The Hedgehog signaling pathway plays an essential role in maintaining the CD44+CD24-/low subpopulation and the side population of breast cancer cells.
The side population (SP) and the CD44(+)/CD24(-/low) population have been reported in separate studies to include more tumorigenic cells than other populations, and to have the ability to form new tumors and undergo heterogeneous differentiation in breast cancer tissue. However, the relationship between these two populations has not yet been explored in breast cancer cells. Here it is shown that the SP and the CD44(+)/CD24(-/low) populations are overlapping. Both populations were resistant to paclitaxel. Components of the Hedgehog (Hh) signaling pathway were more highly expressed in these cell populations at both the mRNA and protein levels compared with other populations. Furthermore, inhibition of Hh signaling activity suppressed the proliferation of both populations. The significance of Hh signaling activity in the proliferation of both populations was confirmed by the effect of an si-RNA against Gli1, a trans-activator of the Hh signaling pathway, on the proliferation of both populations. These data suggest that the Hh signaling pathway is essential for the proliferation of the tumorigenic population of breast cancer cells, and that this pathway might represent a new candidate for breast cancer therapy targeting cancer stem cells.


Bonded amalgam restorations: using a glass-ionomer as an adhesive liner.
Due to the lack of adhesiveness of amalgam to tooth structure, several adhesive cements have been utilized in bonded amalgam restorations. This study evaluated whether Fuji-II glass-ionomer cement is an appropriate adhesive liner in bonded amalgam restorations. Two adhesive composite luting cements (Amalgambond Plus and Panavia-21) and Copalite cavity liner were compared. The study was conducted in two phases. In the first part, we quantitatively assessed the tensile bond strengths as well as the failure modes of amalgam bonded to human dentin, using different adhesive liners. In each group, the flat dentin surface was treated with the assigned adhesive cement with a Teflon mold, followed by condensation of amalgam (Valiant PhD) onto it. Each group's mean tensile bond strengths were recorded and the statistical analysis by one way ANOVA showed no significant differences among groups (p > 0.05). Similar to the fracture patterns of the Amalgambond Plus and Panavia-21 groups, the failure mode of Fuji-II group was predominantly adhesive fracture. In the second part, the fracture strengths of amalgam restored teeth were measured using different adhesive liners. Standard MOD cavities were prepared in each tooth except for the intact tooth group. After treatment with the assigned adhesives or varnish, the cavities were restored with amalgam. Fracture strengths were then measured and the fractured interfaces examined using a scanning electron microscope. The fracture strengths of the intact tooth, Amalgambond Plus, Panavia-21 and Fuji-II groups were significantly higher than those of the Copalite and prepared cavity without restoration groups (p < 0.01). Accordingly, Fuji-II glass-ionomer cement, when used as an adhesive liner of amalgam restoration, may effectively reinforce the remaining tooth structure and, therefore, enhance the fracture resistance of the amalgam-restored teeth.


[Morphofunctional features of the hypothalamo-hypophyseal system in experimental cerebral abscess].
The morphological characteristics of the hypothalamo-pituitary neurosecretory system (HPNS) were studied in 123 rats with an experimental abscess in the temporal area of the brain. It was found that changes in the HPNS in this pathology ran 2 stages corresponding to the periods of the development of the pyoinflammatory process in the cerebral tissue. In the first period (at the 3rd-10th day of the development of a cerebral abscess) the functional activity of the HPNS was inhibited: a decrease in both synthesis and excretion of neurohormones was evident. The mortality rate at this period was the highest (21 of 23 rats). At the second period (the 15th-30th day of experiment) there was an increase in the activity of neurosecretory nuclei and a decrease in the mortality rate (2 rats). It is suggested that the absence of NPNS activation was one of the causes of the high mortality rate at the first period of the experiment which was related to the direct damaging action of the abscess localized in the cerebral portions having the direct impact on the neurosecretory system.


