratory values as predictors of hospital-acquired falls is warranted.


Nematoda from the terrestrial deep subsurface of South Africa.
Since its discovery over two decades ago, the deep subsurface biosphere has been considered to be the realm of single-cell organisms, extending over three kilometres into the Earth's crust and comprising a significant fraction of the global biosphere. The constraints of temperature, energy, dioxygen and space seemed to preclude the possibility of more-complex, multicellular organisms from surviving at these depths. Here we report species of the phylum Nematoda that have been detected in or recovered from 0.9-3.6-kilometre-deep fracture water in the deep mines of South Africa but have not been detected in the mining water. These subsurface nematodes, including a new species, Halicephalobus mephisto, tolerate high temperature, reproduce asexually and preferentially feed upon subsurface bacteria. Carbon-14 data indicate that the fracture water in which the nematodes reside is 3,000-12,000-year-old palaeometeoric water. Our data suggest that nematodes should be found in other deep hypoxic settings where temperature permits, and that they may control the microbial population density by grazing on fracture surface biofilm patches. Our results expand the known metazoan biosphere and demonstrate that deep ecosystems are more complex than previously accepted. The discovery of multicellular life in the deep subsurface of the Earth also has important implications for the search for subsurface life on other planets in our Solar System.


The architecture of actin filaments and the ultrastructural location of actin-binding protein in the periphery of lung macrophages.
A highly branched filament network is the principal structure in the periphery of detergent-extracted cytoskeletons of macrophages that have been spread on a surface and either freeze or critical point dried, and then rotary shadowed with platinum-carbon. This array of filaments completely fills lamellae extended from the cell and bifurcates to form 0.2-0.5 micron thick layers on the top and bottom of the cell body. Reaction of the macrophage cytoskeletons with anti-actin IgG and with anti-IgG bound to colloidal gold produces dense staining of these filaments, and incubation with myosin subfragment 1 uniformly decorates these filaments, identifying them as actin. 45% of the total cellular actin and approximately 70% of actin-binding protein remains in the detergent-insoluble cell residue. The soluble actin is not filamentous as determined by sedimentation analysis, the DNAase I inhibition assay, and electron microscopy, indicating that the cytoskeleton is not fragmented by detergent extraction. The spacing between the ramifications of the actin network is 94 +/- 47 nm and 118 +/- 72 nm in cytoskeletons prepared for electron microscopy by freeze drying and critical point drying, respectively. Free filament ends are rare, except for a few which project upward from the body of the network or which extend down to the substrate. Filaments of the network intersect predominantly at right angles to form either T-shaped and X-shaped overlaps having striking perpendicularity or else Y-shaped intersections composed of filaments intersecting at 120-130 degrees angles. The actin filament concentration in the lamellae is high, with an average value of 12.5 mg/ml. The concentration was much more uniform in freeze-dried preparations than in critical point-dried specimens, indicating that there is less collapse associated with the freezing technique. The orthogonal actin network of the macrophage cortical cytoplasm resembles actin gels made with actin-binding protein. Reaction of cell cytoskeletons and of an actin gel made with actin-binding protein with anti-actin-binding protein IgG and anti-IgG-coated gold beads resulted in the deposition of clusters of gold at points where filaments intersect and at the ends of filaments that may have been in contact with the membrane before its removal with detergent. In the actin gel made with actin-binding protein, 75% of actin-fiber intersections labeled, and the filament spacing between intersections is consistent with that predicted on theoretical grounds if each added actin-binding protein molecule cross-links two filaments to form an intersection in the gel.(ABSTRACT TRUNCATED AT 400 WORDS)


Changes in subfoveal choroidal thickness and choroidal extravascular density by spectral domain optical coherence tomography after haemodialysis: a pilot study.
To examine the changes in the subfoveal choroidal thickness (SFCT) and choroidal density using spectral domain optical coherence tomography (SD-OCT) before and after haemodialysis (HD). 28 eyes of 19 patients with chronic renal failure (CRF) undergoing HD were included. Ophthalmologic examinations including SD-OCT were performed 1 h before and after HD. The SFCT was measured manually using Image J software, and the relationships between the change in SFCT and in the systemic parameters after HD were evaluated. The changes in choroidal extravascular density of the OCT image after HD were evaluated by comparing brightness value obtained with Adobe Photoshop software. The mean SFCT of all eyes increased significantly from 276.94±58.73 µm to 288.29±65.57 µm (p=0.003). In the univariate generalised estimating equation (GEE), the SFCT increased significantly after HD (p=0.006). After adjusting for age, gender and other significant factors in univariate analysis, the SFCT increased significantly after HD (p=0.032). The decrease in systolic blood pressure (SBP) was associated with the increase in SFCT (p=0.013). The choroidal extravascular density of OCT image increased after HD (p<0.001) and the mean change was 12.35±9.72. In the SD-OCT image, the SFCT became thicker and the choroidal extravascular density increased after HD in patients with CRF. The decrease in SBP after HD was associated with an increase in SFCT. The choroidal autoregulatory control of ocular hemodynamic change and shifting of fluid and molecules between the blood and choroidal interstitium might be involved in the mechanism of these choroidal changes.


[When should consider antiphospholipid syndrome?].
In current practice, the occurrence of thrombosis--venous or arterial--is not rare. Moreover, during the follow-up of pregnancies, gynecologists often have to deal with fetal losses of their patients. Up to which point can these events be considered as "ordinary"? When and on which criteria can we consider an antiphospholipid syndrome? Efforts have been put these last years to better codify the diagnosis of this syndrome, so much on the laboratory side as on the clinical side. With a view to standardize these elements, a first consensus conference took place in 1999 in Sapporo, with an update in 2004 in Sydney, that has recently been published. The goal of these lines is to focus on new elements connected to the actual classification and on the resulting diagnosis elements, with the aim of obtaining a diagnosis of antiphospholipid syndrome in a rigorous way, and to initiate the appropriate treatment in different situations linked to this syndrome.


The role of the addition of ovarian suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or regain menstruation after chemotherapy (ASTRRA): study protocol for a randomized controlled trial and progress.
Ovarian function suppression (OFS) has been shown to be effective as adjuvant endocrine therapy in premenopausal women with hormone receptor-positive breast cancer. However, it is currently unclear if addition of OFS to standard tamoxifen therapy after completion of adjuvant chemotherapy results in a survival benefit. In 2008, the Korean Breast Cancer Society Study Group initiated the ASTRRA randomized phase III trial to evaluate the efficacy of OFS in addition to standard tamoxifen treatment in hormone receptor-positive breast cancer patients who remain or regain premenopausal status after chemotherapy. Premenopausal women with estrogen receptor-positive breast cancer treated with definitive surgery were enrolled after completion of neoadjuvant or adjuvant chemotherapy. Ovarian function was assessed at the time of enrollment and every 6 months for 2 years by follicular-stimulating hormone levels and bleeding history. If ovarian function was confirmed as premenopausal status, the patient was randomized to receive 2 years of goserelin plus 5 years of tamoxifen treatment or 5 years of tamoxifen alone. The primary end point will be the comparison of the 5-year disease-free survival rates between the OFS and tamoxifen alone groups. Patient recruitment was finished on March 2014 with the inclusion of a total of 1483 patients. The interim analysis will be performed at the time of the observation of the 187th event. This study will provide evidence of the benefit of OFS plus tamoxifen compared with tamoxifen only in premenopausal patients with estrogen receptor-positive breast cancer treated with chemotherapy. ClinicalTrials.gov Identifier NCT00912548 . Registered May 31 2009. Korean Breast Cancer Society Study Group Register KBCSG005 . Registered October 26 2009.


Anticancer Activity of Key Lime, Citrus aurantifolia.
Citrus aurantifolia (family: Rutaceae) is mainly used in daily consumption, in many cultural cuisines, and in juice production. It is widely used because of its antibacterial, anticancer, antidiabetic, antifungal, anti-hypertensive, anti-inflammation, anti-lipidemia, and antioxidant properties; moreover, it can protect heart, liver, bone, and prevent urinary diseases. Its secondary metabolites are alkaloids, carotenoids, coumarins, essential oils, flavonoids, phenolic acids, and triterpenoids. The other important constituents are apigenin, hesperetin, kaempferol, limonoids, quercetin, naringenin, nobiletin, and rutin, all of these contribute to its remedial properties. The scientific searching platforms were used for publications from 1990 to present. The abstracts and titles were screened, and the full-text articles were selected. The present review is up-to-date of the phytochemical property of C. aurantifolia to provide a reference for further study.


