Epidemiology of type 2 diabetes: risk factors.
A number of cross-sectional and prospective studies that compared the insulin sensitivity of various national and ethnic populations within the U.S. to the total U.S. population were analyzed to find possible risk factors for the development of type 2 diabetes. It was found that the risks for diabetes in African-Americans, Hispanics, and Native Americans are approximately 2, 2.5, and 5 times greater, respectively, than in Caucasians. Studies of the prevalence of type 2 diabetes in Mexican Americans and non-Hispanic whites in San Antonio showed that there is an inverse relationship between socioeconomic status and the prevalence of diabetes. It also appears that cultural effects lead to an increased incidence of obesity in these populations, which may lead to insulin resistance. Genetic factors may also be a contributing factor. A 5-year, prospective study of insulin resistance in Pima Indians showed a relationship between impaired glucose tolerance and subsequent development of type 2 diabetes. In a 7-year study in Mexican Americans, those subjects who had both high insulin secretion and impaired insulin sensitivity had a 14-fold increased risk of developing type 2 diabetes. Regardless of cultural and ethnic factors, the San Antonio Heart Study, which compared Mexican Americans and non-Hispanic whites, showed that in both groups, the strongest predictors of developing type 2 diabetes are elevated fasting insulin concentrations and low insulin secretion.


Breast-feeding and the nutritional status of nursing children in Chile.
The work reported here sought to describe the feeding patterns of Chilean children up to 18 months old and their relation to nutritional status. To this end, a survey was conducted in 1993 of 9330 Chilean children under 18 months old who were receiving care through the National Health Service System-which provides care for 75% of all children under age 6. The children, whose mothers or caretakers were interviewed, constituted 94% of a sample selected at random from 102 of the 320 urban health clinics located throughout the country. The interview served to identify the type of feeding (exclusive breast-feeding, breast-feeding plus bottle-feeding, breast-feeding plus solid food, exclusive bottle-feeding, or bottle-feeding plus solid food) and to determine the nutritional status of the participants in terms of standards used by the United States National Center for Health Statistics and the World Health Organization. Children were deemed at risk of malnutrition if they had z scores on the weight-for-age distribution between 1.0 and 2.0 standard deviations below the US/WHO standard and as actually malnourished if they had z scores of over 2.0 standard deviations below the standard. The survey found exclusive breast-feeding prevalences of 86.5%, 66.7%, and 25.3% among infants 1, 3, and 6 months old. Some 12.1% of the participants were found to have a weight-for-age deficiency, 30.7% exhibited a height-for-age deficiency, and 35.7% were found to be over-weight. The prevalence of weight-for-age and height-for-age deficiencies were found to be considerably higher among bottle-fed children than among breast-fed children. In general, the results demonstrated the benefits of exclusive breast-feeding through the first 6 months of life, the need to complement exclusive breast-feeding with solid food after that time, and the superior nutritional status of breast-fed children within the age groups studied.


Caffeine: effects of acute and chronic exposure on the behavior of neonatal rats.
The behavioral responses of 1- and 10-day-old rats to caffeine, a central nervous system stimulant, were determined using several behaviors readily exhibited by the neonatal rat. In pups of both ages activity as well as attachment latencies in the on-nipple suckling test increased, while weight gain and attachment frequencies in on-mother and on-nipple suckling tests decreased. In addition, the home orientation of 10-day-old rats was disrupted. Similar effects were found in 1-day-old pups exposed to theophylline. Long term exposure to caffeine during gestation (1-day-old pups) or on days 1--9 of lactation (10-day-old pups) increased the pups' activity levels and altered the activity increase observed following an acute caffeine challenge. The absence of a differential response to theophylline indicated these changes were specific to caffeine. These results indicate that biologically relevant behaviors can be used to assess behavioral alterations in the neonate which arise from prenatal or early postnatal exposure to toxic substances.


The nongenotropic synthetic ligand 4-estren-3alpha17beta-diol is a high-affinity genotropic androgen receptor agonist.
The nongenotropic ligand estren (Science 298:843-846, 2002) was evaluated for its transcriptional activity mediated by the human androgen receptor (AR). Our results show that estren can bind, translocate, transactivate, and regulate two known target genes of AR in androgen-responsive cell lines. Estren binds recombinant AR with 10-fold higher affinity than either estrogen receptor (ER)-alpha or ERbeta. Estren-bound AR can translocate AR to the nucleus and stimulate the androgen response element-luciferase reporter activity with an efficacy similar to that of androgen. Estren also increased the expression of prostate-specific antigen (PSA) in a dose-dependent manner in human LnCaP cells. Using chromatin immunoprecipitation analysis, we show that the estren-bound AR coimmunoprecipitates with a region of the PSA gene promoter. Therefore, cotreatment with an AR antagonist, bicalutamide, blocked the estren-induced increase in PSA expression. In contrast, phosphoinositol 3-kinase inhibitor wortmannin, or extracellular signal-regulated kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene (U0126), and ER antagonist ICI-182780 failed to block the effects of estren. In vivo analysis of estren's action on male-orchidectomized ICR mice revealed estren's AR agonist actions on the levator ani and seminal vesicle target tissues. Taken together, our results reveal the hitherto unidentified genotropic action of estren mediated by AR in androgen-responsive cells and tissues.


Gastrointestinal toxicities of 5-fluorouracil increase the proportion of regulatory T cells in intestinal tract: advantages of alternate-day S-1 administration.
5-Fluorouracil (5-FU), a core anticancer agent for malignancies, induces gastrointestinal (GI) toxicities. Despite recent advances in tumor immunology, it still remains unknown how GI toxicities affect antitumor immunity. S-1 is a tegafur-based oral 5-FU prodrug which has been widely introduced in Japan and other countries. The alternate-day S-1 administration has been proposed to minimize its GI and other toxicities without reducing its anticancer efficacy. In this study, two S-1 administration regimens were compared in mice to evaluate their impact of GI toxicities on immunity. In the daily group as a standard administration model, S-1 was administered for 14 days on and 14 days off, and in the alternate-day group as a non-GI toxicity model, S-1 was administered every other day for 28 days. As well as physical findings, regulatory T cells, Th1 cells and other cells in murine lymphoid tissues were analyzed with flow cytometry. Only the daily group exhibited body weight loss and GI toxicities. In the daily group, a proportion of regulatory T cells in the intestinal lymphoid tissue were demonstrated to be six-fold higher than in the control without S-1, and the proportion of Th1 cells showed a decreasing trend. However, the alternate-day group exhibited almost no change in T-cell subsets. GI toxicities of 5-FU may have a negative influence on antitumor immunity due to increased proportions of regulatory T cells and decreased proportions of Th1 cells. The alternate-day S-1 administration may be a useful regimen with its minimal influence on T-cell subsets.


Mucosa-associated lymphoid tissue lymphomas with t(11;18)(q21;q21) and mucosa-associated lymphoid tissue lymphomas with aneuploidy develop along different pathogenetic pathways.
t(11;18)(q21;q21) and aneuploidy are recurrent chromosomal aberrations in mucosa-associated lymphoid tissue (MALT) lymphomas. To investigate their relationship and clinical significance, we developed a two-color fluorescence in situ hybridization (FISH) technique to detect t(11;18) and aneuploidy in nuclei isolated from paraffin-embedded tissue. Thirty-seven MALT lymphomas (all previously evaluated for t(11;18) by reverse transcriptase-polymerase chain reaction), 1 large cell lymphoma (LCL) arising subsequent to MALT lymphoma, and 16 controls were tested by FISH using the t(11;18) probe set and multiple centromeric probes. t(11;18)(q21;q21) was present by FISH in 11 of 12 polymerase chain reaction-positive MALT lymphomas (92%). The LCL and its clonally identical antecedent MALT lymphoma both showed t(11;18). The LCL had trisomy 12, and a small subset of MALT lymphoma cells had trisomy 3 and/or 12. Only one other MALT lymphoma with t(11;18) showed aneuploidy (trisomy 3) in a small clone, whereas 15 of 25 t(11;18)-negative MALT lymphomas (60%) showed trisomy of chromosomes 18 (n = 12), 3 (n = 8), 7 (n = 2), and/or 11 (n = 1). t(11;18) and aneuploidy are primarily mutually exclusive events, suggesting different pathogenetic pathways in the development of MALT lymphomas. Both t(11;18) and aneuploidy were seen disproportionately in lung, and both were associated with recurrent disease.


In silico discovery of mitosis regulation networks associated with early distant metastases in estrogen receptor positive breast cancers.
The aim of this study was to perform comparative analysis of multiple public datasets of gene expression in order to identify common genes as potential prognostic biomarkers. Additionally, the study sought to identify biological processes and pathways that are most significantly associated with early distant metastases (<5 years) in women with estrogen receptor-positive (ER+) breast tumors. Datasets from three published studies were selected for in silico analysis of gene expression profiles of ER+ breast cancer, using time to distant metastasis as the clinical endpoint. A subset of 44 differently expressed genes (DEGs) was found common to all three studies and characterized by mitotic checkpoint genes and pathways that regulate mitotic spindle and chromosome dynamics. DEG promoter regions were enriched with NFY binding sites. Analysis of miRNA target sites identified significant enrichment of miR-192, miR-193B, and miR-16-1 targets. Aberrant mitotic regulation could drive increased genomic instability leading to a progression towards an early onset metastatic phenotype. The relative importance of mitotic instability may reflect the clinical utility of mitotic poisons in metastatic breast cancer, including poisons such as the taxanes, epothilones, and vinca alkaloids.