[Differential surgical treatment of liver cirrhosis].
The work analyzes the data of treatment of 144 patients with the cirrhotic process in the liver. The patients were subjected to 196 different operations. Surgical interventions were fulfilled depending on the stage of cirrhosis, chronic hepatitis--precirrhosis included. To diagnoze and determine the stage of the cirrhotic process the authors used a complex of investigations including the summary assessment of the liver function by the formula developed in the clinic, radioisotopic diagnosis, laparoscopy with target puncture biopsy, splenoportography, lymphography. The cirrhosis stage and the degree of hepatic insufficiency determined the choice of periarterial hepatic neurectomy. Marginal resection of the liver was performed in chronic hepatitis and the initial stage of cirrhosis.


Cyclooxygenase-2 expression in postmastectomy chest wall relapse.
Cyclooxygenase-2 (COX-2) expression has been shown to be associated with radiation resistance, which theoretically could be overcome with the use of COX-2 inhibitors. The purpose of this study was to assess the prognostic significance and clinical correlations of COX-2 expression (COX) in a cohort of patients treated with radiation for postmastectomy chest wall relapse. Between 1975 and 1999, 113 patients were treated for isolated postmastectomy chest wall relapse. All patients were treated with biopsy and/or excision of the chest wall recurrence followed by radiation therapy. Median follow-up was 10 years. All clinical data, including demographics, pathology, staging, receptor status, HER-2/neu status, and adjuvant therapy, were entered into a computerized database. Paraffin-embedded chest wall recurrence specimens were retrieved from 42 patients, of which 38 were evaluated, created into a tissue microarray, stained by immunohistochemical methods for COX, and graded 0 to 3+. A score of 2 to 3+ was considered positive. Overall survival from original diagnosis for entire cohort was 44% at 10 years. Survival rate after chest wall recurrence was 28% at 10 years. The distant metastasis-free survival rate after chest wall recurrence was 40% at 10 years. Local-regional control of disease was achieved in 79% at 10 years after chest wall recurrence. COX was considered positive in 13 of 38 cases. COX was inversely correlated with estrogen receptor (P = 0.045) and progesterone receptor (P = 0.028), and positively correlated with HER-2/neu (P = 0.003). COX was also associated with a shorter time to postmastectomy chest wall relapse. The distant metastasis-free rate for COX-negative patients was 70% at 10 years, compared with 31% at 10 years for COX-2-positive patients (P = 0.029). COX positive had a poorer local-regional progression-free rate of 19% at 10 years, compared with 81% at 10 years for COX negative. This was of high statistical significance with a P value of 0.003. Outcome following radiation therapy for postmastectomy chest wall relapse is relatively poor. Positive COX correlated with other markers of poor outcome, including a shorter time to local relapse, negative estrogen receptor/progesterone receptor, and positive Her-2/neu status. Positive COX correlated with higher distant metastasis and lower local-regional control of disease. If confirmed with larger studies, these data have implications with respect to the concurrent use of COX-2 inhibitors and radiation for postmastectomy chest wall relapse.


Complexes of streptavidin-fused antigens with biotinylated antibodies targeting receptors on dendritic cell surface: a novel tool for induction of specific T-cell immune responses.
The choice of tools that enable efficient targeting of exogenous antigens (Ag) for processing and presentation by professional Ag-presenting cells (APC) remains limited. This represents, indeed, a bottleneck in development of vaccines inducing specific T-cell responses. Here, we describe a novel strategy of Ag delivery into APCs. The Ag of choice is fused to the N- or C-terminus of streptavidin (SA) and tetrameric Ag-SA or SA-Ag fusion proteins are produced in E. coli and purified by 2-Iminobiotin-Agarose affinity chromatography. Alternatively, Ag-SA proteins are purified from urea extracts of E. coli inclusion bodies and refolded in vitro into functional tetramers. Complexes with biotinylated antibodies targeting cell surface receptors are formed and used to deliver the Ags of choice for processing and presentation by APCs and induction of Ag-specific CD4+ and CD8+ T-cell responses in vitro and in vivo.