Through the eyes of the beholder: Simulated eye-movement experience ("SEE") modulates valence bias in response to emotional ambiguity.
Although some facial expressions provide clear information about people's emotions and intentions (happy, angry), others (surprise) are ambiguous because they can signal both positive (e.g., surprise party) and negative outcomes (e.g., witnessing an accident). Without a clarifying context, surprise is interpreted as positive by some and negative by others, and this valence bias is stable across time. When compared to fearful expressions, which are consistently rated as negative, surprise and fear share similar morphological features (e.g., widened eyes) primarily in the upper part of the face. Recently, we demonstrated that the valence bias was associated with a specific pattern of eye movements (positive bias associated with faster fixation to the lower part of the face). In this follow-up, we identified two participants from our previous study who had the most positive and most negative valence bias. We used their eye movements to create a moving window such that new participants viewed faces through the eyes of one our previous participants (subjects saw only the areas of the face that were directly fixated by the original participants in the exact order they were fixated; i.e., Simulated Eye-movement Experience). The input provided by these windows modulated the valence ratings of surprise, but not fear faces. These findings suggest there are meaningful individual differences in how people process faces, and that these differences impact our emotional perceptions. Furthermore, this study is unique in its approach to examining individual differences in emotion by creating a new methodology adapted from those used primarily in the vision/attention domain. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Florida mammographer disability training vs needs.
There is currently no minimum required competency for mammographers regarding imaging patients with physical disabilities. Yet, as disability prevalence rates increase, mammographers interact with more women with disabilities at breast imaging facilities. To better understand the disability training that mammographers receive and desire, and the advice they would extend to colleagues regarding improving the experience when performing mammography on women with disabilities. Within the context of a community and academic partnership, in-depth telephone interviews were conducted with 14 mammographers practicing in north central Florida. Grounded theory techniques facilitated analysis for major themes. The extent, content, and delivery of disability training varied among participants. Analysis revealed respondents' personal desires for training focused on positioning to "get the best breast image," while mammographers' advice to colleagues focused on the need to afford patience and respect to the patient. Four identified themes included learning on the job, asking for help, desired training to acquire the best possible image, and advice to other mammographers regarding patience. Mammographers value the disability training they receive as a foundation for continued learning on the job. Training should comprise both technical and social aspects of performing mammography on women with disabilities, including positioning, disability etiquette, and disability advocacy.


Exome-level comparison of primary well-differentiated neuroendocrine tumors and their cell lines.
Neuroendocrine cancer cell lines are used to investigate therapeutic targets in neuroendocrine tumors (NET) and have been instrumental in the design of clinical trials targeting the PI3K/AKT/mTOR pathways, VEGF inhibitors, and somatostatin analogues. It remains unknown, however, whether the genomic makeup of NET cell lines reflect that of primary NET since comprehensive unbiased genome sequencing has not been performed on the cell lines. Four bronchopulmonary NET (BP-NET)-NCI-H720, NCI-H727, NCI-H835, and UMC11-and two pancreatic neuroendocrine tumors (panNET)-BON-1 and QGP1-were cultured. DNA was isolated, and exome sequencing was done. GATK and EXCAVATOR were used for bioinformatic analysis. We detected a total of 1,764 nonsynonymous single nucleotide variants at a rate of 8 per Mb in BP-NET and 4.3 per Mb in panNET cell lines, including 52 mutated COSMIC cancer genes in these cell lines, such as TP53, BRCA1, RB1, TSC2, NOTCH1, EP300, GNAS, KDR, STK11, and APC but not ATRX, DAXX, nor MEN1. Our data suggest that mutation rate, the pattern of copy number variations, and the mutational spectra in the BP-NET cell lines are more similar to the changes observed in small cell lung cancer than those found in primary BP-NET. Likewise, mutation rate and pattern including the absence of mutations in ATRX/DAXX, MEN1, and YY1 in the panNET cell lines BON1 and QGP1 suggest that these cell lines do not have the genetic signatures of a primary panNET. These results suggest that results from experiments with BP-NET and panNET cell lines need to be interpreted with caution.


Tumor progression of murine epidermal cells after treatment in vitro with 12-O-tetradecanoylphorbol-13-acetate or retinoic acid.
Tumor-promoting or antipromoting agents potentially may act directly on initiated squamous epithelial cells or indirectly through effects on normal keratinocytes or immune cells. The purpose of this study was to examine direct effects by comparing in vitro and in vivo treatment of initiated cell populations with 12-O-tetradecanoylphorbol-13-acetate (TPA) or retinoic acid. Keratinocytes were initiated by treatment in vitro with 7,12-dimethylbenz[alpha]anthracene. Replicate cultures of a cloned initiated cell line were exposed to TPA or retinoic acid with acetone as control. After an equivalent number of population doublings, cultured cell sheets were transplanted as skin grafts to athymic nude mice. Replicate grafts from each in vitro treatment group were then treated with TPA or retinoic acid for 8 months. Promotion was quantified by tumor incidence (graft sites with tumor per total sites) and by tumor growth rate. The findings were as follows: (a) TPA increased tumor incidence whether it was applied in vitro or in vivo; (b) TPA in vitro favored more progressive tumors than TPA in vivo; (c) stages of malignant progression from cloned keratinocytes treated in vitro were histologically identical to those following treatment of skin in vivo, including papilloma, dysplastic invasive papilloma, squamous cell carcinoma, and metastasis to lymph node and lung; (d) retinoic acid treatment in vivo reduced tumor incidence and tumor growth rate in initiated cells previously exposed to TPA but not in cells previously exposed to retinoic acid. The results indicated the following: (a) direct effects of TPA on initiated keratinocyte populations were a significant component of tumor promotion; (b) factors in vivo modified the TPA response toward less progressive growth; and (c) the effect of retinoic acid was modulated by prior treatment history.


Next-Generation Sequencing of Aquatic Oligochaetes: Comparison of Experimental Communities.
Aquatic oligochaetes are a common group of freshwater benthic invertebrates known to be very sensitive to environmental changes and currently used as bioindicators in some countries. However, more extensive application of oligochaetes for assessing the ecological quality of sediments in watercourses and lakes would require overcoming the difficulties related to morphology-based identification of oligochaetes species. This study tested the Next-Generation Sequencing (NGS) of a standard cytochrome c oxydase I (COI) barcode as a tool for the rapid assessment of oligochaete diversity in environmental samples, based on mixed specimen samples. To know the composition of each sample we Sanger sequenced every specimen present in these samples. Our study showed that a large majority of OTUs (Operational Taxonomic Unit) could be detected by NGS analyses. We also observed congruence between the NGS and specimen abundance data for several but not all OTUs. Because the differences in sequence abundance data were consistent across samples, we exploited these variations to empirically design correction factors. We showed that such factors increased the congruence between the values of oligochaetes-based indices inferred from the NGS and the Sanger-sequenced specimen data. The validation of these correction factors by further experimental studies will be needed for the adaptation and use of NGS technology in biomonitoring studies based on oligochaete communities.


Deep learning enabled inorganic material generator.
Recent years have witnessed utilization of modern machine learning approaches for predicting the properties of materials using available datasets. However, to identify potential candidates for material discovery, one has to systematically scan through a large chemical space and subsequently calculate the properties of all such samples. On the other hand, generative methods are capable of efficiently sampling the chemical space and can generate molecules/materials with desired properties. In this study, we report a deep learning based inorganic material generator (DING) framework consisting of a generator module and a predictor module. The generator module is developed based on conditional variational autoencoders (CVAEs) and the predictor module consists of three deep neural networks trained for predicting the enthalpy of formation, volume per atom and energy per atom chosen to demonstrate the proposed method. The predictor and generator modules have been developed using a one-hot key representation of the material composition. A series of tests were done to examine the robustness of the predictor models, to demonstrate the continuity of the latent material space, and its ability to generate materials exhibiting target property values. The DING architecture proposed in this paper can be extended to other properties based on which the chemical space can be efficiently explored for interesting materials/molecules.


How are PCORI-funded researchers engaging patients in research and what are the ethical implications?
Despite growing interest in patient engagement in research, there are few empirical investigations of the nature of engagement and its effects. This information is important, not only to inform practical decisions researchers and funders must make, but also to inform discussion of the ethical implications of engaging patients, which has received little attention to date. The aim of this study was to characterize patient engagement in research funded by the Patient-Centered Outcomes Research Institute (PCORI) as a step toward enhancing current understanding of the nature and effects of engagement and prompting an in-depth consideration of the ethical implications of engaging patients in research. Qualitative interviews were conducted with 19 PCORI-funded principal investigators and with 33 patients engaged in 18 of the same 19 projects. Reasons cited for engaging patients included to enhance relevance and feasibility and to improve dissemination. While engagement occurred at different points during the research, patients were most commonly engaged in reviewing study materials and less commonly engaged at earlier points. Engagement varied by approach, frequency of interaction, and the extent to which patient input changed the research. Impacts of engagement included improving the relevance, feasibility, acceptability, and quality of the research. Our findings on the nature and impacts of engagement have importance not only for practical questions researchers, funders, and patients might raise, but also for several ethical considerations regarding patient engagement related to why patients are engaged, the kinds of patients engaged, when patients are engaged, and how patients are engaged. We discuss our findings in consideration of the main ethical issues they imply, including ethical rationales for engagement, justice-related concerns, and ethical concerns arising from when and how patients are engaged. As efforts to engage patients increase, this discussion provides insights that researchers, funders, and patients may find valuable.