[Spinal cord injury and chronic pain].
Prevalence of chronic pain which develops after spinal cord injury (SCI) varies, but in average is 65%. There are many questionnaires and scales for characterisation and classification of chronic SCI pain. One of them is LANSS (Leeds Assesment of Neuropathic Symptoms and Signs) scale for differentiation of neuropathic pain. Aims of this study were: (1) To assess prevalence of chronic pain in the sample of patients with SCl; (2) To classify the pain; (3) To analyse its correlations with demographic and neurological features as well as with activities of daily life (ADL); (4) To evaluate pain treatment. Retrospective, randomized, observational study based on personal interview, Visual Analog Scale (VAS) for pain intensity evaluation, graded from 0 to 10, and on LANSS scale included 100 patients. 50% of patients reported existence of chronic pain. In 80% of them pain was below the level of SCI and in 20% of them pain was at the level of SCI. 92% of patients with chronic pain fulfilled LANNS score for neuropathic pain. VAS showed higher intensity of pain among men (average 7.4) than in women (average 6.6). There were positive correlations: between VAS and LANSS scale (p = 0.002), between VAS and age (p = 0.040) and between VAS and level of injury (Pearson rho = 0.329; p = 0.020). 60% of patients declared pain interference with ADL. 24% of patients did not treat pain at all, 16% treated pain with physical procedures and 60% treated pain pharmacologically. RESULTS of this study confirmed high prevalence of chronic pain among patients with SCI, and its features indicated neuropathic type of pain. Pain intensity had positive correlation with gender, age, level of SCI and ADL. RESULTS showed that pharmacological treatment of this pain is much more in use than non-pharmacological one.


Enhancement and switch effect of equal-spin Andreev reflection in ferromagnet/insulator/Ising superconductor junctions.
We study the property of equal-spin Andreev reflection (ESAR) in the ferromagnet/insulator/Ising superconductor junction where Ising spin-orbit coupling is taken into account in the insulator. It is found that the ESAR exhibits a regular oscillation with the insulating barrier, the amplitude and period of which can be effectively controlled by the chemical potentials. Compared to that in the ferromagnet/Ising superconductor junction, the ESAR is greatly increased due to the resonant mode, suggesting an enhanced spin-triplet pairing. As an application, the proposed junction may work as a switch to turn on and off the ESAR. Furthermore, the insulating barrier does not change the magnetoanisotropic period of ESAR because of the invariant symmetry of the system, however, the magnetoanisotropy is strengthened.


Vaccine effectiveness of live attenuated and trivalent inactivated influenza vaccination in 2010/11 to 2015/16: the SIVE II record linkage study.
There is good evidence of vaccine effectiveness in healthy individuals but less robust evidence for vaccine effectiveness in the populations targeted for influenza vaccination. The live attenuated influenza vaccine (LAIV) has recently been recommended for children in the UK. The trivalent influenza vaccine (TIV) is recommended for all people aged ≥ 65 years and for those aged < 65 years who are at an increased risk of complications from influenza infection (e.g. people with asthma). To examine the vaccine effectiveness of LAIV and TIV. Cohort study and test-negative designs to estimate vaccine effectiveness. A self-case series study to ascertain adverse events associated with vaccination. A national linkage of patient-level general practice (GP) data from 230 Scottish GPs to the Scottish Immunisation & Recall Service, Health Protection Scotland virology database, admissions to Scottish hospitals and the Scottish death register. A total of 1,250,000 people. LAIV for 2- to 11-year-olds and TIV for older people (aged ≥ 65 years) and those aged < 65 years who are at risk of diseases, from 2010/11 to 2015/16. The main outcome measures include vaccine effectiveness against laboratory-confirmed influenza using real-time reverse-transcription polymerase chain reaction (RT-PCR), influenza-related morbidity and mortality, and adverse events associated with vaccination. Two-fifths (40%) of preschool-aged children and three-fifths (60%) of primary school-aged children registered in study practices were vaccinated. Uptake varied among groups [e.g. most affluent vs. most deprived in 2- to 4-year-olds, odds ratio 1.76, 95% confidence interval (CI) 1.70 to 1.82]. LAIV-adjusted vaccine effectiveness among children (aged 2-11 years) for preventing RT-PCR laboratory-confirmed influenza was 21% (95% CI -19% to 47%) in 2014/15 and 58% (95% CI 39% to 71%) in 2015/16. No significant adverse events were associated with LAIV. Among at-risk 18- to 64-year-olds, significant trivalent influenza vaccine effectiveness was found for four of the six seasons, with the highest vaccine effectiveness in 2010/11 (53%, 95% CI 21% to 72%). The seasons with non-significant vaccine effectiveness had low levels of circulating influenza virus (2011/12, 5%; 2013/14, 9%). Among those people aged ≥ 65 years, TIV effectiveness was positive in all six seasons, but in only one of the six seasons (2013/14) was significance achieved (57%, 95% CI 20% to 76%). The study found that LAIV was safe and effective in decreasing RT-PCR-confirmed influenza in children. TIV was safe and significantly effective in most seasons for 18- to 64-year-olds, with positive vaccine effectiveness in most seasons for those people aged ≥ 65 years (although this was significant in only one season). The UK Joint Committee on Vaccination and Immunisation has recommended the use of adjuvanted injectable vaccine for those people aged ≥ 65 years from season 2018/19 onwards. A future study will be required to evaluate this vaccine. Current Controlled Trials ISRCTN88072400. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 67. See the NIHR Journals Library website for further project information.


Embedment of Multiple Transition Metal Impurities into WS2 Monolayer for Bandstructure Modulation.
Band structure by design in 2D layered semiconductors is highly desirable, with the goal to acquire the electronic properties of interest through the engineering of chemical composition, structure, defect, stacking, or doping. For atomically thin transition metal dichalcogenides, substitutional doping with more than one single type of transition metals is the task for which no feasible approach is proposed. Here, the growth of WS2 monolayer is shown codoped with multiple kinds of transition metal impurities via chemical vapor deposition controlled in a diffusion-limited mode. Multielement embedment of Cr, Fe, Nb, and Mo into the host lattice is exemplified. Abundant impurity states thus generate in the bandgap of the resultant WS2 and provide a robust switch of charging/discharging states upon sweep of an electric filed. A profound memory window exists in the transfer curves of doped WS2 field-effect transistors, forming the basis of binary states for robust nonvolatile memory. The doping technique presented in this work brings one step closer to the rational design of 2D semiconductors with desired electronic properties.


Hf-Nd isotopic variability in mineral dust from Chinese and Mongolian deserts: implications for sources and dispersal.
Mineral dust provenances are closely related to the orogenic processes which may have distinct Hf-Nd isotopic signatures. Here we report the clay-sized (<2 μm) Hf-Nd isotope data from Asian dust sources to better constrain the source and transport dynamics of dust deposition in the North Pacific. Our results show that there is a more positive radiogenic Hf isotopic composition with clay-sized fractions than the corresponding bulk sample and a decoupling of the Hf-Nd couplets in the clay formation during the weathering process. The clay-sized Hf-Nd isotopic compositions of the desert samples from the Sino-Korean-Tarim Craton (SKTC) are different from those of the Gobi and deserts from the Central Asian Orogeny Belt (CAOB) due to varying tectonic and weathering controls. The Hf-Nd isotopic compositions of dust in the North Pacific central province (NPC) match closely with those from the Taklimakan, Badain Jaran and adjacent Tengger deserts, implying that the NPC dust was mainly transported from these potential sources by the westerly jet. Our study indicates that dusts from the CAOB Gobi deserts either didn't arrive in NPC or were quantitatively insignificant, but they were likely transported to the North Pacific margin province (NPM) by East Asian winter monsoon.


Postoperative pain experience and barriers to pain management in Chinese adult patients undergoing thoracic surgery.
The purpose of this study was (1) to explore postoperative pain experience among Chinese thoracotomy patients during hospitalisation; (2) to identify patient-related barriers to pain management; and (3) to explore how these barriers were related to patients' pain experience. Major thoracotomy causes severe pain and extreme stress for patients. Unrelieved postoperative pain leads to high risks of postoperative complications and chronic post-thoracotomy pain syndrome, compromising the quality of life for those patients. Cross-sectional design. A tertiary general hospital in mainland China was selected for this study. A total of 94 patients undergoing scheduled major thoracotomy operations participated in the study. All patients completed Brief Pain Inventory-Chinese version, the Barrier Questionnaire-Taiwan Form Surgical version and a demographic questionnaire. Patients suffered moderate to severe pain and experienced extremely high interferences with daily activities after major thoracotomy operation. Patients reported the four highest barrier scores in the subscale of Barrier Questionnaire-Taiwan Form Surgical version were fear of tolerance, inhibition of wound healing, time intervals and distracting the physician from treating the disease. Patient's demographic data had no significant impact on their concerns about communicating pain and using of analgesics with exception of the subscale 'fatalism' of the Barrier Questionnaire-Taiwan Form Surgical version in patients with higher education levels or patients with 'non-farmer' occupation. However, there were no significant correlations indicated either between Barrier Questionnaire-Taiwan Form Surgical version score and pain severity or pain interference. Patients were underexposure of pain treatment after thoracotomy operation in the study, while patients' concerns about reporting pain and using analgesics had minimal impacts on their pain experience. Education approach for patients is inadequate to improve the status of unrelieved postoperative pain. Appropriate pain management regime together with attentive nursing care should be provided to achieve better pain relief for Chinese patients.


Effects of molybdate and selenite on formate and nitrate metabolism in Escherichia coli.
The effects of adding molybdate and selenite to a glucose-minimal salts medium on the formation of enzymes involved in the anaerobic metabolism of formate and nitrate in Escherichia coli have been studied. When cells were grown anaerobically in the presence of nitrate, molybdate stimulated the formation of nitrate reductase and a b-type cytochrome, resulting in cells that had the capacity for active nitrate reduction in the absence of formate dehydrogenase. Under the same conditions, selenite in addition to molybdate was required for forming the enzyme system which permits formate to serve as an effective electron donor for nitrate reduction. When cells were grown anaerobically on a glucose-minimal salts medium without nitrate, active hydrogen production from formate as well as formate dehydrogenase activity depended on the presence of both selenite and molybdate. The effects of these metals on the formation of formate dehydrogenase was blocked by chloramphenicol, suggesting that protein synthesis is required for the increases observed. It is proposed that the same formate dehydrogenase is involved in nitrate reduction, hydrogen production, and in aerobic formate oxidation.