Effects of materials parameters on mineralization and degradation of sol-gel bioactive glasses with 3D-ordered macroporous structures.
Bioactive glasses (BGs) with three-dimensionally ordered macroporous (3DOM) structures were prepared by combining a sol-gel synthesis with colloidal crystal templating. 3DOM sol-gel BGs with two compositions (20 mol % CaO-80% SiO2 and 20 mol % CaO-4% P2O5-76% SiO2) and three macropore sizes (average: 345, 440, and 790 nm) were prepared. Glasses were separated into two particle sizes (212 microm< small < 355 microm and 600 microm < large < 1000 microm). The glasses were soaked in simulated body fluid at 37 degrees C for 2 or 4 days and the effects of composition, particle size, and macropore size on the formation of apatite and glass degradation were characterized. Within the parameter range of the experiments, several comparisons could be made. First, the formation of apatite and degradation of the glass were slightly enhanced for the phosphate containing composition. Second, large particles formed less apatite and degraded less completely compared with small particles. Lastly, an increase in macropore size slowed down the glass degradation and apatite formation processes, an effect related to the decreased internal surface area of the larger pore materials.


How a choice between emission trading and tax schemes affects an environment-biased Environmental Protection Bureau's discretion?
In choosing environmental regulatory instrument and setting standards, a government relies on an Environmental Protection Bureau's (EPB) informational advantage, even though these two entities may have different preferences for internalizing environmental damage. A three-level hierarchical model between the government, the EPB and polluting firms is constructed to derive the government's optimal delegation policy for the EPB. Given the uncertainty in firms' costs and asymmetric information on transaction costs, this paper presents a demonstration of the communication process between the government and the EPB in formulating the standards of environmental regulation and choosing between the instruments of emission trading and tax schemes. This paper seeks to determine how the decisions in the environmental regulation should be delegated for the government to trade-off the cost to it of EPB's discretion versus the benefits of taking advantage of the EFB's expertise. Results suggest the bureaucratic political issue leads to a tendency towards either an emission trading or a tax scheme, depending on the direction of the EPB's environmental preferences. Compared with the case where only emission trading can be chosen, the choice of instrument results in less discretion left to the EPB in setting up the trading emission allowance and a higher tax, irrespective of whether the EPB is more or less concerned about the environmental damage than the government.


Transverse modes of a laser using volume Bragg grating as the cavity mirror.
A simulation and experiment were performed to demonstrate that a laser using volume Bragg grating as one of the cavity mirrors can achieve lasing even if the laser cavity length exceeds the traditional stable cavity condition. The laser transverse mode changes from a Gaussian beam into a ring-shaped mode as the laser cavity length increases from stable to unstable cavity conditions. At the same time, the effective modal reflectivity is reduced as the cavity length increases.


[Vaccination coverage in a pediatric population attended by a primary health care center].
It is hereby presented a quality control study of a systematic vaccination program developed in an urban primary care center. Target population were children between 0 and 8 years attended in the center. They were considered as having a correct vaccination coverage those cases in which it was possible to verify documented accomplishment of the local vaccination schedule. Out of the 538 children included in our study, 168 (31%) were founded not to have appropriate vaccination coverage evidenced in their clinical records, and their families were requested for an interview: 126 (75%) attended de appointment. In 93 of them it was founded a recording mistake, and 33 cases were verified as no correctly covered. Vaccination coverage rate was 86%, being inverse relationship between age and coverage rate. They are discussed corrective actions derived from the quality control.