Health related quality of life assessment after radical prostatectomy in men with prostate specific antigen only recurrence.
The health related quality of life assessment is becoming increasingly important among patients with prostate cancer. Meanwhile, treatment of patients with increasing prostate specific antigen (PSA) after radical retropubic prostatectomy remains controversial. We attempt to define the impact of PSA recurrence on the health related quality of life of patients after radical retropubic prostatectomy. Of 604 consecutive patients who underwent radical retropubic prostatectomy between March 1991 and September 1998, 510 (84%) were available for followup. Each patient was mailed the RAND 36-Item Health Survey and University of California, Los Angeles, Prostate Cancer Index questionnaire. A total of 348 (70%) questionnaires were returned. Health related quality of life scores were then compared between patients with and without PSA recurrence. A multivariate analysis was also performed to elucidate further the cause of differences between the groups. Overall, 88 (25%) patients had PSA recurrence. In regard to health related quality of life there were small (less than 10%) but statistically significant differences in 2 of 4 physical health domains (RAND 36-Item Health Survey). There was a significant decrease in only 1 category of the mental health domain for patients with PSA recurrence. Only sexual function was statistically lower on the University of California, Los Angeles, Prostate Cancer Index. This result reflects the lower incidence of nerve sparing in these patients, as confirmed by the multivariate analysis. Overall patient satisfaction was similar between those with and without PSA recurrence (76% and 79%, respectively). Our study demonstrates small health related quality of life differences in patients with biochemical PSA recurrence versus those without. These findings provide a baseline assessment of general and disease specific health related quality of life domains among these patients. Future studies should focus on differences in the measure of cancer anxiety before and after administration of adjuvant therapy in these asymptomatic patients.


Feedback control for noise-aided parallel micromanipulation of several particles using dielectrophoresis.
The paper describes a novel control strategy for simultaneous manipulation of several microscale particles over a planar microelectrode array using dielectrophoresis. The approach is based on a combination of numerical nonlinear optimization, which gives a systematic computational procedure for finding the voltages applied to the individual electrodes, and exploitation of the intrinsic noise, which compensates for the loss of controllability when two identical particles are exposed to identical forces. Although interesting on its own, the proposed functionality can also be seen as a preliminary achievement in a quest for a technique for separation of two particles. The approach is tested experimentally with polystyrene beads (50 microns in diameter) immersed in deionized water on a flat microelectrode array with parallel electrodes. A digital camera and computer vision algorithm are used to measure the positions. Two distinguishing features of the proposed control strategy are that the range of motion is not limited to interelectrode gaps and that independent manipulation of several particles simultaneously is feasible even on a simple microelectrode array.


Laugh or cringe? Common and distinct processes of reward-based schadenfreude and empathy-based fremdscham.
Witnessing others' plights can be funny for observers, but may also trigger one to empathically cringe with the victim of the predicament. In the present study, we examined the common and distinct neural networks involved in schadenfreude (i.e. pleasure derived from another's misfortune) and fremdscham (i.e. empathically sharing the embarrassment about another's misfortune). Using functional magnetic resonance imaging we examined a total of N = 34 participants while they observed social integrity threats of a misfortunate other and either reported on their schadenfreude or fremdscham. In this between-subject design, we found that despite a broad overlap in brain regions involved in social cognition, the left anterior insula (AI) was activated less if observers were asked to focus on their schadenfreude. Further, the nucleus accumben's activity exclusively covaried with the intensity of the schadenfreude experience and had a higher functional connectivity with the left AI in the context of schadenfreude than during fremdscham. With the present findings, we demonstrate that the valence and intensity of interpersonal emotions strongly depend on the experimental context and that empathy and reward circuits are involved in shaping the subjective experience.


CDKN2A/p16 is inactivated in most melanoma cell lines.
The CDKN2A gene maps to chromosome 9p21-22 and is responsible for melanoma susceptibility in some families. Its product, p16, binds specifically to CDK4 and CDK6 in vitro and in vivo, inhibiting their kinase activity. CDKN2A is homozygously deleted or mutated in a large proportion of tumor cell lines and some primary tumors, including melanomas. The aim of this study was to investigate the involvement of CDKN2A and elucidate the mechanisms of p16 inactivation in a panel of 60 cell lines derived from sporadic melanomas. Twenty-six (43%) of the melanoma lines were homozygously deleted for CDKN2A, and an additional 15 (25%) lines carried missense, nonsense, or frameshift mutations. All but one of the latter group were shown by microsatellite analysis to be hemizygous for the region of 9p surrounding CDKN2A. p16 was detected by Western blotting in only five of the cell lines carrying mutations. Immunoprecipitation of p16 in these lines, followed by Western blotting to detect the coprecipitation of CDK4 and CDK6, revealed that p16 was functionally compromised in all cell lines but the one that carried a heterozygous CDKN2A mutation. In the remaining 19 lines that carried wild-type CDKN2A alleles, Western blot analysis and immunoprecipitation indicated that 11 cell lines expressed a wild-type protein. Northern blotting was performed on the remaining eight cell lines and revealed that one cell line carried an aberrantly sized RNA transcript, and two other cell lines failed to express RNA. The promoter was found to be methylated in five cell lines that expressed CDKN2A transcript but not p16. Presumably, the message seen by Northern blotting in these cell lines is the result of cross-hybridization of the total cDNA probe with the exon 1beta transcript. Microsatellite analysis revealed that the majority of these cell lines were hemi/homozygous for the region surrounding CDKN2A, indicating that the wild-type allele had been lost. In the 11 cell lines that expressed functional p16, microsatellite analysis revealed loss of heterozygosity at the markers immediately surrounding CDKN2A in five cases, and the previously characterized R24C mutation of CDK4 was identified in one of the remaining 6 lines. These data indicate that 55 of 60 (92%) melanoma cell lines demonstrated some aberration of CDKN2A or CDK4, thus suggesting that this pathway is a primary genetic target in melanoma development.


Age-structured non-pharmaceutical interventions for optimal control of COVID-19 epidemic.
In an epidemic, individuals can widely differ in the way they spread the infection depending on their age or on the number of days they have been infected for. In the absence of pharmaceutical interventions such as a vaccine or treatment, non-pharmaceutical interventions (e.g. physical or social distancing) are essential to mitigate the pandemic. We develop an original approach to identify the optimal age-stratified control strategy to implement as a function of the time since the onset of the epidemic. This is based on a model with a double continuous structure in terms of host age and time since infection. By applying optimal control theory to this model, we identify a solution that minimizes deaths and costs associated with the implementation of the control strategy itself. We also implement this strategy for three countries with contrasted age distributions (Burkina-Faso, France, and Vietnam). Overall, the optimal strategy varies throughout the epidemic, with a more intense control early on, and depending on host age, with a stronger control for the older population, except in the scenario where the cost associated with the control is low. In the latter scenario, we find strong differences across countries because the control extends to the younger population for France and Vietnam 2 to 3 months after the onset of the epidemic, but not for Burkina Faso. Finally, we show that the optimal control strategy strongly outperforms a constant uniform control exerted over the whole population or over its younger fraction. This improved understanding of the effect of age-based control interventions opens new perspectives for the field, especially for age-based contact tracing.


Risk Factors for Preterm Birth and Low Birth Weight Among Pregnant Indian Women: A Hospital-based Prospective Study.
The present study was undertaken to study the maternal risk factors for preterm birth (PTB) and low birth weight (LBW) with a special emphasis on assessing the proportions of maternal genitourinary and periodontal infections among Indian women and their association with adverse pregnancy outcomes. A hospital-based prospective study comprising 790 pregnant women visiting the obstetrics clinic for a routine antenatal check-up was undertaken. Once recruited, all study participants underwent clinical and microbiological investigations for genitourinary infections followed by a dental check-up for the presence of periodontitis. The study participants were followed up until their delivery to record the pregnancy outcomes. Infectious and non-infectious risk factors for PTB and LBW were assessed using univariate and multivariate Cox regression analysis. Independent risk factors for PTB and LBW were reported in terms of adjusted relative risk (ARR) with the 95% confidence interval (CI). Rates of PTB and LBW in the study population were 7.6% and 11.4%, respectively. Previous preterm delivery (ARR, 5.37; 95% CI, 1.5 to 19.1), periodontitis (ARR, 2.39; 95% CI, 1.1 to 4.9), Oligohydramnios (ARR, 5.23; 95% CI, 2.4 to 11.5), presence of Nugent's intermediate vaginal flora (ARR, 2.75; 95% CI, 1.4 to 5.1), gestational diabetes mellitus (ARR, 2.91; 95% CI, 1.0 to 8.3), and maternal height <1.50 m (ARR, 2.21; 95% CI, 1.1 to 4.1) were risk factors for PTB, while periodontitis (ARR, 3.38; 95% CI, 1.6 to 6.9), gestational hypertension (ARR, 3.70; 95% CI, 1.3 to 10.8), maternal height <1.50 m (ARR, 2.66; 95% CI, 1.3 to 5.1) and genital infection during later stages of pregnancy (ARR, 2.79; 95% CI, 1.2 to 6.1) were independent risk factors for LBW. Our study findings underscore the need to consider screening for potential genitourinary and periodontal infections during routine antenatal care in developing countries.