Non-polymeric asymmetric binary glass-formers. I. Main relaxations studied by dielectric, 2H NMR, and 31P NMR spectroscopy.
In Paper I of this series of two papers we study the main relaxations of a binary glass former made of the low-Tg component tripropyl phosphate (TPP, Tg = 134 K) and of a specially synthesized (deuterated) spirobichroman derivative (SBC, Tg = 356 K) as the non-polymeric high-Tg component for the full concentration range. A large Tg contrast of the neat components is put into effect. Dielectric spectroscopy and different techniques of 2H nuclear magnetic resonance (NMR) as well as of 31P NMR spectroscopy allow to selectively probe the dynamics of the components. For all concentrations, two well separated liquid-like processes are identified. The faster α2-process associated with the low-Tg component TPP shows pronounced dynamic heterogeneities reflected by quasi-logarithmic correlation functions at low TPP concentrations. The slower α1-process involves the reorientation of the high-Tg component SBC. Its correlation function is Kohlrausch-like as in neat glass formers. The corresponding time constants and consequently their glass transition temperatures Tg1 and Tg2 differ more the lower the TPP concentration is. Plasticizer and anti-plasticizer effect, respectively, is observed. At low temperatures a situation arises that the TPP molecules isotropically reorient in an arrested SBC matrix (Tg2 < T < Tg1). At T < Tg2 the liquid-like reorientation of TPP gets arrested too. We find indications that a fraction of the TPP molecule takes part in the slower α1-process of the high-Tg component. All the features known from polymer-plasticizer systems are rediscovered in this non-polymeric highly asymmetric binary mixture. In Paper II [B. Pötzschner et al., J. Chem. Phys. 146, 164504 (2017)] we study the secondary (β-) relaxations of the mixtures.


Biliary atresia: an overview.
Biliary Atresia is the most common cause of persistently direct (conjugated) hyperbilirubinemia in the first three months of life. It is a progressive inflammatory obliteration of the extra- and intrahepatic bile ducts whose pathogenesis remains speculative. This review updates the history, etio-pathological considerations, clinical manifestations, methods of diagnosis, surgical management, and results of this terrible disease in young infants. We will emphasize that persistent jaundice in the newborn period must be managed urgently, a diagnosis should be established early in life, and Kasai portoenterostomy offered to those infants with Biliary Atresia before their eighth week of life. This will allow more than one-third of children to survive. Hepatic transplantation is reserved for those children with failed portoenterostomy, progressive liver failure or late-referral to surgery.


Relations as patterns: bridging the gap between OBO and OWL.
most biomedical ontologies are represented in the OBO Flatfile Format, which is an easy-to-use graph-based ontology language. The semantics of the OBO Flatfile Format 1.2 enforces a strict predetermined interpretation of relationship statements between classes. It does not allow flexible specifications that provide better approximations of the intuitive understanding of the considered relations. If relations cannot be accurately expressed then ontologies built upon them may contain false assertions and hence lead to false inferences. Ontologies in the OBO Foundry must formalize the semantics of relations according to the OBO Relationship Ontology (RO). Therefore, being able to accurately express the intended meaning of relations is of crucial importance. Since the Web Ontology Language (OWL) is an expressive language with a formal semantics, it is suitable to de ne the meaning of relations accurately. we developed a method to provide definition patterns for relations between classes using OWL and describe a novel implementation of the RO based on this method. We implemented our extension in software that converts ontologies in the OBO Flatfile Format to OWL, and also provide a prototype to extract relational patterns from OWL ontologies using automated reasoning. The conversion software is freely available at http://bioonto.de/obo2owl, and can be accessed via a web interface. explicitly defining relations permits their use in reasoning software and leads to a more flexible and powerful way of representing biomedical ontologies. Using the extended langua0067e and semantics avoids several mistakes commonly made in formalizing biomedical ontologies, and can be used to automatically detect inconsistencies. The use of our method enables the use of graph-based ontologies in OWL, and makes complex OWL ontologies accessible in a graph-based form. Thereby, our method provides the means to gradually move the representation of biomedical ontologies into formal knowledge representation languages that incorporates an explicit semantics. Our method facilitates the use of OWL-based software in the back-end while ontology curators may continue to develop ontologies with an OBO-style front-end.


Tissue transglutaminase antibodies in celiac disease: assessment of a commercial kit.
Tissue transglutaminase was identified as the autoantigen eliciting endomysial antibody. A homemade enzyme-linked immunosorbent assay (ELISA)-based test was recently developed to determine quantitative titers of IgA antitissue transglutaminase antibody. Our objective in this study was to assess the suitability of a newly developed commercial kit for quantitative determination of antibody in patients with untreated celiac disease. We tested serum samples from 79 untreated celiac patients, 42 healthy blood donors, and 18 patients with nonceliac intestinal disorders evaluated in two different centers. Samples were tested for antitissue transglutaminase, and antiendomysial and antigliadin antibodies in the center where diagnosis was performed. To assess interlaboratory variability of methods, 24 samples randomly selected were blindly tested in both centers. Antitissue transglutaminase antibodies were determined using a commercial kit (INOVA Diagnostics, Inc., San Diego, CA). Untreated celiac patients had significantly higher titers of antitissue transglutaminase than healthy and disease controls (p < 0.00001). According to the cut-off provided by the manufacturers (20 AU/mL), overall sensitivity was 92% (85% for one center and 100% for the other) and specificity was 98% (100% and 95%, respectively). Antiendomysial antibody was 86% sensitive and 100% specific. Discordance between antitissue transglutaminase and antiendomysial antibodies was detected in 13% of patients. Although two antitissue transglutaminase-negative cases had a positive antiendomysial antibody, the inverse situation was found in eight cases. A blind determination of antitissue transglutaminase on the same samples evidenced a good agreement (kappa statistic: 0.66) between both centers when assessment was qualitative (based on the decision of positive or negative). Although correlation of titers for both determinations was highly significant (r: 0.902, p < 0.00001), a very wide interlaboratory variability (median: 50%) was detected when absolute values were considered. The quantitative determination of antitissue transglutaminase using a commercial kit was highly sensitive and specific for detection of celiac disease. We observed an incomplete overlapping with antiendomysial antibody. The very high variability of values between laboratories still remains to be solved so as to propose the commercial ELISA assay for the screening of celiac disease.


To B or not to B: B cells and the Th2-type immune response to helminths.
Similar T helper (Th)2-type immune responses are generated against different helminth parasites, but the mechanisms that initiate Th2 immunity, and the specific immune components that mediate protection against these parasites, can vary greatly. B cells are increasingly recognized as important during the Th2-type immune response to helminths, and B cell activation might be a target for effective vaccine development. Antibody production is a function of B cells during helminth infection and understanding how polyclonal and antigen-specific antibodies contribute should provide important insights into how protective immunity develops. In addition, B cells might also contribute to the host response against helminths through antibody-independent functions including, antigen presentation, as well as regulatory and effector activity. In this review, we examine the role of B cells during Th2-type immune response to these multicellular parasites.


Role of zoledronic acid in the prevention and treatment of osteoporosis.
Taken once a year, intravenous zoledronic acid (Zol) (Reclast® or Aclasta®) is a third-generation nitrogen-containing bisphosphonate that is effective compared with placebo in reducing the risk of fractures in patients with postmenopausal osteoporosis and recent low-trauma hip fracture. In glucocorticoid-induced osteoporosis, there is no significant difference between Zol and risedronate for new fractures. Improvements in bone mineral density and early reduction of bone remodeling markers are observed in postmenopausal osteoporosis, recent low-trauma hip fracture, and glucocorticoid-induced osteoporosis. Given that Zol is generally well tolerated and very convenient, it is an interesting therapeutic option for aging patients who take multiple oral drugs, who have adherence or gastrointestinal tolerance issues, and who have an indication for oral bisphosphonates. Zol is not recommended for patients with severe renal impairment. Vitamin D deficiency should be corrected before the administration of Zol.


Origins of fluorescence in evolved bacteriophytochromes.
Use of fluorescent proteins to study in vivo processes in mammals requires near-infrared (NIR) biomarkers that exploit the ability of light in this range to penetrate tissue. Bacteriophytochromes (BphPs) are photoreceptors that couple absorbance of NIR light to photoisomerization, protein conformational changes, and signal transduction. BphPs have been engineered to form NIR fluorophores, including IFP1.4, Wi-Phy, and the iRFP series, initially by replacement of Asp-207 by His. This position was suggestive because its main chain carbonyl is within hydrogen-bonding distance to pyrrole ring nitrogens of the biliverdin chromophore, thus potentially functioning as a crucial transient proton sink during photoconversion. To explain the origin of fluorescence in these phytofluors, we solved the crystal structures of IFP1.4 and a comparison non-fluorescent monomeric phytochrome DrCBDmon. Met-186 and Val-288 in IFP1.4 are responsible for the formation of a tightly packed hydrophobic hub around the biliverdin D ring. Met-186 is also largely responsible for the blue-shifted IFP1.4 excitation maximum relative to the parent BphP. The structure of IFP1.4 revealed decreased structural heterogeneity and a contraction of two surface regions as direct consequences of side chain substitutions. Unexpectedly, IFP1.4 with Asp-207 reinstalled (IFPrev) has a higher fluorescence quantum yield (∼9%) than most NIR phytofluors published to date. In agreement, fluorescence lifetime measurements confirm the exceptionally long excited state lifetimes, up to 815 ps, in IFP1.4 and IFPrev. Our research helps delineate the origin of fluorescence in engineered BphPs and will facilitate the wide-spread adoption of phytofluors as biomarkers.


Virtual groups for patient WBAN monitoring in medical environments.
Wireless body area networks (WBAN) provide a tremendous opportunity for remote health monitoring. However, engineering WBAN health monitoring systems encounters a number of challenges including efficient WBAN monitoring information extraction, dynamically fine tuning the monitoring process to suit the quality of data, and to allow the translation of high-level requirements of medical officers to low-level sensor reconfiguration. This paper addresses these challenges, by proposing an architecture that allows virtual groups to be formed between devices of patients, nurses, and doctors in order to enable remote analysis of WBAN data. Group formation and modification is performed with respect to patients' conditions and medical officers' requirements, which could be easily adjusted through high-level policies. We also propose, a new metric called the Quality of Health Monitoring, which allows medical officers to provide feedback on the quality of WBAN data received. The WBAN data gathered are transmitted to the virtual group members through an underlying environmental sensor network. The proposed approach is evaluated through a series of simulation.


The Cardiac Rehabilitation Model Improves Fitness, Quality of Life, and Depression in Breast Cancer Survivors.
Exercise is a demonstrated, therapeutic strategy for cancer survivors to minimize many treatment-induced side effects and may decrease risk of recurrence. Nonetheless, structured programs that combine exercise and education are not yet standardized within cancer care. The Health, Exercise, Active Living, Therapeutic lifestyle (HEALTh) program is a clinical exercise program based on the established cardiac rehabilitation model, but customized for female breast cancer survivors. This study assessed the effects of a cardiac rehabilitation program on cardiorespiratory fitness, quality of life, and depressive symptoms in breast cancer survivors. Charts were reviewed to evaluate the cardiac rehabilitation model. The program consisted of 1 weekly supervised session for 22 group sessions. Each patient was provided with personalized aerobic and resistance exercises plus 12 group educational sessions to encourage behavioral adoption to a healthy lifestyle. Cardiorespiratory fitness (direct (Equation is included in full-text article.)O2peak), quality of life (Short Form-36 Health Status [SF-36] and Functional Assessment of Cancer Therapy-Breast [FACT-B]), and depression (Centre of Epidemiological Studies Depression [CES-D]) were assessed at baseline and after program completion. Two hundred seventy-four files were accessed with 152 eligible files analyzed. Baseline cardiorespiratory fitness and quality-of-life values were below population norms. Program adherence was 66.6%. Cardiorespiratory fitness improved by 14% (21 ± 6 to 24 ± 7 mL/kg/min, P < .001), with significant improvements in quality of life (P < .001) and depression scores (P = .019). Bodily pain was the only domain not significantly affected (P = .311). The cardiac rehabilitation model improved physical and mental health in breast cancer survivors. These results provide support for the collaborative effort between cardiology and oncology to improve patient care across the cancer care continuum.


Endoscopic endonasal management of cerebrospinal fluid rhinorrhea.
The authors review their 5 years' experience with endonasal endoscopic repair of the anterior skull base fistulas presenting with cerebrospinal fluid (CSF) rhinorrhea. A total of 12 patients were managed endoscopically between 2004 and 2008. Seven patients (58.3%) had nonsurgical posttraumatic CSF rhinorrhea, 2 patients (16.7%) had CSF rhinorrhea due to surgical/iatrogenic trauma, and 3 patients (25%) had spontaneous onset of CSF rhinorrhea. Radiosurgical correlation for CSF fistula identification was positive in all patients. The most common site of leak was the fovea ethmoidalis. The repair method consisted of an extradural underlay closure of a defect with fascia lata. The largest diameter of a defect to be closed was 15 mm. Immediate results were good in all patients, but later in the follow-up, CSF rhinorrhea recurred in 2 patients, and each patient had a revision 2 times. In the first revisions, transcranial approach was used, whereas in the second revisions endonasal endoscopic route was resorted. The primary closure rate was 83.3%, and the overall closure rate was 100%. The average follow-up period thus far is 21 months. Endonasal endoscopic technique well known to otolaryngologists should be considered as the first choice of surgery in the repair of CSF rhinorrhea because of low morbidity and a higher closure rate. The possibility of revision with the same technique makes this approach ideal for the repair of cranionasal osteodural defects.


Human capital gains associated with robotic assisted laparoscopic pyeloplasty in children compared to open pyeloplasty.
Robotic assisted laparoscopic pyeloplasty is an emerging, minimally invasive alternative to open pyeloplasty in children for ureteropelvic junction obstruction. The procedure is associated with smaller incisions and shorter hospital stays. To our knowledge previous outcome analyses have not included human capital calculations, especially regarding loss of parental workdays. We compared perioperative factors in patients who underwent robotic assisted laparoscopic and open pyeloplasty at a single institution, especially in regard to human capital changes, in an institutional cost analysis. A total of 44 patients 2 years old or older from a single institution underwent robotic assisted (37) or open (7) pyeloplasty from 2008 to 2010. We retrospectively reviewed the charts to collect demographic and perioperative data. The human capital approach was used to calculate parental productivity losses. Patients who underwent robotic assisted laparoscopic pyeloplasty had a significantly shorter average hospital length of stay (1.6 vs 2.8 days, p <0.05). This correlated with an average savings of lost parental wages of $90.01 and hospitalization expenses of $612.80 per patient when excluding amortized robot costs. However, cost savings were not achieved by varying length of stay when amortized costs were included. Robotic assisted laparoscopic pyeloplasty in children is associated with human capital gains, eg decreased lost parental wages, and lower hospitalization expenses. Future comparative outcome analyses in children should include financial factors such as human capital loss, which can be especially important for families with young children.


Cultural adaptation of the mental health first aid guidelines for depression used in English-speaking countries for China: a Delphi expert consensus study.
Most people who meet the criteria for a diagnosis of depression in China do not receive treatment. Family and friends can play a role in recognising the signs of depression and encouraging the person to seek treatment. However, many of them may lack the knowledge and skills to offer such help. The aim of this study was to culturally adapt the existing English-language mental health first aid (MHFA) guidelines for helping a person with depression to the Chinese context. A Delphi expert consensus study was conducted, in which two Chinese expert panels of mental health professionals (with experience in the field of clinical management of depression, n = 37) and consumers and carers (with lived experience, n = 30) rated the importance of actions that could be taken to help a person experiencing depression in mainland China. Data were collected over 3 survey rounds. In the 1st round questionnaire, 175 statements translated into Chinese from the English-language guidelines were presented to the expert panels and 12 new statements were generated from panellists' comments. Of these 187 statements, 173 were endorsed for inclusion in the adapted guidelines for China. Although the adapted guidelines were still quite similar to the guidelines for English-speaking countries, they also incorporated some new actions for the Chinese context, including those relating to different ways of respecting the autonomy of a person with depression and the role of their families. Further research is needed to explore the use of these guidelines by the Chinese public, including how they may be incorporated in Mental Health First Aid training.


Cross-View Action Recognition via Transferable Dictionary Learning.
Discriminative appearance features are effective for recognizing actions in a fixed view, but may not generalize well to a new view. In this paper, we present two effective approaches to learn dictionaries for robust action recognition across views. In the first approach, we learn a set of view-specific dictionaries where each dictionary corresponds to one camera view. These dictionaries are learned simultaneously from the sets of correspondence videos taken at different views with the aim of encouraging each video in the set to have the same sparse representation. In the second approach, we additionally learn a common dictionary shared by different views to model view-shared features. This approach represents the videos in each view using a view-specific dictionary and the common dictionary. More importantly, it encourages the set of videos taken from the different views of the same action to have the similar sparse representations. The learned common dictionary not only has the capability to represent actions from unseen views, but also makes our approach effective in a semi-supervised setting where no correspondence videos exist and only a few labeled videos exist in the target view. The extensive experiments using three public datasets demonstrate that the proposed approach outperforms recently developed approaches for cross-view action recognition.


Pre-treatment with Beta Carotene Gives Protection Against Nephrotoxicity Induced by Bromobenzene via Modulation of Antioxidant System, Pro-inflammatory Cytokines and Pro-apoptotic Factors.
Bromobenzene is an environmental toxin which causes hepatotoxicity, and the secondary metabolites on biotransformation cause nephrotoxicity. The objective of this study was to assess the alleviation of the nephrotoxic effect of bromobenzene by beta carotene in female Wistar albino rats. Beta carotene (10 mg/kg b.w.p.o.) was delivered orally to the rats for 9 days before bromobenzene (10 mM/kg b.w.p.o.) was intragastrically intubated. Kidney markers, antioxidant status and lipid peroxidation were evaluated. In addition, the levels of TNF-α, IL-6 and IL-1β were measured in serum and in kidney tissue homogenate using ELISA. Caspase, COX-2 and NF-κB were measured with the help of Western blotting. Histopathological analysis of the kidney was done for the control and experimental rats. Bromobenzene induction caused elevation in levels of creatinine, urea, uric acid, cytokines and lipid per oxidation along with deterioration in histological observations and antioxidant status. Pre-treatment with beta carotene significantly (*p < 0.05) normalised the levels of kidney markers and pro-inflammatory cytokines. It also reduced oxidative stress and lipid peroxidation, as shown by improved antioxidant status. The anti-apoptotic activity was evidenced by inhibition of protein expression of caspase, COX-2 and NF-κB. This significant reversal (*p < 0.05) of the above variations in comparison with the control group as noticed in the bromobenzene-administered rats demonstrates that beta carotene possesses promising nephroprotective effect through its antioxidant, anti-inflammatory and anti-apoptotic activity and therefore suggests its use as a potential therapeutic agent for protection from bromobenzene and hence environmental pollutant toxicity.


The roots of phylogeny: how did Haeckel build his trees?
Haeckel created much of our current vocabulary in evolutionary biology, such as the term phylogeny, which is currently used to designate trees. Assuming that Haeckel gave the same meaning to this term, one often reproduces Haeckel's trees as the first illustrations of phylogenetic trees. A detailed analysis of Haeckel's own evolutionary vocabulary and theory revealed that Haeckel's trees were genealogical trees and that Haeckel's phylogeny was a morphological concept. However, phylogeny was actually the core of Haeckel's tree reconstruction, and understanding the exact meaning Haeckel gave to phylogeny is crucial to understanding the information Haeckel wanted to convey in his famous trees. Haeckel's phylogeny was a linear series of main morphological stages along the line of descent of a given species. The phylogeny of a single species would provide a trunk around which lateral branches were added as mere ornament; the phylogeny selected for drawing a tree of a given group was considered the most complete line of progress from lower to higher forms of this group, such as the phylogeny of Man for the genealogical tree of Vertebrates. Haeckel's phylogeny was mainly inspired by the idea of the scala naturae, or scale of being. Therefore, Haeckel's genealogical trees, which were only branched on the surface, mainly represented the old idea of scale of being. Even though Haeckel decided to draw genealogical trees after reading On the Origin of Species and was called the German Darwin, he did not draw Darwinian branching diagrams. Although Haeckel always saw Lamarck, Goethe, and Darwin as the three fathers of the theory of evolution, he was mainly influenced by Lamarck and Goethe in his approach to tree reconstruction.