Developing a student-led health and wellbeing clinic in an underserved community: collaborative learning, health outcomes and cost savings.
The University of New England (UNE), Australia decided to develop innovative placement opportunities for its increasing numbers of nursing students. Extensive community and stakeholder consultation determined that a community centre in rural New South Wales was the welcomed site of the student-led clinic because it fit the goals of the project-to increase access to health care services in an underserved area while providing service learning for students. Supported by a grant from Health Workforce Australia and in partnership with several community organisations, UNE established a student-led clinic in a disadvantaged community using an engaged scholarship approach which joins academic service learning with community based action research. The clinic was managed and run by the students, who were supervised by university staff and worked in collaboration with residents and local health and community services. Local families, many of whom were Indigenous Australians, received increased access to culturally appropriate health services. In the first year, the clinic increased from a one day per week to a three day per week service and offered over 1000 occasions of care and involved 1500 additional community members in health promotion activities. This has led to improved health outcomes for the community and cost savings to the health service estimated to be $430,000. The students learned from members of the community and community members learned from the students, in a collaborative process. Community members benefited from access to drop in help that was self-determined. The model of developing student-led community health and wellbeing clinics in underserved communities not only fulfils the local, State Government, Federal Government and international health reform agenda but it also represents good value for money. It offers free health services in a disadvantaged community, thereby improving overall health and wellbeing. The student-led clinic is an invaluable and sustainable link between students, health care professionals, community based organisations, the university, and the community. The community benefits from the clinic by learning to self-manage health and wellbeing issues. The benefits for students are that they gain practical experience in an interdisciplinary setting and through exposure to a community with unique and severe needs.


Molecular and functional characterization of two isoforms of chalcone synthase and their expression analysis in relation to flavonoid constituents in Grewia asiatica L.
Chalcone synthase constitutes a functionally diverse gene family producing wide range of flavonoids by catalyzing the initial step of the phenylpropanoid pathway. There is a pivotal role of flavonoids in pollen function as they are imperative for pollen maturation and pollen tube growth during sexual reproduction in flowering plants. Here we focused on medicinally important fruit-bearing shrub Grewia asiatica. It is a rich repository of flavonoids. The fruits are highly acclaimed for various putative health benefits. Despite its importance, full commercial exploitation is hampered due to two drawbacks which include short shelf life of its fruits and larger seed volume. To circumvent these constraints, seed abortion is one of the viable options. Molecular interventions tested in a number of economic crops have been to impair male reproductive function by disrupting the chalcone synthase (CHS) gene activity. Against this backdrop the aim of the present study included cloning and characterization of two full-length cDNA clones of GaCHS isoforms from the CHS multigene family. These included GaCHS1 (NCBI acc. KX129910) and GaCHS2 (NCBI acc. KX129911) with an ORF of 1176 and 1170 bp, respectively. GaCHSs were heterologously expressed and purified in E. coli to validate their functionality. Functionality of CHS isoforms was also characterized via enzyme kinetic studies using five different substrates. We observed differential substrate specificities in terms of their Km and Vmax values. Accumulation of flavonoid constituents naringenin and quercetin were also quantified and their relative concentrations corroborated well with the expression levels of GaCHSs. Further, our results demonstrate that GaCHS isoforms show differential expression patterns at different reproductive phenological stages. Transcript levels of GaCHS2 were more than its isoform GaCHS1 at the anthesis stage of flower development pointing towards its probable role in male reproductive maturity.


Uric acid and oxidative stress.
Uric acid is the final product of purine metabolism in humans. The final two reactions of its production catalyzing the conversion of hypoxanthine to xanthine and the latter to uric acid are catalysed by the enzyme xanthine oxidoreductase, which may attain two inter-convertible forms, namely xanthine dehydrogenase or xanthine oxidase. The latter uses molecular oxygen as electron acceptor and generates superoxide anion and other reactive oxygen products. The role of uric acid in conditions associated with oxidative stress is not entirely clear. Evidence mainly based on epidemiological studies suggests that increased serum levels of uric acid are a risk factor for cardiovascular disease where oxidative stress plays an important pathophysiological role. Also, allopurinol, a xanthine oxidoreductase inhibitor that lowers serum levels of uric acid exerts protective effects in situations associated with oxidative stress (e.g. ischaemia-reperfusion injury, cardiovascular disease). However, there is increasing experimental and clinical evidence showing that uric acid has an important role in vivo as an antioxidant. This review presents the current evidence regarding the antioxidant role of uric acid and suggests that it has an important role as an oxidative stress marker and a potential therapeutic role as an antioxidant. Further well designed clinical studies are needed to clarify the potential use of uric acid (or uric acid precursors) in diseases associated with oxidative stress.


Bmp4 and morphological variation of beaks in Darwin's finches.
Darwin's finches are a classic example of species diversification by natural selection. Their impressive variation in beak morphology is associated with the exploitation of a variety of ecological niches, but its developmental basis is unknown. We performed a comparative analysis of expression patterns of various growth factors in species comprising the genus Geospiza. We found that expression of Bmp4 in the mesenchyme of the upper beaks strongly correlated with deep and broad beak morphology. When misexpressed in chicken embryos, Bmp4 caused morphological transformations paralleling the beak morphology of the large ground finch G. magnirostris.


Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells.
Tissue glucocorticoid (GC) levels are regulated by the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme is expressed in cells and tissues arising from mesenchymal stromal cells. Proinflammatory cytokines dramatically increase expression of 11β-HSD1 in stromal cells, an effect that has been implicated in inflammatory arthritis, osteoporosis, obesity, and myopathy. Additionally, GCs act synergistically with proinflammatory cytokines to further increase enzyme expression. The present study was undertaken to investigate the mechanisms underlying this regulation. Gene reporter analysis, rapid amplification of complementary DNA ends (RACE), chemical inhibition experiments, and genetic disruption of intracellular signaling pathways in mouse embryonic fibroblasts (MEFs) were used to define the molecular mechanisms underlying the regulation of 11β-HSD1 expression. Gene reporter, RACE, and chemical inhibitor studies demonstrated that the increase in 11β-HSD1 expression with tumor necrosis factor α (TNFα)/interleukin-1β (IL-1β) occurred via the proximal HSD11B1 gene promoter and depended on NF-κB signaling. These findings were confirmed using MEFs with targeted disruption of NF-κB signaling, in which RelA (p65) deletion prevented TNFα/IL-1β induction of 11β-HSD1. GC treatment did not prevent TNFα-induced NF-κB nuclear translocation. The synergistic enhancement of TNFα-induced 11β-HSD1 expression with GCs was reproduced by specific inhibitors of p38 MAPK. Inhibitor and gene deletion studies indicated that the effects of GCs on p38 MAPK activity occurred primarily through induction of dual-specificity phosphatase 1 expression. The mechanism by which stromal cell expression of 11β-HSD1 is regulated is novel and distinct from that in other tissues. These findings open new opportunities for development of therapeutic interventions aimed at inhibiting or stimulating local GC levels in cells of mesenchymal stromal lineage during inflammation.


The clinical approach to small fibre neuropathy and painful channelopathy.
Small fibre neuropathy (SFN) is characterised by structural injury selectively affecting small diameter sensory and/or autonomic axons. The clinical presentation is dominated by pain. SFN complicates a number of common diseases such as diabetes mellitus and is likely to be increasingly encountered. The diagnosis of SFN is demanding as clinical features can be vague and nerve conduction studies normal. New diagnostic techniques, in particular measurement of intraepidermal nerve fibre density, have significantly improved the diagnostic efficiency of SFN. Management is focused on the treatment of the underlying cause and analgesia, as there is no neuroprotective therapy. A recent and significant advance is the finding that a proportion of cases labelled as idiopathic SFN are in fact associated with gain of function mutations of the voltage-gated sodium channels Nav1.7 and Nav1.8 (encoded by the genes SCN9A and SCN10A, respectively). There is a further group of heritable painful conditions in which gain of function mutations in ion channels alter excitability of sensory neurones but do not cause frank axon degeneration; these include mutations in Nav1.7 (causing erythromelalgia and paroxysmal extreme pain disorder) and TRPA1 (resulting in familial episodic pain disorder). These conditions are exceptionally rare but have provided great insight into the nociceptive system as well as yielding potential analgesic drug targets. In patients with no pre-existing risk factor, the investigation of an underlying cause of SFN should be systematic and appropriate for the patient population. In this review, we focus on how to incorporate recent developments in the diagnosis and pathophysiology of SFN into clinical practice.


In vivo regulation of human skeletal muscle gene expression by thyroid hormone.
Thyroid hormones are key regulators of metabolism that modulate transcription via nuclear receptors. Hyperthyroidism is associated with increased metabolic rate, protein breakdown, and weight loss. Although the molecular actions of thyroid hormones have been studied thoroughly, their pleiotropic effects are mediated by complex changes in expression of an unknown number of target genes. Here, we measured patterns of skeletal muscle gene expression in five healthy men treated for 14 days with 75 microg of triiodothyronine, using 24,000 cDNA element microarrays. To analyze the data, we used a new statistical method that identifies significant changes in expression and estimates the false discovery rate. The 381 up-regulated genes were involved in a wide range of cellular functions including transcriptional control, mRNA maturation, protein turnover, signal transduction, cellular trafficking, and energy metabolism. Only two genes were down-regulated. Most of the genes are novel targets of thyroid hormone. Cluster analysis of triiodothyronine-regulated gene expression among 19 different human tissues or cell lines revealed sets of coregulated genes that serve similar biologic functions. These results define molecular signatures that help to understand the physiology and pathophysiology of thyroid hormone action.