Positive psychosocial factors and NKT cells in ovarian cancer patients.
Psychosocial factors are known to be associated with properties of both NK cells and T cells in cancer patients. Less is known about the relationship between psychosocial factors and NKT cells, a rare group of lymphocytes that have known relevance for tumor control. We examined four psychosocial factors and percentage and number of CD3+CD56+ NKT cells, CD3-CD56+ NK cells, and CD3+CD56- T cells in peripheral blood lymphocytes (PBL), ascites, and tumor of 35 ovarian cancer patients and 28 patients with benign pelvic masses. Patients awaiting surgery for a suspected cancerous mass completed questionnaires and gave a pre-surgical blood sample. Ascites and tumor were taken during surgery. After lymphocyte isolation, subpopulations were analyzed by flow cytometry. Benign and cancer patients did not differ on PBL subpopulations. Among cancer patients, NKT cell percentage was significantly higher in tumor and ascites than in PBL; T cell percentage was significantly higher in PBL than tumor. NKT, NK, and T cell number were significantly higher in peripheral blood than in ascites. Positive reframing was related to significantly higher NKT cell percentage and number in PBL. Social support was related to significantly higher NKT cell percentage in tumor. Vigor was related to significantly higher NKT cell percentage in PBL. Total mood disturbance was not related to NKT cell percentage or number. No significant relationships were found between psychosocial factors and NK cell percentage and number and T cell percentage and number. Given the anti-tumor activity of CD3+CD56+ cells, these relationships may have relevance for cancer control.


Synthesis, Isolation, and Equilibration of 1,9- and 7,8-C70H2.
Equilibration of 1,9- and 7,8-C(70)H(2) has allowed the relative free energy of these isomers to be measured. These "simplest hydrocarbon derivatives of C(70)" are formed by hydroboration of C(70) at room temperature. Analysis of the platinum-catalyzed equilibration of these isomers yielded a relative free energy at 295 kelvin of 1.4 +/- 0.2 kilocalories per mole, with the 1,9 isomer being more stable. This value is in excellent agreement with the ab initio HF/6-31 G(*) calculated energy difference of 1.3 kilocalories per mole, whereas semiempirical calculations gave poor agreement.


Tissue factor and Toll-like receptor (TLR)4 in hyperglycaemia-hyperinsulinaemia. Effects in healthy subjects, and type 1 and type 2 diabetes mellitus.
Diabetes mellitus (DM) patients have an increased incidence of cardiovascular events. Blood tissue factor-procoagulant activity (TF-PCA), the initiating mechanism for blood coagulation, is elevated in DM. We have shown that hyperglycaemia (HG), hyperinsulinaemia (HI) and combined HG+HI (induced using 24-hour infusion clamps) increases TF-PCA in healthy and type 2 DM (T2DM) subjects, but not in type 1 DM (T1DM) subjects. The mechanisms for this are unknown. DM patients have elevated plasma lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 ligand. We postulated that TLR4 plays a role in modulating TF levels. We studied the effect of HG+HI on TLR4 and TF-PCA in vivo during 24-hour HG+HI infusion clamps in healthy subjects, and T1DM and T2DM subjects, and in vitro in blood. In vivo, in healthy subjects, 24-hour HG + HI infusion increased TLR4 six-fold, which correlated with TF-PCA (r= 0.91, p<0.0001). T2DM patients showed smaller increases in both. In T1DM subjects, TLR4 declined (50%, p<0.05) and correlated with TF-PCA (r=0.55; p<0.05). In vitro, HG (200 mg/dl added glucose) and HI (1-100 nM added insulin) increased TF-PCA in healthy subjects (~2-fold, 2-4 hours). Insulin inhibited by ~30% LPS-induced increase in TF-PCA and high glucose reversed it. TLR4 levels paralleled TF-PCA (r=0.71, p<0.0001); HG and HI increased TLR4 and insulin inhibited LPS-induced TLR4 increase. This is first evidence that even in healthy subjects, HG of short duration increases TLR4 and TF-PCA, key players in inflammation and thrombosis. TLR4-TF interplay is strikingly different in non-diabetic, T1DM and T2DM subjects.


Diffusive transport of radon in a column of moisturized sand.
Diffusive transport of radon in a moisturized sand column was investigated under well-defined and controlled conditions using a laboratory facility that consists of a cylindrical vessel (height and diameter 2 m) filled with sand. Equilibrium pore-gas radon-concentration profiles in the sand column were measured as a function of depth for several different levels of the ground-water table. The measurements were performed in the framework of a systematic validation study that also covered experiments with dry sand. The experimental data were compared with results of model calculations. Most parameters in the transport model were obtained from separate experiments on small sand samples. In this manner, the radon diffusion coefficient and emanation coefficient were determined as functions of pore-water content, as well as the water-retention characteristics of the sand. In general, the experimental data are reasonably well reproduced by the calculations with differences of 10%-40%. However, with respect to earlier results with dry sand indicating differences of generally smaller than 10%, the agreement between experiment and model for moisturized sand is clearly worse. The main part of the disagreement probably results from inhomegeneities in the sand column that are not accounted for in the transport model.


Immunomodulatory Polyketides from a Phoma-like Fungus Isolated from a Soft Coral.
Fourteen new polyketides with a trans-fused decalin ring system, libertalides A-N (3-16), together with two known analogues, aspermytin A and its acetate (1, 2), were isolated from the fermentation extract of a coral-derived Libertasomyces sp. fungus. Their relative configurations were elucidated on the basis of detailed spectroscopic analysis, and the absolute configurations were determined by TDDFT-ECD and optical rotation (OR) calculations. The OR of 1 and 2 were found to have opposite signs in CH3CN and CHCl3, which was in agreement with the OR calculations producing alternating signs for the optical rotation depending on the applied conditions. Because the signs of the OR for 1 and 2 showed high solvent dependence, they may not be used alone to correlate the absolute configurations. Compound 16 displayed structural novelty characterized by an α-enol ether bridge conjugated with an aldehyde group. In in vitro immunomodulatory screening, compounds 1, 4, and 10 significantly induced the proliferation of CD3+ T cells, while compounds 2, 7, 11, and 14 significantly increased the CD4+/CD8+ ratio at 3 μM. A preliminary structure-activity analysis revealed a crucial role of Δ7 and a terminal OH group in the regulation of CD3+ T cell proliferation. This is the first report of immunoregulatory activity for metabolites of this kind.


Interdependence of spatial properties and projection patterns of medial vestibulospinal tract neurons in the cat.
Activity of vestibular nucleus neurons with axons in the ipsi- or contralateral medial vestibulospinal tract was studied in decerebrate cats during sinusoidal, whole-body rotations in many planes in three-dimensional space. Antidromic activation of axon collaterals distinguished between neurons projecting only to neck segments from those with collaterals to C6 and/or oculomotor nucleus. Secondary neurons were identified by monosynaptic activation after labyrinth stimulation. A three-dimensional maximum activation direction vector (MAD) summarized the spatial properties of 151 of 169 neurons. The majority of secondary neurons (71%) terminated above the C6 segment. Of these, 43% had ascending collaterals to the oculomotor nucleus (VOC neurons), and 57% did not (VC neurons). The majority of VOC and VC neurons projected contralaterally and ipsilaterally, respectively. Most C6-projecting neurons could not be activated from oculomotor nucleus (V-C6 neurons) and projected primarily ipsilaterally. All VO-C6 neurons projected contralaterally. The distributions of MADs for secondary neurons with different projection patterns were different. Most VOC (84%) and contralaterally projecting VC (91%) neurons had MADs close to the activation vector of a semicircular canal pair, compared with 54% of ipsilaterally projecting VC (i-VC) and 39% of V-C6 neurons. Many i-VC (44%) and V-C6 (48%) neurons had responses suggesting convergent input from horizontal and vertical canal pairs. Horizontal and vertical gains were comparable for some, making it difficult to assign a primary canal input. MADs consistent with vertical-vertical canal pair convergence were less common. Type II yaw or type II roll responses were seen for 22% of the i-VC neurons, 68% of the V-C6 neurons, and no VOC cells. VO-C6 neurons had spatial properties between those of VOC and V-C6 neurons. These results suggest that secondary VOC neurons convey semicircular canal pair signals to both ocular and neck motor centers, perhaps linking eye and head movements. Secondary VC and V-C6 neurons carry more processed signals, possibly to drive neck and forelimb reflexes more selectively. Two groups of secondary i-VC neurons exhibited vertical-horizontal canal convergence similar to that present on neck muscles. The vertical-vertical canal convergence present on many neck muscles, however, was not present on medial vestibulospinal neurons. Spatial transformations achieved by the vestibulocollic reflex may occur in part on secondary neurons but further combination of canal signals must take place to generate compensatory muscle activity.


Depression severity and drug injection HIV risk behaviors.
This study examined the association of depression severity and drug injection HIV risk behavior among injection drug users. Injection drug users who met the DSM-IV criteria for major depressive disorder, dysthymia, or substance-induced mood disorder lasting at least 3 months were asked how often they used "needles or syringes that someone else had used" (injection risk behavior) in the past 90 days. Depression severity was measured by using the Modified Hamilton Rating Scale for Depression. Of the 109 subjects, 63% were male, 82% were Caucasian, and 10% were HIV positive. The subjects' mean modified Hamilton depression scale score was 21.0 (SD=3.9). The mean number of reported instances of injection risk behavior (needle sharing) in the past 90 days was 57.5 (SD=134.7). In a logistic regression analysis in which the effects of age, race, gender, number of days on which injection drugs were used (injection days), and average number of injections per injection day were controlled, depression severity was associated with injection risk (odds ratio=1.5; 95% confidence interval=1.1-2.3). Greater severity of depression is associated with greater frequency of injection risk behavior among depressed injection drug users. Risk reduction programs that target depressed injection drug users need to be designed.


Detecting selective sweeps: a new approach based on hidden markov models.
Detecting and localizing selective sweeps on the basis of SNP data has recently received considerable attention. Here we introduce the use of hidden Markov models (HMMs) for the detection of selective sweeps in DNA sequences. Like previously published methods, our HMMs use the site frequency spectrum, and the spatial pattern of diversity along the sequence, to identify selection. In contrast to earlier approaches, our HMMs explicitly model the correlation structure between linked sites. The detection power of our methods, and their accuracy for estimating the selected site location, is similar to that of competing methods for constant size populations. In the case of population bottlenecks, however, our methods frequently showed fewer false positives.


Horizontal Transfer of a Retrotransposon from the Rice Planthopper to the Genome of an Insect DNA Virus.
Horizontal transfer of genetic materials between virus and host has been frequently identified. Three rice planthoppers, Laodelphax striatellus, Nilaparvata lugens, and Sogatella furcifera, are agriculturally important insects because they are destructive rice pests and also the vector of a number of phytopathogenic viruses. In this study, we discovered that a small region (∼300 nucleotides [nt]) of the genome of invertebrate iridescent virus 6 (IIV-6; genus Iridovirus, family Iridoviridae), a giant DNA virus that infects invertebrates but is not known to infect planthoppers, is highly homologous to the sequences present in high copy numbers in these three planthopper genomes. These sequences are related to the short interspersed nuclear elements (SINEs), a class of non-long terminal repeat (LTR) retrotransposons (retroposons), suggesting a horizontal transfer event of a transposable element from the rice planthopper genome to the IIV-6 genome. In addition, a number of planthopper transcripts mapped to these rice planthopper SINE-like sequences (RPSlSs) were identified and appear to be transcriptionally regulated along the different developmental stages of planthoppers. Small RNAs derived from these RPSlSs are predominantly 26 to 28 nt long, which is a typical characteristic of PIWI-interacting RNAs. Phylogenetic analysis suggests that IIV-6 acquires a SINE-like retrotransposon from S. furcifera after the evolutionary divergence of the three rice planthoppers. This study provides further examples of the horizontal transfer of an insect transposon to virus and suggests the association of rice planthoppers with iridoviruses in the past or present.IMPORTANCE This study provides an example of the horizontal transfer event from a rice planthopper genome to an IIV-6 genome. A small region of the IIV-6 genome (∼300 nt) is highly homologous to the sequences presented in high copy numbers of three rice planthopper genomes that are related to the SINEs, a class of retroposons. The expression of these planthopper SINE-like sequences was confirmed, and corresponding Piwi-interacting RNA-like small RNAs were identified and comprehensively characterized. Phylogenetic analysis suggests that the giant invertebrate iridovirus IIV-6 obtains this SINE-related sequence from Sogatella furcifera through a horizontal transfer event in the past. To the best of our knowledge, this is the first report of a horizontal transfer event between a planthopper and a giant DNA virus and also is the first evidence for the eukaryotic origin of genetic material in iridoviruses.


Noninvasive Hemodynamic Assessment of Shock Severity and Mortality Risk Prediction in the Cardiac Intensive Care Unit.
This study sought to define the 2-dimensional and Doppler echocardiographic hemodynamics associated with each Society for Cardiovascular Angiography and Interventions (SCAI) stage, and to determine their association with mortality. The SCAI shock stages classification stratifies mortality risk in cardiac intensive care unit (CICU) patients, but the echocardiographic and hemodynamic parameters that define these SCAI shock stages are unknown. Unique CICU patients admitted from 2007 to 2015 who had a transthoracic echocardiogram within 1 day of CICU admission were included. Echocardiographic variables were evaluated as a function of SCAI shock stage. Multivariable logistic regression determined the association between echocardiographic parameters with adjusted hospital mortality. We included 5,453 patients with a median age of 69.3 years (interquartile range: 58.2 to 79.0 years) (37% women), and a median left ventricular ejection fraction (LVEF) of 50% (interquartile range: 35% to 61%). Higher SCAI shock stages were associated with lower LVEF and worse systemic hemodynamics. Hospital mortality was higher in patients with LVEF <40%, cardiac index <1.8 l/min/m2, stroke volume index <35 ml/m2, cardiac power output <0.6 W, or medial early mitral valve inflow velocity to early diastolic annular velocity (E/e') ratio >15 (particularly in SCAI shock Stages A to C). After multivariable adjustment, only stroke volume index <35 ml/m2 (adjusted odds ratio: 2.0; 95% confidence interval: 1.4 to 3.0; p < 0.001) and E/e' ratio >15 (adjusted odds ratio: 1.52; 95% confidence interval: 1.04 to 2.23; p = 0.03) remained associated with higher hospital mortality. Noninvasive 2-dimensional and Doppler echocardiographic parameters correlate with the SCAI shock stages and improve risk stratification for hospital mortality in CICU patients. Low stroke volume index and high E/e' ratio demonstrated the strongest association with hospital mortality.


Exploration of chlamydial type III secretion system reconstitution in Escherichia coli.
Type III secretion system is a virulent factor for many pathogens, and is thought to play multiple roles in the development cycle and pathogenesis of chlamydia, an important human pathogen. However, due to the obligate intracellular parasitical nature of chlamydiae and a lack of convenient genetic methodology for the organisms, very limited approaches are available to study the chlamydial type III secretion system. In this study, we explored the reconstitution of a chlamydial type III secretion in Escherichia coli. We successfully cloned all 6 genomic DNA clusters of the chlamydial type III secretion system into three bacterial plasmids. 5 of the 6 clusters were found to direct mRNA synthesis from their own promoters in Escherichia coli transformed with the three plasmids. Cluster 5 failed to express mRNA using its own promoters. However, fusion of cluster 5 to cluster 6 resulted in the expression of cluster 5 mRNA. Although only two of the type III secretion system proteins were detected transformed E. coli due to limited antibody availability, type III secretion system-like structures were detected in ultrathin sections in a small proportion of transformed E. coli. We have successfully generated E. coli expressing all genes of the chlamydial type III secretion system. This serves as a foundation for optimal expression and assembly of the recombinant chlamydial type III secretion system, which may be extremely useful for the characterization of the chlamydial type III secretion system and for studying its role in chlamydial pathogenicity.


Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice.
Murine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 x CBA)F(1) mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3(+) mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves' hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.


Baseline predictors of progression of Parkinson's disease in a sample of Egyptian patients: clinical and biochemical.
Clinical progression of Parkinson's disease (PD) is highly heterogeneous, and its predictors are generally lacking. Identifying predictors of early disease progression is important for patients' management and follow-up. The current study aims to identify clinical, neuroimaging and biochemical baseline predictors of motor progression in patients with PD. Forty-five PD patients were assessed at baseline, 6 months and 1 year using MDS-UPDRS total and subscores, Hoehn and Yahr (H&Y), Schwab and England (S&E), International Physical Activity Questionnaire (IPAQ). Baseline New Freezing of Gait Questionnaire (NFOG-Q), Berg Balance Scale (BBS), Ten-Meter Walking Test (10-MWT), and Time Up and Go Test (TUG), Non-Motor Symptoms Scale (NMSS), Beck Depression Inventory (BDI), PD questionnaire 39 (PDQ-39), MRI brain, uric acid, lipid profile and glycated hemoglobin were performed. Significant worsening of MDS-UPDRS total, part III scores, H&Y, S&E and IPAQ (p < 0.001) was detected. One-year progression of H&Y and S&E were significantly correlated to disease duration (p = 0.014, p = 0.025, respectively). Progression of H&Y was correlated to baseline TUG (p = 0.035). S&E progression was correlated to baseline MDS-UPDRS total score (rho = 0.478, p = 0.001) and part III (rho = 0.350, p = 0.020), H&Y (rho = 0.401, p = 0.007), PIGD (rho = 0.591, p < 0.001), NFOG-Q (rho = 0.498, p = 0.001), and TUG (rho = 0.565, p = 0.001). Using linear regression, there was no predictors of clinical progression among the used baseline variables. Despite the significant motor and physical activity progression over 1 year that was correlated to baseline motor and gait severity, but without predictive value, further similar and longitudinal studies are warranted to detect predictors of early progression and confirm findings. The online version contains supplementary material available at 10.1186/s41983-022-00445-1.


Ketones prevent oxidative impairment of hippocampal synaptic integrity through KATP channels.
Dietary and metabolic therapies are increasingly being considered for a variety of neurological disorders, based in part on growing evidence for the neuroprotective properties of the ketogenic diet (KD) and ketones. Earlier, we demonstrated that ketones afford hippocampal synaptic protection against exogenous oxidative stress, but the mechanisms underlying these actions remain unclear. Recent studies have shown that ketones may modulate neuronal firing through interactions with ATP-sensitive potassium (KATP) channels. Here, we used a combination of electrophysiological, pharmacological, and biochemical assays to determine whether hippocampal synaptic protection by ketones is a consequence of KATP channel activation. Ketones dose-dependently reversed oxidative impairment of hippocampal synaptic integrity, neuronal viability, and bioenergetic capacity, and this action was mirrored by the KATP channel activator diazoxide. Inhibition of KATP channels reversed ketone-evoked hippocampal protection, and genetic ablation of the inwardly rectifying K+ channel subunit Kir6.2, a critical component of KATP channels, partially negated the synaptic protection afforded by ketones. This partial protection was completely reversed by co-application of the KATP blocker, 5-hydoxydecanoate (5HD). We conclude that, under conditions of oxidative injury, ketones induce synaptic protection in part through activation of KATP channels.


Interrupting antiretroviral treatment in HIV cure research: scientific and ethical considerations.
Over the past several years there has been intense activity directed at the possibility of achieving remission or eradication of HIV infection. Current assays for the measurement of latent HIV are insufficient to demonstrate complete clearance of replication-competent HIV. Therefore, the ultimate test for assessing whether investigational interventions have resulted in HIV remission or eradication is to interrupt standard antiretroviral therapy (ART) in a carefully controlled clinical trial setting. These procedures, known as analytic treatment interruptions (ATIs), raise important scientific and ethical questions. The lack of definitive assays for measuring viral reservoirs not only makes research on HIV remission or cure challenging, it also affects the ability to assess risks from ATIs themselves. In spite of these challenges, basic ethical criteria can be met with careful study design and close monitoring. In this brief report we outline ethical standards for HIV cure research involving ATIs. These criteria should be revisited as the science evolves.