Isolation of an English uukuvirus (family Bunyaviridae).
A virus of the Uukuniemi serogroup was isolated from various organs of a moribund kittiwake (Rissa tridactyla) and from ticks (Ixodes uriae) that were feeding on the bird. The kittiwake was found on Marsden beach, north-east England. This is the first virus in the family Bunyaviridae to have been isolated in England and only the second English arthropod-borne virus after louping ill virus, family Togaviridae (Smith & Varma, 1981). The possibility of infection of humans by uukuviruses is discussed.


Exome sequencing and genetic testing for MODY.
Genetic testing for monogenic diabetes is important for patient care. Given the extensive genetic and clinical heterogeneity of diabetes, exome sequencing might provide additional diagnostic potential when standard Sanger sequencing-based diagnostics is inconclusive. The aim of the study was to examine the performance of exome sequencing for a molecular diagnosis of MODY in patients who have undergone conventional diagnostic sequencing of candidate genes with negative results. We performed exome enrichment followed by high-throughput sequencing in nine patients with suspected MODY. They were Sanger sequencing-negative for mutations in the HNF1A, HNF4A, GCK, HNF1B and INS genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 111 genes implicated in glucose metabolism. On average, we obtained 45 X median coverage of the entire targeted exome and found 199 rare coding variants per individual. We identified 0-4 rare non-synonymous and nonsense variants per individual in our a priori list of 111 candidate genes. Three of the variants were considered pathogenic (in ABCC8, HNF4A and PPARG, respectively), thus exome sequencing led to a genetic diagnosis in at least three of the nine patients. Approximately 91% of known heterozygous SNPs in the target exomes were detected, but we also found low coverage in some key diabetes genes using our current exome sequencing approach. Novel variants in the genes ARAP1, GLIS3, MADD, NOTCH2 and WFS1 need further investigation to reveal their possible role in diabetes. Our results demonstrate that exome sequencing can improve molecular diagnostics of MODY when used as a complement to Sanger sequencing. However, improvements will be needed, especially concerning coverage, before the full potential of exome sequencing can be realized.


Deleterious effect of glucose pretreatment on recovery from diffuse cerebral ischemia in the cat. I. Local cerebral blood flow and glucose utilization.
Diffuse cerebral ischemia was created in pentobarbital-anesthetized cats by basilar and bilateral carotid artery occlusions and hypotension. Local cerebral blood flow (ICBF) was assessed autoradiographically with 14C-antipyrine, and local cerebral glucose utilization with 14C-2-deoxyglucose. In animals without glucose pretreatment, 15 min of ischemia led to a homogeneous reduction of post-ischemic cerebral perfusion to 31% of control; ischemia of 30 min produced post-ischemic perfusion heterogeneities in the cerebral cortex and deep gray structures. In animals pretreated with dextrose, 1.5 gm/kg intravenously, heterogeneous cerebral perfusion was observed following only 15 min of ischemia, and a severe global impairment of cerebral reperfusion occurred after the 30 min insult. Deoxyglucose autoradiograms in the latter animals were remarkable for a complete suppression of tracer uptake in the cerebral cortex and a paradoxically increased tracer concentration in the cerebral white matter. Mean plasma glucose in the treated animals exceeded 1000 mg/100 ml. Large glucose loads prior to ischemia dramatically impair post-ischemic cerebral perfusion.


Absence of Toxemia in Clostridioides difficile Infection: Results from Ultrasensitive Toxin Assay of Serum.
Clostridioides difficile infection (CDI) is caused by Toxins A and B, secreted from pathogenic strains of C. difficle. This infection can vary greatly in symptom severity and in clinical presentation. Current assays used to diagnose CDI may lack the required sensitivity to detect the exotoxins circulating in blood. The ultrasensitive single molecule array (Simoa) assay was modified to separately detect toxin A and toxin B in serum with a limit of detection at the low picogram level. When applied to a diverse cohort, Simoa was unable to detect toxins A or B in serum from patients with CDI, including many classified as having severe disease. The detection of toxin may be limited by the inference of antitoxin antibodies circulating in serum. This result does not support the hypothesis that toxemia occurs in C. difficile infection, conflicting with the findings of other published reports.


Use of point-of-sale data to assess food and nutrient quality in remote stores.
To examine the feasibility of using point-of-sale data to assess dietary quality of food sales in remote stores. A multi-site cross-sectional assessment of food and nutrient composition of food sales. Point-of-sale data were linked to Australian Food and Nutrient Data and compared across study sites and with nutrient requirements. Remote Aboriginal Australia. Six stores. Point-of-sale data were readily available and provided a low-cost, efficient and objective assessment of food and nutrient sales. Similar patterns in macronutrient distribution, food expenditure and key food sources of nutrients were observed across stores. In all stores, beverages, cereal and cereal products, and meat and meat products comprised approximately half of food sales (range 49–57 %). Fruit and vegetable sales comprised 10.4 (SD 1.9) % on average. Carbohydrate contributed 54.4 (SD 3.0) % to energy; protein 13.5 (SD 1.1) %; total sugars 28.9 (SD 4.3) %; and the contribution of total saturated fat to energy ranged from 11.0 to 14.4% across stores. Mg, Ca, K and fibre were limiting nutrients, and Na was four to five times higher than the midpoint of the average intake range. Relatively few foods were major sources of nutrients. Point-of-sale data enabled an assessment of dietary quality within stores and across stores with no burden on communities and at no cost, other than time required for analysis and reporting. Similar food spending patterns and nutrient profiles were observed across the six stores. This suggests potential in using point-of-sale data to monitor and evaluate dietary quality in remote Australian communities.


Egg donation--the donor's view: an aid to future recruitment.
The major stumbling block for egg donation lies in the recruitment of sufficient suitable donors. This study ascertained the views of egg donors in the UK by analysing 113 completed questionnaires that asked questions about demographics, stimulus to donate, support network available, ethics, the 'process' of donation and payment. Ideas for future recruitment were also sought. The mean age of donors was 31.7 years, and most donors were donating for the first time. Ninety-one per cent of donors were Caucasian and 93% had children of their own. Ninety-six (85%) donors felt fully supported in their decision to become an egg donor and 60 (53%) discussed their donation with their GP. Information regarding egg donation came from many sources. The main motivation to donate was a desire to help childless couples. Many respondents had themselves suffered, or knew of couples with, infertility. Eighty-three (73.5%) respondents felt that expenses alone should be paid to egg donors, and many expressed concerns that large financial incentives may attract the 'wrong women' to donate. Forty-nine (43%) respondents found the procedure painful or stressful in some way, although 95% had no regrets concerning their donation, and 72% would donate again. A common reason for donors not wishing to donate again was age restriction. Respondents were asked their opinion with regard to recruitment and the enthusiasm they expressed needs to be harnessed if the current shortcomings in available donors are to be overcome. Specific recommendations to achieve this are made.


Planar waveguide concentrator used with a seasonal tracker.
Solar concentrators offer good promise for reducing the cost of solar power. Planar waveguides equipped with a microlens slab have already been proposed as an excellent approach to produce medium to high concentration levels. Instead, we suggest the use of a cylindrical microlens array to get useful concentration without tracking during the day. To use only a seasonal tracking system and get the highest possible concentration, cylindrical microlenses are placed in the east-west orientation. Our new design has an acceptance angle in the north-south direction of ±9° and ±54° in the east-west axis. Simulation of our optimized system achieves a 4.6× average concentration level from 8:30 to 16:30 with a maximum of 8.1× and 80% optical efficiency. The low-cost advantage of waveguide-based solar concentrators could support their use in roof-mounted solar panels and eliminate the need for an expensive and heavy active tracker.


Whole rolled sunflower seeds with or without additional limestone in lactating dairy cattle rations.
Thirty lactating Holstein cows were in a continuous trial from 21 to 120 days postpartum to evaluate diets containing whole, rolled sunflower seeds with or without additional limestone. Cows were fed individually total mixed rations of (dry matter) 47% corn silage, 9% alfalfa hay, and 44% concentrate. Concentrates were corn and soybean meal (control); corn, soybean meal, and 22% sunflower seeds; or corn, soybean meal, and sunflower seeds plus 3.5% additional limestone. Milk yield (32.2, 32.0, and 32.8 kg/day) was similar among rations. Yield of 4% fat-corrected milk was lower for cows fed sunflower seeds without additional limestone (30.2, 28.1, and 30.2 kg/day) because of lower milk fat percentages (3.57, 3.19, and 3.51). Milk protein percentage tended to be lower for cows fed sunflower seeds with additional limestone (3.01, 2.97, and 2.90). Milk, flavor score was acceptable but tended to be lower for milk from cows fed sunflower seeds with additional limestone (8.4, 8.5, and 7.9). Milk fat from cows fed sunflower seed rations contained less carbon-14:0, 16:0, and 16:1 fatty acids but more carbon-18:0. Dry matter intakes were 21.0, 18.4, and 20.0 kg/day. Dry matter digestibilities, body weight changes, and ruminal volatile fatty acid concentrations were similar among treatments. Total cholesterol in blood serum was elevated in cows fed sunflower seed rations. Insoluble salts of fatty acids were increased in ruminal fluid dry matter from cows fed sunflower seeds but were not increased further by additional limestone. Concentrations of nonesterified carbon-18:1 fatty acids in ruminal fluid dry matter were lower for cows fed sunflower seeds with additional limestone.