Long-term oncological outcomes of men undergoing radical prostatectomy with preoperative prostate-specific antigen <2.5 ng/ml and 2.5-4 ng/ml.
Prostate-specific antigen (PSA) screening has increased the detection of small, organ-confined tumors, and studies suggest that these patients may have favorable outcomes following radical prostatectomy (RP). To date, there are limited data available on the outcomes of patients diagnosed with low PSA (≤ 4 ng/ml) who underwent RP. This study aimed to evaluate long-term oncological outcomes of patients undergoing RP with preoperative PSA <2.5 and 2.5-4 ng/ml compared with PSA 4.1-10 ng/ml. Data were analyzed from 3,621 men who underwent RP between 1988 and 2010 at our institution. Patients were stratified into 3 PSA groups: <2.5 ng/ml (n = 280), 2.5-4 ng/ml (n = 563), and 4.1-10 ng/ml (n = 2,778). Patient and disease characteristics were compared. Overall, biochemical disease-free (bDFS), and PCa-specific survivals were analyzed and compared between the groups. Multivariable analyses were conducted using proportional hazards model. Compared with the 4.1-10 ng/ml PSA group, Gleason score >7, extracapsular extension, and non-organ-confined disease were less common in patients with PSA ≤ 4 ng/ml (all P < 0.001). The incidence of organ-confined disease was similar between the PSA < 2.5 and 2.5-4 ng/ml groups while perineural invasion (P = 0.050) and Gleason score ≥ 7 (P = 0.026) were more common in the 2.5-4 ng/ml PSA group. Estimated 10-year overall and PCa-specific survivals were comparable across all PSA groups, whereas bDFS was significantly lower in PSA 4.1-10 group (P < 0.001). bDFS was not statistically different between PSA <2.5 and 2.5-4 groups (P = 0.300). 10-year bDFS were 59.0%, 70.1%, and 76.4% in PSA 4.1-10, 2.5-4, and <2.5, respectively. For the PSA ≤ 4 ng/ml groups, age, race, margin status, pathologic stage, but not PSA were independent predictors of bDFS, whereas age, pathologic Gleason, and biochemical recurrence were associated with overall survival. Long-term oncological outcomes (overall, bDFS, PCa-specific survivals) of patients presenting with low PSA (≤ 4 ng/ml) were excellent in this study. Compared with PSA 4.1-10 ng/ml, patients presenting with PSA ≤ 4 ng/ml had better bDFS outcomes. However, there was no difference in long-term outcomes between PSA <2.5 and 2.5-4 ng/ml.


Genomic and gene expression signatures of radiation in medulloblastomas after low-dose irradiation in Ptch1 heterozygous mice.
Accurate cancer risk assessment of low-dose radiation poses many challenges that are partly due to the inability to distinguish radiation-induced tumors from spontaneous ones. To elucidate characteristic features of radiation-induced tumors, we analyzed 163 medulloblastomas that developed either spontaneously or after X-ray irradiation at doses of 0.05-3 Gy in Ptch1 heterozygous mice. All spontaneous tumors showed loss of heterozygosity in broad regions on chromosome 13, with losses at all consecutive markers distal to Ptch1 locus (S-type). In contrast, all tumors that developed after 3 Gy irradiation exhibited interstitial losses around Ptch1 with distal markers retained (R-type). There was a clear dose-dependent increase in the proportion of R-type tumors within the intermediate dose range, indicating that the R-type change is a reliable radiation signature. Importantly, the incidence of R-type tumors increased significantly (P = 0.007) at a dose as low as 50 mGy. Integrated array-comparative genomic hybridization and expression microarray analyses demonstrated that expression levels of many genes around the Ptch1 locus faithfully reflected the signature-associated reduction in genomic copy number. Furthermore, 573 genes on other chromosomes were also expressed differently between S-type and R-type tumors. They include genes whose expression changes during early cerebellar development such as Plagl1 and Tgfb2, suggesting a recapitulation of gene subsets functioning at distinct developmental stages. These findings provide, for the first time, solid experimental evidence for a significant increase in cancer risk by low-dose radiation at diagnostic levels and imply that radiation-induced carcinogenesis accompanies both genomic and gene expression signatures.


T-type calcium channel enhancer SAK3 promotes dopamine and serotonin releases in the hippocampus in naive and amyloid precursor protein knock-in mice.
T-type calcium channels in the brain mediate the pathophysiology of epilepsy, pain, and sleep. Recently, we developed a novel therapeutic candidate, SAK3 (ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a] pyridine]-2-ene-3-carboxylate), for Alzheimer's disease (AD). The cognitive improvement by SAK3 is closely associated with enhanced acetylcholine (ACh) release in the hippocampus. Since monoamines such as dopamine (DA), noradrenaline (NA), and serotonin (5-HT) are also involved in hippocampus-dependent learning and psychomotor behaviors in mice, we investigated the effects of SAK3 on these monoamine releases in the mouse brain. Oral administration of SAK3 (0.5 mg/kg, p.o.) significantly promoted DA and 5-HT releases in the naive mouse hippocampal CA1 region but not in the medial prefrontal cortex (mPFC), while SAK3 did not affect NA release in either brain region. The T-type calcium channel-specific inhibitor, NNC 55-0396 (1 μM) significantly antagonized SAK3-enhanced DA and 5-HT releases in the hippocampus. Interestingly, the α7 nicotinic ACh receptor (nAChR) antagonist, methyllycaconitine (1 nM) significantly inhibited DA release, and the α4 nAChR antagonist, dihydro-β-erythroidine (100 μM) significantly blocked both DA and 5-HT releases following SAK3 (0.5 mg/kg, p.o.) administration in the hippocampus. SAK3 did not alter basal monoamine contents both in the mPFC and hippocampus. SAK3 (0.5 mg/kg, p.o.) administration also significantly elevated DA and 5-HT releases in the hippocampal CA1 region of amyloid-precursor protein (APP)NL-GF knock-in (KI) mice. Moreover, hippocampal DA and 5-HT contents were significantly decreased in APPNL-GF KI mice. Taken together, our data suggest that SAK3 promotes monoamine DA and 5-HT releases by enhancing the T-type calcium channel and nAChR in the mouse hippocampus.


Studies of Twin Responses to Understand Exercise Therapy (STRUETH): Body Composition.
We studied individual variability in exercise responses in twins. We hypothesized that 1) endurance (END) training would reduce fat mass whereas resistance (RES) training would increase lean mass, 2) individuals who did not respond to one modality would respond to the other, and 3) cross-sectional heritability estimates would be higher than estimates based on training responses. DXA was undertaken in 84 same-sex untrained twins (30 monozygotic [MZ], 12 dizygotic [DZ]). Participants underwent 3 months of END and RES training, separated by 3 months washout. Twins trained in pairs. RES (P < 0.001) and END (P = 0.002) increased lean mass, with a greater change in RES (P < 0.001). Similarly, RES (P = 0.04) and END (P = 0.006) decreased fat mass. Eighty-four percent of subjects responded positively to RES for lean mass and 58% to END (P < 0.001). For fat mass, RES and END induced 56% and 66% responder rates, respectively (P = 0.28). Cross-sectional intraclass correlations, used to assess the similarity in twin responses, were higher for MZ than DZ pairs for all variables. Following training, only MZ pairs were significantly correlated (P < 0.001) for change in lean mass to RES. To our knowledge, this study is the first to report individual responsiveness in body composition to both RES and END in the same subjects. Although RES and END induced favorable changes in fat mass, RES was superior for lean mass. The frequency of lean mass responders to RES exceeded that for END, whereas response rates for fat mass were similar. Cross-sectional heritability estimates were higher than training response estimates, and shared environment had the largest influence on changes in body composition. This study suggests that exercise professionals should consider modality and environmental factors when optimizing exercise interventions.


Do Bilateral Pleural Effusions Always Have the Same Cause?
A 67-year-old man with a history of seropositive rheumatoid arthritis (RA) was admitted to the Internal Medicine ward for bilateral pleural effusion. Two years before this episode, coinciding with an exacerbation of the RA, he was incidentally diagnosed with asymptomatic left pleural effusion compatible with rheumatoid exudate, which was resolved with a tube thoracostomy. Three weeks before admission, the patient developed asthenia, orthopnoea and progressive dyspnoea. A chest x-ray revealed bilateral pleural effusion occupying the lower third of the left hemithorax and a smaller portion of the right hemithorax along with marked elevation of N-terminal fragment of pro-brain natriuretic peptide levels. The patient was admitted with a diagnosis of left-sided heart failure. Transthoracic echocardiography and cardiac catheterization confirmed the existence of ischaemic cardiomyopathy. After 2 days of diuretic treatment, the right pleural effusion resolved, but the left effusion persisted. A needle thoracentesis was performed, draining 800 ml of milky fluid compatible with rheumatoid pseudochylothorax. Bilateral pleural effusions nearly always have the same cause, and usually thoracentesis on only one side is needed.Rarely, however, there can be two separate causes: this is known as Contarini's syndrome.


Patient experience of expanded-scope-of-practice musculoskeletal physiotherapy in the emergency department: a qualitative study.
The increasing number of people presenting to hospital with musculoskeletal conditions places pressure on existing services, and has resulted in expanding the scope of practice of musculoskeletal physiotherapists working in emergency departments (ED). The aim of the present study was to qualitatively explore the perspectives of patients presenting with an isolated musculoskeletal condition seen by a musculoskeletal physiotherapist in the ED of two Australian hospitals situated in contrasting geographical locations. Semistructured interviews were conducted with nine participants from a major metropolitan hospital and 16 participants from a remote hospital. Interviews were transcribed, coded and analysed using a thematic approach. RESULTS. The emerging themes from the two datasets were remarkably similar, so the final themes were merged. The major themes were: (1) participants were satisfied with the process and service provided by the physiotherapist; (2) the personal attributes of the physiotherapists were important to participants; (3) participant confidence in the skills and attributes of the physiotherapist made them a suitable alternative to a doctor in these situations; and (4) the timing and efficiency of the physiotherapy service was better than expected and valued. Participants from both settings described their experience in positive terms, reflecting satisfaction with their management by an expanded scope of practice musculoskeletal physiotherapist.


Pharmacotherapy for hypertension in the elderly.
To quantify the long-term effects of antihypertensive drug therapy on morbidity and mortality in the elderly. To characterize co morbid risk profiles of trial participants. Electronic search of WHO-ISH Collaboration register (August 1997), The Cochrane Library (1997; Issue 1), MEDLINE (1966 to April 1997) and two Japanese databases (1973-1995); references from reviews, trials and 10 previously published meta-analyses; and experts. Randomized controlled trials of at least one year duration in hypertensive elders (at least 60 years old) assessing antihypertensive drug therapy and providing morbidity and mortality data. At least two independent reviewers abstracted data on morbidity and mortality results and trial characteristics. The following outcomes were assessed: total mortality; coronary heart disease (CHD) mortality; combined CHD morbidity and mortality; cerebrovascular mortality; combined cerebrovascular morbidity and mortality; cardiovascular mortality; combined cardiovascular morbidity and mortality; and drop outs due to side effects of treatment. Fifteen trials including 21,908 elderly subjects were identified. The average prevalence of cardiovascular risk factors, cardiovascular disease, and competing co morbid diseases was lower among trial participants than the general population of hypertensive elderly persons. Most subjects were 60 to 80 years old. Most trials were conducted in Western, industrialized countries and evaluated diuretic and beta-blocker therapies. Event rates per 1000 participants over approximately 5 years indicated that antihypertensive drug therapy was beneficial. Cardiovascular morbidity and mortality was reduced from 177 to 126 events (95% CI of the difference 31 to 73). Cardiovascular mortality was reduced from 69 to 50 deaths (95% CI of the difference 9 to 31). Total mortality was reduced from 129 to 111 deaths (95% CI of difference 4 to 28). The data from the three trials restricted to persons with isolated systolic hypertension indicated a significant benefit: cardiovascular morbidity and mortality over approximately 5 years was reduced from 157 to 104 events per 1000 participants (95% CI of the difference 12 to 89). Numbers of participants who dropped out of trials secondary to adverse drug effects were often not reported. The four trials that did report this data showed a wide variation in drop out rates ranging from no significant differences between treatment and control groups to as many as one out of four patients dropping out due to side effects of treatment. Randomized controlled trials establish that treating healthy older persons with hypertension is highly efficacious. Benefits of treatment with low dose diuretics or beta-blockers are clear for persons in their 60s to 70s with either diastolic or systolic hypertension. Differential treatment effects based on patient risk factors, pre-existing cardiovascular disease and competing co-morbidities could not be established from the published trial data.


Fermenter growth of Streptococcus agalactiae and large-scale production of CAMP factor.
Streptococcus agalactiae (group B) was grown in Todd-Hewitt broth (36.4 g l-1, pH 7.8) in a Braun Fermenter (type B20) to investigate the conditions of optimal bacterial growth and maximal production of CAMP factor. The influence of different gas atmospheres (air, N2, CO2, and gas mixtures) on growth, CAMP production and chain length of S. agalactiae was studied. The organisms grew best in the presence of 2% (w/v) glucose, at pH 6.2, with a constant flow of CO2. The number of diplococci and monococci under these conditions reached almost 80% of the total population.


Reconstructing the paradigm: teaching across the disciplines.
In this article, Caroline Brown, a literature professor who focuses on American and African Diasporic writing, and Alexia Pollack, a biology professor with expertise in neuropharmacology, recount their experiences teaching across the disciplines in one another's respective classrooms, finding points of intersection and divergence, and creating classroom dialogues from the resultant encounters. Central to this process is permitting students to enter discipline-specific discourses from other disciplinary perspectives. In Caroline Brown's first year general education seminar, Examining Consciousness, a course constructed around the study of the representation of the brain through the reading of scientific writings, popular essays, personal narratives, fiction, and poetry, Alexia Pollack presented scientific lectures on neurotransmission, brain organization and structure, with an emphasis on how the brain is affected by drug addiction and organic disease. In Alexia Pollack's undergraduate and graduate courses, Neurobiology and Biology of Learning and Memory, Caroline Brown lectured on the intersection of artistry and science in American literature, tracing the depiction of learning and memory in Realistic, Modern, and Post-Modern novels, and how scientific developments influenced their representation. During these encounters the students were introduced to discipline-specific approaches, which were distinct from the perspectives of their respective classrooms. As a result, larger classroom discussions were created, allowing students to perceive intersecting dimensions of very different disciplines. This conceptual flexibility permitted students to "think outside the box" in order to develop a more complete appreciation of their particular discipline and to recognize its place in the world at large.


Optimization of linezolid therapy in the critically ill: the effect of adjusted infusion regimens.
Insufficient linezolid levels, which are associated with a poorer outcome, are often observed in ICU patients who receive standard dosing. Although strategies to overcome these insufficient levels have been discussed, appropriate alternative dosing regimens remain to be identified. Various infusion regimens (1200-3600 mg/day; q6h, q8h, q12h and continuous) were simulated in 67 000 ICU patients. The probability of attaining pharmacodynamic targets ( T >MIC ≥85%, AUC/MIC ≥100, cumulative fraction of response for Staphylococcus aureus and Enterococcus spp., PTA for an MIC of 0.5-4 mg/L) as well as the avoidance of toxic concentrations and concentrations constantly below the MIC (lack of antibiotic effect) or inside a mutant selection window (resistance development) were evaluated. Best target attainment according to T >MIC was observed for continuous infusions, followed by q6h, q8h and q12h. A substantially reduced target attainment was observed in patients with acute respiratory distress syndrome (ARDS). In patients without ARDS, 1200 mg/day was insufficient irrespective of the regimen, while a dose of 1400 mg/day administered q6h or by continuous infusions provided an acceptable target attainment (e.g. cumulative fraction of response with regards to T >MIC ≥93%). Higher rates of potentially toxic trough concentrations (28% versus 12%) and concentrations constantly inside the mutant selection window (15% versus <0.1%) were observed with continuous infusions compared with q6h infusions (1400 mg/day, patients without ARDS). Irrespective of the regimen, 1200 mg/day linezolid might be insufficient for the treatment of ICU patients. Patients without ARDS might particularly benefit from q6h infusions with increased daily doses (e.g. 1400 mg/day).


Effectiveness of malaria control during changing climate conditions in Eritrea, 1998-2003.
To assess the effectiveness of impregnated mosquito nets, indoor residual spraying and larval control relative to the impacts of climate variability in the decline of malaria cases in Eritrea. Monthly data on clinical malaria cases by subzoba (district) in three zobas (zones) of Eritrea for 1998-2003 were used in Poisson regression models to determine whether there is statistical evidence for reduction in cases by DDT, malathion, impregnated nets and larval control used over the period, while analysing the effects of satellite-derived climate variables in the same geographic areas. Both indoor residual spraying (with DDT or malathion) and impregnated nets were independently and significantly negatively associated with reduction in malaria cases, as was larval control in one zoba. Malaria cases were significantly positively related to differences in current and previous months' vegetation (NDVI) anomalies. The relationship to rainfall differences 2 and 3 months previously was also significant, but the direction of the effect varied by zoba. Standardized regression coefficients indicated a greater effect of climate in the zoba with less intense malaria transmission. The results support the view that both indoor residual spraying and impregnated nets have been independently effective against malaria, and that larval control was also effective in one area. Thus climate, while significant, is not the only explanation for the recent decline in malaria cases in Eritrea. If appropriate statistical approaches are used, routine surveillance data from cases attending health facilities can be useful for assessing control programme success and providing estimates of the effectiveness of individual control measures. Effectiveness estimates suitable for use in cost-effectiveness analysis have been obtained.


Adequate Number of Swallows for Pharyngeal Pressure Measurement of a Subject using High-resolution Manometry.
Introduction The number of pressure measurements that need to be recorded using high-resolution manometry (HRM) for the accurate evaluation of pharyngeal function is not well established. Objective The purpose of this study is to clarify the number of swallows required to obtain an accurate pharyngeal manometric profile of a person. Methods Forty healthy adults performed a dry swallow and bolus swallows using 3-, 5-, or 10 ml of water and underwent measurements using the Starlet HRM system. Each subject underwent 10 swallows for each of the four bolus volume conditions. Results The mean of up to seven measurements of maximum pre-swallow upper esophageal sphincter pressure with 10 ml of swallow was close to the mean of up to eight measurements in 95% of the subjects. Similarly, the rate of change of the average for the eighth and ninth measurements and the rate of change for the average of the ninth and tenth measurements were less than 5%. When the other parameters were similarly measured up to the sixth measurement, no major change in the average value was observed even if more measurements were taken. Conclusion A minimum of six measurements are required, and seven swallows are sufficient for evaluating the pharyngeal manometric profile of a single person. This number of measurements can be a useful criterion when performing HRM measurements on individual subjects.


Patients' knowledge of psoriasis: pilot study.
A brief questionnaire was constructed to sample patients' factual knowledge of the nature of psoriasis. The study demonstrated that many patients with psoriasis have gaps in their knowledge of the disease or misconceptions that could be obstacles to effective treatment and disease prevention. The results of the questionnaire study are discussed as well as the need for patients to be aware of factors to improve self-care and extrinsic conditions that can exacerbate this disease.


Isolated sural neuropathy: report of two cases.
Two cases of isolated sural neuropathy are reported. In 1 case it was thought that the neuropathy was a direct result of compression of the sural nerve by a combat boot. In the 2nd case the etiology possibly involved 2 factors: chronic trauma to the nerve by walking on an inverted foot and irritative neuritis secondary to chronic, low-grade thrombophlebitis of the small saphenous vein. In both cases nonsurgical treatment was successful. Although isolated sural neuropathy occurs infrequently, the diagnosis should be considered in patients who have numbness along the lateral aspects of the foot.


Self-recognition by an intrinsically disordered protein.
The intrinsically disordered translocation domain (T-domain) of the protein antibiotic colicin N binds to periplasmic receptors of target Escherichia coli cells in order to penetrate their inner membranes. We report here that the specific 27 consecutive residues of the T-domain of colicin N known to bind to the helper protein TolA in target cells also interacts intramolecularly with folded regions of colicin N. We suggest that this specific self-recognition helps intrinsically disordered domains to bury their hydrophobic recognition motifs and protect them against degradation, showing that an impaired self-recognition leads to increased protease susceptibility.


Immunohistochemical expression of p53 in animal tumors: a methodological study using four anti-human p53 antibodies.
Mutations in the p53 tumor suppressor gene are the most common genetic alterations in human cancers. These mutations usually lead to strongly enhanced protein stabilization and allow detection by immunohistochemistry. Two monoclonal (DO-7 and PAb-240) and two polyclonal (Ab-7 and CM-1) antibodies were evaluated by standard immunoperoxidase method in domestic animal tumors, chiefly squamous cell carcinomas (SCC), and osteosarcomas as positive controls. Immunoreactivity was detected in SCC of cattle, sheep, horse and cat as well as in feline actinic keratosis, with PAb-240 and CM-1 antibodies. One polyclonal antibody (Ab-7) did not give positive result at all, whereas DO-7 monoclonal antibody did not react in dogs and cats. Immunodetection of p53 protein is thus possible in all domestic species tested, especially with CM-1 and PAb-240 antibodies, and p53 alterations seem to occur early in carcinogenesis of feline SCC as in comparable human lesions.