Binding Specificity of Two PBPs in the Yellow Peach Moth Conogethes punctiferalis (Guenée).
Pheromone binding proteins (PBPs) play an important role in olfaction of insects by transporting sex pheromones across the sensillum lymph to odorant receptors. To obtain a better understanding of the molecular basis between PBPs and semiochemicals, we have cloned, expressed, and purified two PBPs (CpunPBP2 and CpunPBP5) from the antennae of Conogethes punctiferalis. Fluorescence competitive binding assays were used to investigate binding affinities of CpunPBP2 and CpunPBP5 to sex pheromone and volatiles. Results indicate both CpunPBP2 and CpunPBP5 bind sex pheromones E10-16:Ald, Z10-16:Ald and hexadecanal with higher affinities. In addition, CpunPBP2 and CpunPBP5 also could bind some odorants, such as 1-tetradecanol, trans-caryopyllene, farnesene, and β-farnesene. Homology modeling to predict 3D structure and molecular docking to predict key binding sites were used, to better understand interactions of CpunPBP2 and CpunPBP5 with sex pheromones E10-16:Ald and Z10-16:Ald. According to the results, Phe9, Phe33, Ser53, and Phe115 were key binding sites predicted for CpunPBP2, as were Ser9, Phe12, Val115, and Arg120 for CpunPBP5. Binding affinities of four mutants of CpunPBP2 and four mutants of CpunPBP5 with the two sex pheromones were investigated by fluorescence competitive binding assays. Results indicate that single nucleotides mutation may affect interactions between PBPs and sex pheromones. Expression levels of CpunPBP2 and CpunPBP5 in different tissues were evaluated using qPCR. Results show that CpunPBP2 and CpunPBP5 were largely amplified in the antennae, with low expression levels in other tissues. CpunPBP2 was expressed mainly in male antennae, whereas CpunPBP5 was expressed mainly in female antennae. These results provide new insights into understanding the recognition between PBPs and ligands.


Mechanical properties of model atherosclerotic lesion lipid pools.
Structural analysis of atherosclerotic coronary arteries has suggested that stress concentrations are associated with plaque rupture and that these stress concentrations are critically dependent on the geometry and mechanical properties of the fibrous cap and lipid pool. Recent clinical trials of lipid-lowering therapy have shown a significant reduction in cardiac events associated with plaque rupture perhaps because of the changing composition of subintimal lipid pools. To test the hypothesis that changes in lipid composition can change the mechanical properties of lipid pools, we measured the dynamic shear moduli of combinations of cholesterol monohydrate crystals, phospholipids, and triglycerides similar to those found in atherosclerotic lesions. Increasing the cholesterol monohydrate concentration from 0% to 50% increased the real component of the dynamic shear modulus (storage modulus or stiffness) by 4.5 times at a frequency of 1 Hz (P < .001). All specimens demonstrated an increase in stiffness with increasing frequencies of stress ranging from 0.1 to 3 Hz. We conclude that the stiffness of model atherosclerotic plaque lipid pools is related to the concentration of cholesterol monohydrate crystals. Because the relative concentration of cholesterol monohydrate increases during early regression of experimental atherosclerosis, the resultant stiffening of the lipid pool may reduce stresses in plaque caps. However, the magnitude of the contribution of changing lipid stiffness to the reduction of cardiac events seen in clinical studies is unclear.


18F-FDG PET/CT assessment of histopathologically confirmed mediastinal lymph nodes in non-small cell lung cancer using a penalised likelihood reconstruction.
To investigate whether using a Bayesian penalised likelihood reconstruction (BPL) improves signal-to-background (SBR), signal-to-noise (SNR) and SUVmax when evaluating mediastinal nodal disease in non-small cell lung cancer (NSCLC) compared to ordered subset expectation maximum (OSEM) reconstruction. 18F-FDG PET/CT scans for NSCLC staging in 47 patients (112 nodal stations with histopathological confirmation) were reconstructed using BPL and compared to OSEM. Node and multiple background SUV parameters were analysed semi-quantitatively and visually. Comparing BPL to OSEM, there were significant increases in SUVmax (mean 3.2-4.0, p<0.0001), SBR (mean 2.2-2.6, p<0.0001) and SNR (mean 27.7-40.9, p<0.0001). Mean background SNR on OSEM was 10.4 (range 7.6-14.0), increasing to 12.4 (range 8.2-16.7, p<0.0001). Changes in background SUVs were minimal (largest mean difference 0.17 for liver SUVmean, p<0.001). There was no significant difference between either algorithm on receiver operating characteristic analysis (p=0.26), although on visual analysis, there was an increase in sensitivity and small decrease in specificity and accuracy on BPL. BPL increases SBR, SNR and SUVmax of mediastinal nodes in NSCLC compared to OSEM, but did not improve the accuracy for determining nodal involvement. • Penalised likelihood PET reconstruction was applied for assessing mediastinal nodes in NSCLC. • The new reconstruction generated significant increases in signal-to-background, signal-to-noise and SUVmax. • This led to an improvement in visual sensitivity using the new algorithm. • Higher SUV max thresholds may be appropriate for semi-quantitative analyses with penalised likelihood.


Personalizing Breast Cancer Screening Based on Polygenic Risk and Family History.
We assessed the clinical utility of a first-degree breast cancer family history and polygenic risk score (PRS) to inform screening decisions among women aged 30-50 years. Two established breast cancer models evaluated digital mammography screening strategies in the 1985 US birth cohort by risk groups defined by family history and PRS based on 313 single nucleotide polymorphisms. Strategies varied in initiation age (30, 35, 40, 45, and 50 years) and interval (annual, hybrid, biennial, triennial). The benefits (breast cancer deaths averted, life-years gained) and harms (false-positive mammograms, overdiagnoses) were compared with those seen with 3 established screening guidelines. Women with a breast cancer family history who initiated biennial screening at age 40 years (vs 50 years) had a 36% (model range = 29%-40%) increase in life-years gained and 20% (model range = 16%-24%) more breast cancer deaths averted, but 21% (model range = 17%-23%) more overdiagnoses and 63% (model range = 62%-64%) more false positives. Screening tailored to PRS vs biennial screening from 50 to 74 years had smaller positive effects on life-years gained (20%) and breast cancer deaths averted (11%) but also smaller increases in overdiagnoses (10%) and false positives (26%). Combined use of family history and PRS vs biennial screening from 50 to 74 years had the greatest increase in life-years gained (29%) and breast cancer deaths averted (18%). Our results suggest that breast cancer family history and PRS could guide screening decisions before age 50 years among women at increased risk for breast cancer but expected increases in overdiagnoses and false positives should be expected.


[Psychopathology and social functioning among offspring of depressed women].
Offspring of depressive parents have two times more risk of developing a depression, other psychiatric diseases or a poor social functioning. To assess psychopathology and social functioning among offspring of currently depressed mothers. We enrolled 290 depressed mother-child pairs in five primary-care clinics in Santiago. A two-stage screening process to identify female primary-care patients with current major depressive illness with children aged 6-16 years, was used. AH eligible and consenting patients were asked to complete the general health questionnaire (GHQ-12). Those scoring 5 or more were invited to participate in a baseline assessment. The final sample consisted of 290 mother-child pairs. Patients with a current DSM-IV diagnosis of major depression were eligible unless they had current psychotic symptoms, imminent suicide risk, history of mania, or current alcohol abuse. Child psychopathology was assessed with the Child Behavior Checklist (CBCL), a highly reliable and widely used parent-rated checklist to assess competencies and behavioural and emotional problems in children 4 to 18 years of age. Fifty percent (95% confidence interval (CI): 43.9-55.7) of children had overall CBCL psychopathology scores in clinical range. Internalizing symptoms were more prevalent than externalizing symptoms (62.2% [9596CI: 56.3-67.8] and 35.7% [9596CI: 30.2-41.5]. A large proportion of children of depressed poor mothers attending primary care clinics in Chile, had psychopathological symptom scores in the clinical range, with a predominance of internalizing symptoms. These results are similar to those previously reported in the United States of America.


Values, Quality, and Evaluation in Ethics Consultation.
The American Society for Bioethics and Humanities has recommended regular evaluation of the quality of Health Care Ethics Consultation. This manuscript discusses the impact of ethics consultation on clinicians' perceptions of a patient's plan of care and on the personal values of clinicians who participated in an ethics consultation. Following IRB approval, select data points were abstracted from case file report forms for ethics consultations over a 12 month period. Clinicians involved in the care of a patient who was the focus of an ethics consultation were invited to participate in an anonymous online survey. Clinicians who initiated an ethics consultation, were interviewed during the course of an ethics consultation, or were present at a patient care conference attended by an ethics consultant were invited to participate. A purposive sampling approach was used to invite clinicians to participate in an in-person interview. The survey response rate was 44.4% (123 respondents from 277 invited). Over 60% of participants felt the consultation helped clarify the values of the patient and/or patient's family and helped them clarify their own values. Only 32% of participants indicated the patient's plan of care changed as a result of the ethics consultation, yet 75% indicated their confidence in the plan of care increased as a result of the ethics consultation. Preliminary findings from the qualitative interviews support the overall positive assessments reported by survey respondents. Ethics consultation can help clinicians clarify their own values and helps them clarify the values of patients and patients' families. Ethics consultation offers meaningful support when clinicians face ethically challenging cases, provides an opportunity to address moral distress, and is viewed favorably by those who experience the resource.


Effects of insulin-like growth factor I (IGF-I) therapy on body composition and insulin resistance in IGF-I gene deletion.
We have recently reported a patient with a homozygous partial deletion of the insulin-like growth factor-I (IGF-I) gene, resulting in IGF-I deficiency, insulin resistance, and short stature. Recombinant human IGF-I (rhIGF-I) therapy has been shown to improve insulin sensitivity (Si) and growth in other causes of IGF-I deficiency. We now report results of 1 yr of rhIGF-I therapy on body composition, bone mineral density (BMD), insulin sensitivity, and linear growth in this patient. rhIGF-I therapy was initiated at age 16.07 yr (bone age, 14.2 yr), at a starting dose of 40 microg/kg daily, increasing after 3 months to 80 microg/kg daily. Body composition, BMD, markers of bone mineralization, and auxological parameters (height, weight) were measured at 0, 6, and 12 months after start of therapy. Si, acute insulin response to glucose, and glucose effectiveness were determined at baseline, 3 months, and 12 months into therapy. On IGF-I therapy, body mass index increased from 17 kg/m2 to 18.6 kg/m2. Body composition studies (dual-energy x-ray absorbtiometry) revealed an initial decrease in total body fat, from 19.9% at baseline to 15.1% at 6 months; but by 12 months of therapy, this had reversed, with an increase to 21.8%. Si, calculated using Bergman's minimal model, was substantially reduced at baseline at 1.45 x 10-4 min-1 (microU/mL) [normal value, 5.1 x 10-4 min 1 (lean adult male)]. rhIGF-I therapy resulted in a dose-related improvement of Si into the normal range (NR) (rhIGF-I dose: 40 microg/kg x day, Si = 2.06 x 10-4 min-l; rhIGF-I dose: 80 microg/kg x day, Si = 4.39 x 10-4 min-1). Baseline reduction in Si was accompanied by elevated acute insulin response to glucose, which also fell in a dose-dependent manner. Baseline BMD was severely reduced when compared with age-matched controls (-4.88 SD); however, calculation of bone mineral apparent density indicated that the true reduction in BMD was minimal. rhIGF-I therapy increased BMD by 17% and bone mineral apparent density by 7%, indicating that IGF-I has a greater effect on bone growth than bone mineralization. Bone turnover markers also increased on rhIGF-I; mean serum osteocalcin: 8.3 ng/mL pretreatment, 21.7 ng/mL after 6 months of rhIGF-I (NR for adult male, 3.4-9.1 ng/mL); mean bone specific alkaline phosphatase: 36.5 U/L pretreatment, 82.2 U/L after 6 months of therapy (NR for adult male, 15-41). Height velocity increased from 3.8 cm/yr pretreatment to 7.3 cm/yr on 80 microg/kg.day of rhIGF-I. In this patient with severe insulin resistance, therapy with rhIGF-I resulted in beneficial effects on Si, body composition, bone size, and linear growth. These results have implications for IGF-I therapy in a variety insulin resistant states.


Mechanism of action of an imidopiperidine inhibitor of human polynucleotide kinase/phosphatase.
The small molecule, 2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A12B4C3), is a potent inhibitor of the phosphatase activity of human polynucleotide kinase/phosphatase (PNKP) in vitro. Kinetic analysis revealed that A12B4C3 acts as a noncompetitive inhibitor, and this was confirmed by fluorescence quenching, which showed that the inhibitor can form a ternary complex with PNKP and a DNA substrate, i.e. A12B4C3 does not prevent DNA from binding to the phosphatase DNA binding site. Conformational analysis using circular dichroism, UV difference spectroscopy, and fluorescence resonance energy transfer all indicate that A12B4C3 disrupts the secondary structure of PNKP. Investigation of the potential site of binding of A12B4C3 to PNKP using site-directed mutagenesis pointed to interaction between Trp(402) of PNKP and the inhibitor. Cellular studies revealed that A12B4C3 sensitizes A549 human lung cancer cells to the topoisomerase I poison, camptothecin, but not the topoisomerase II poison, etoposide, in a manner similar to small interfering RNA against PNKP. A12B4C3 also inhibits the repair of DNA single and double strand breaks following exposure of cells to ionizing radiation, but does not inhibit two other key strand-break repair enzymes, DNA polymerase beta or DNA ligase III, providing additional evidence that PNKP is the cellular target of the inhibitor.


Confirmation and extension of association of blood lead with attention-deficit/hyperactivity disorder (ADHD) and ADHD symptom domains at population-typical exposure levels.
Recent studies have suggested that child attention-deficit/hyperactivity disorder (ADHD) and its symptom domains are related to blood lead level, even at background exposure levels typical in western countries. However, recent studies disagreed as to whether lead was related to inattention or hyperactivity-impulsivity within the ADHD domain. More definitive evaluation of these questions was sought. Two hundred and thirty-six (236) children aged 6-17 years participated (61 ADHD-Combined type, 47 ADHD Predominantly Inattentive type, 99 non-ADHD control, 29 unclassified borderline, situational, or not otherwise specified (NOS) cases). Formal diagnosis was reliably established by a best estimate procedure based on a semi-structured clinical interview and parent and teacher ratings. Lead was assayed from whole blood using inductively coupled plasma mass spectrometry with a method detection limit of .3 microg/dL. Blood lead levels were slightly below United States and Western Europe population exposure averages, with a mean of .73 and a maximum of 2.2 microg/dL. This is the lowest level of blood lead ever studied in relation to ADHD. After statistical control for covariates including IQ and prenatal smoking exposure, blood lead was associated with ADHD-combined type but not inattentive type. Parent and teacher report indicated association of blood lead with Conners cognitive problems, but only teacher report showed effects on DSM-IV inattention symptoms. Blood lead was associated with hyperactivity-impulsivity in parent report regardless of measurement method, whereas teacher report effects depended on child treatment history. These findings confirm that in children with typical US population lead exposure, careful identification of children with ADHD also identifies children with slightly elevated blood lead.


Overview of Coronary Heart Disease Risk Initiatives in South Asia.
Cardiovascular disease (CVD) is now the leading cause of morbidity and mortality worldwide. Industrialization and economic growth have led to an unprecedented increment in the burden of CVD and their risk factors in less industrialized regions of the world. While there are abundant data on CVD and their risk factors from longitudinal cohort studies done in the West, good-quality data from South Asia are lacking. Several multi-institutional, observational, prospective registries, and epidemiologic cohorts in South Asia have been established to systematically evaluate the burden of CVD and their risk factors. The PINNACLE (Practice Innovation and Clinical Excellence) India Quality Improvement Program (PIQIP), the Kerala Acute Coronary Syndrome (ACS), and Trivandrum Heart Failure registries have focused on secondary prevention of CVD and performance measurement in both outpatient and inpatient settings, respectively. The Prospective Urban and Rural Epidemiology (PURE), Centre for Cardiometabolic Risk Reduction in South Asia (CARRS), and other epidemiologic and genetic studies have focused on primary prevention of CVD and evaluated variables such as environment, smoking, physical activity, health systems, food and nutrition policy, dietary consumption patterns, socioeconomic factors, and healthy neighborhoods. The international cardiovascular community has been responsive to a burgeoning cardiovascular disease burden in South Asia. Several collaborations have formed between the West (North America in particular) and South Asia to catalyze evidence-based and data-driven changes in the federal health policy in this part of the world to promote cardiovascular health and mitigate cardiovascular risk.


Traditional Persian Medicine and management of metabolic dysfunction in polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Its cause is unknown and it remains the most enigmatic of reproductive disorders. The extant written documents of Traditional Persian Medicine (TPM) - with holistic approaches towards human health - contain remedies used for centuries. Before further experimental research on any of these treatments, it is appropriate to study current related scientific evidence on their possible pharmacological actions. This work aims to study PCOS and its treatments in TPM. To collect data from medieval medicinal texts, six of the most famous manuscripts of Persian medicine were studied. Medicinal treatments for a problem similar to PCOS were searched for in these books. The plants were listed and their authentications were confirmed in accordance with botanical books. PubMed and ScienceDirect databases were searched for related mechanisms of action or pharmacological activities of the medicinal plants reported. From numerous articles, the current work tried to cite the latest publications with regard to each reported plant and PCOS-related mechanisms of action. We studied herbal treatments recommended by ancient Persians to treat a condition called Habs-e-tams, which had the same symptoms of PCOS. It could be concluded that ancient physicians not only wanted to treat the irregular menstrual cycle-which is the most obvious symptom of PCOS-but also their treatment options were aimed at ameliorating the related underlying metabolic dysfunctions. The recommended herbs, which have the most scientific proof for their related actions, can be studied further in experimental analyses.


Phonon coupling and transport in individual polyethylene chains: a comparison study with the bulk crystal.
Using the first-principles-based anharmonic lattice dynamics, we calculate the thermal conductivities (κ) of both bulk and single-chain polyethylene (PE) and characterize the mode-wise phonon transport and scattering channels. A significantly higher room-temperature axial thermal conductivity in single-chain PE (1400 W m-1 K-1) is observed compared to bulk PE crystals (237 W m-1 K-1). The reduction of scattering phase space caused by the diminished inter-chain van der Waals interactions explains the much larger κ in single-chain PE. Different from many previous studies, the thermal conductivity of single-chain PE is predicted to converge at a chain length of ∼1 mm at 300 K. The convergence is explained by the indirect thermal resistance from momentum-conserving scatterings of long-wavelength phonons. It is also found that longitudinal phonon modes dominate the thermal transport in PE chains, while transverse phonon branches with quadratic dispersions contribute little to κ due to their vanishing group velocities and limited lifetimes in the long wavelength limit. The predicted high κ of bulk crystalline and single-chain PE show great potential for use of polymers in thermal management, and the unveiled phonon transport mechanisms offer guides for their molecule-level design.


Induction of hepatocyte lipopolysaccharide binding protein in models of sepsis and the acute-phase response.
Lipopolysaccharide binding protein (LBP) is a serum glycoprotein that complexes with lipopolysaccharide (LPS) to facilitate macrophage response to endotoxin. To determine the conditions that stimulate LBP production in vivo, we measured the induction of LBP in models of inflammation produced by LPS, Corynebacterium parvum, and turpentine injection. Plasma aspartate aminotransferase and alanine aminotransferase concentrations and hepatocyte fibrinogen synthesis were elevated in all models. Northern blot analysis revealed 17-, 14-, and 20-fold upregulation of hepatocyte LBP mRNA following treatment with LPS, C parvum, and turpentine, respectively. Peritoneal macrophage interleukin 6 and tumor necrosis factor production following endotoxin stimulation was augmented by cultured hepatocyte supernatants, suggesting increased LBP synthesis in these groups. The results show that LBP mRNA is induced during hepatic inflammation and suggest that LBP is an acute-phase protein important in regulating the in vivo response to endotoxin.


Antibiotic resistance in hospitals: a ward-specific random effect model in a low antibiotic consumption environment.
Association between previous antibiotic use and emergence of antibiotic resistance has been reported for several microorganisms. The relationship has been extensively studied, and although the causes of antibiotic resistance are multi-factorial, clear evidence of antibiotic use as a major risk factor exists. Most studies are carried out in countries with high consumption of antibiotics and corresponding high levels of antibiotic resistance, and currently, little is known whether and at what level the associations are detectable in a low antibiotic consumption environment. We conduct an ecological, retrospective study aimed at determining the impact of antibiotic consumption on antibiotic-resistant Pseudomonas aeruginosa in three hospitals in Norway, a country with low levels of antibiotic use. We construct a sophisticated statistical model to capture such low signals. To reduce noise, we conduct our study at hospital ward level. We propose a random effect Poisson or binomial regression model, with a reparametrisation that allows us to reduce the number of parameters. Inference is likelihood based. Through scenario simulation, we study the potential effects of reduced or increased antibiotic use. Results clearly indicate that the effects of consumption on resistance are present under conditions with relatively low use of antibiotic agents. This strengthens the recommendation on prudent use of antibiotics, even when consumption is relatively low.


A dominant negative mutant of PG13 suppresses transcription from a cauliflower mosaic virus 35S truncated promoter in transgenic tobacco plants.
TGA1a and PG13 constitute a family of tobacco basic leucine zipper (bZIP) proteins that bind to activating sequence-1 (as-1), which is one of the multiple regulatory cis elements of the cauliflower mosaic virus (CaMV) 35S promoter. After truncation of the CaMV 35S promoter down to position -90 (CaMV 35S [-90] promoter), transcription stringently depends on the presence of as-1, which is recognized by nuclear DNA binding proteins called ASF-1. The role of the TGA1a/PG13 bZIP family in the formation of ASF-1 and in transcriptional activation of the CaMV 35S (-90) promoter has not yet been demonstrated in vivo. We constructed transgenic tobacco plants expressing a mutant of potato PG13, which lacks its wild-type DNA binding domain. This mutant acts as a trans-dominant inhibitor of ASF-1 formation and of expression from the CaMV 35S (-90) promoter, showing that PG13 can specifically interact with proteins necessary for these processes. Although we did not observe any other obvious phenotypic changes, these transgenic plants are a potentially valuable tool in identifying whether TGA1a and PG13 are involved in controlling promoters encoded in the plant genome.


Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size.
The efficacy of novel cancer therapeutics has been hampered by the ability to deliver these agents to the tumor at effective concentrations. Liposomes have been used as a method to overcome some delivery issues and, in combination with hyperthermia, have been shown to increase drug delivery to tumors. Particle size has been shown to affect the delivery of liposomes, but it is not known how hyperthermia affects size dependence. This study investigates the effect of hyperthermia (42 degrees C) on the extravasation of different sized nanoparticles (albumin; 100-, 200-, and 400-nm liposomes) from tumor microvasculature in a human tumor (SKOV-3 ovarian carcinoma) xenograft grown in mouse window chambers. In this model (at 34 degrees C), no liposomes were able to extravasate into the tumor interstitium. Hyperthermia enabled liposome extravasation of all sizes. The magnitude of hyperthermia-induced extravasation was inversely proportional to particle size. Thus, at normothermia (34 degrees C), the pore cutoff size for this model was between 7 and 100 nm (e.g., liposomes did not extravasate). At 42 degrees C, the pore cutoff size was increased to >400 nm, allowing all nanoparticles tested to be delivered to the tumor interstitium to some degree. With hyperthermia, the 100-nm liposome experienced the largest relative increase in extravasation from tumor vasculature. Hyperthermia did not enable extravasation of 100-nm liposomes from normal vasculature, potentially allowing for tumor-specific delivery. These experiments indicate that hyperthermia can enable and augment liposomal drug delivery to tumors and potentially help target liposomes specifically to tumors.


[Altitudinal richness patterns of Papilionidae, Pieridae and Nymphalidae (Lepidoptera) in Mexican mountain areas].
Altitudinal richness patterns of Papilionidae, Pieridae and Nymphalidae (Lepidoptera) in Mexican mountain areas. Butterflies constitute an useful group to investigate biodiversity patterns in specific geographic areas. The aim of this study was to describe the altitudinal patterns distribution and to recognize the main grouping factors of these families. We conducted a comparative study between the butterfly fauna (Papilionidae, Pieridae and Nymphalidae) of five Mexican mountain ranges (Sierra de Manantlán, Sierra de Atoyac de Alvarez, Loxicha Region, Teocelo-Xalapa and Sierra de Juárez), that included 34 sites of altitudinal ranges from 100 to 2 820m. Data was obtained from the Zoology Museum of the National University of Mexico, and comprised more than 60 000 butterfly records of 398 taxa (subspecies level) proceeding during the last 35 years. Fauna similarity between localities were analyzed using a cluster analysis by Sorensen similarity coefficient. Species richness showed a general tendency to decrease with altitude; the main difference was found between the locality with higher altitude and the rest of the sites. The principal factors affecting the identified clusters followed this order: the location in Pacific or Atlantic slope, and location on a particular mountain range. Three altitudinal levels (low elevations, up to 1 200m; intermediate elevations, from 1200 to 1800 m; and high elevations, from 1800 to 2500 m) were described in accordance to their main characteristic taxa. While Neartic elements were common in the highest altitudinal floor, Neotropical taxa were common in the lowest one. It was more difficult to characterize the intermediate level in which a high number of localities were clustered; this intermediate level was characterized by the presence of some endemic species. The results suggest that historical factors are preeminent in butterfly fauna composition in these areas. Future studies may include other Mexican mountain areas to obtain more information on the different factors (latitude, altitude, slope) influencing biodiversity patterns.


Health status and health care use in persons with inflammatory bowel disease. A national sample.
We randomly surveyed 997 members of the Crohn's and Colitis Foundation of America with inflammatory bowel disease (320 ulcerative colitis and 671 Crohn's disease) in order to: (1) assess their health status, (2) compare members with ulcerative colitis and Crohn's disease, and (3) determine the correlates of health care use. Data collection included variables relating to physical and psychological symptoms, medication use, daily functional status, perceptions of health, and coping styles. The findings indicate that: (1) despite a number of symptoms and complications related to inflammatory bowel disease, the health status of this population is generally good and may be a result of effective coping styles; (2) those with Crohn's disease have more psychosocial difficulties, which appear related to greater symptom severity; (3) both psychosocial and physical health variables are related to number of physician visits, while primarily physical health variables are related to number of hospitalizations and surgeries. Further studies are needed to determine the representativeness of this self-selected sample with others having IBD. In this study, we have provided the basis for developing a more sensitive measure of health status than currently exists, and one which may have implications for future clinical studies.