Asymmetry in distribution of diaphragmatic endometriotic lesions: evidence in favour of the menstrual reflux theory.
If the menstrual reflux or implantation theory of endometriosis is true, refluxed endometrial cells could reach the right hypochondrium transported by the clockwise peritoneal fluid current and would implant more easily on the right diaphragmatic leaf as they are stuck there by the falciform ligament. To investigate if a lateral asymmetry exists in diaphragmatic endometriotic lesion distribution, all articles on diaphragmatic endometriosis identified by MEDLINE, EMBASE and PUBMED database searches were retrieved, and additional reports were collected by systematically reviewing all references. The number of women and the side of the lesion with respect to the falciform ligament of the liver were obtained from individual studies, and the combined frequency of right- and left-side diaphragmatic endometriosis was computed. In addition, seven personal cases were described. There were 16 reports including 47 subjects selected. Diaphragmatic endometriosis was on the right side in 31 (66%) patients, on the left in 3 (6%) and bilateral in 13 (27%). In the personal series, lesions were on the right side in five cases, on the left in one and bilateral in one. Considering only unilateral lesions, the observed proportion of right-sided endometriotic implants (36/40) was 90% (95% CI 76-97%; chi(2)(1) 32.6, P < 0.0001). The observed major asymmetry in diaphragmatic endometriotic lesion distribution in favour of the right leaf supports the menstrual reflux theory.


Achieving Independence and Mastery in School: An Open Trial in the Outpatient Setting.
Youth with autism spectrum disorders (ASD) without intellectual disability frequently experience academic problems, in part due to executive functioning (EF) deficits. There are currently no evidence-based interventions targeting academic EF skills (e.g., organization, prioritization, etc.) for middle school youth with ASD. The need is critical given increasing demands on these skills during the transition from elementary to middle school. An intervention targeting academic EF skills, Achieving Independence and Mastery in School (AIMS), was recently developed. This paper reports on an open trial of the AIMS-Outpatient intervention with 21 middle schoolers with ASD. Results suggest high feasibility/satisfaction, and improved EF, particularly in the domains of organization and materials management. These promising results support further intervention development work and suggest that academic EF skills are malleable in youth with ASD.


Nutrition in palliative care.
Nutrition in palliative care and at the end of life should be one of the goals for improving quality of life. It is important to address issues of food and feeding at this time to assist in the management of troublesome symptoms as well as to enhance the remaining life. While this paper focuses upon the nutritional aspects of cancer in palliative care, the sentiments are applicable to other serious chronic illnesses such as advanced cardiac failure, chronic obstructive pulmonary disease and dementia. Cancer and its treatments exert a major impact upon physical and psychological reserves and at the end of life problems with appetite and the ability to eat and drink compound such impact. The aims of nutritional care minimize food-related discomfort and maximize food enjoyment. Identification of any nutritional problems can facilitate the employment of strategies which need to be discussed with the patient and their families and reviewed regularly as conditions change. Ethical questions will be raised concerning the provision of food and fluids to a person nearing the end of their life. Nurses need to acknowledge that food has greater significance than the provision of nutrients.


Preference by sheep and goats among hay of eight tall fescue cultivars.
Grazing ruminants use both visual cues and taste in selecting their diet. Preference during grazing may not be the same when forage is dried for hay and cut into lengths prior to feeding in confinement. Eight cultivars of tall fescue (Festuca arundinacea Schreb.), previously evaluated for preference while grazed, were harvested three times over a period of 2 yr. The hays were air-dried, baled, and passed through a hydraulic bale processor prior to feeding. Five experiments were conducted. All three harvests were evaluated with sheep and the last two also with goats, using six animals each time. During an adaptation phase, hays were offered alone as meals. In the experimental phase, every possible pair of hays (28 pairs) was presented for a meal. Data were analyzed by multidimensional scaling and by traditional analyses. Preference was significant among cultivars in all experiments. Multidimensional scaling showed that selection was based on two criteria with two dimensions being significant. Sheep preferred KENHY followed by KENTUCKY 31 and STARGRAZER but preferenced against BARCEL. HIMAG, MO-96, and C1 were intermediate and MOZARK was variable. Goats were similar to sheep in preferring KENHY followed by STARGRAZER and selected against MOZARK and BARCEL. KENTUCKY 31, HIMAG, MO-96, and C1 were intermediate. In all five experiments, the general association was positive for available carbohydrate fractions and negative for fiber fractions that contribute to cell wall rigidity.


Metabolic rate in acute respiratory failure complicating sepsis.
A simple, reproducible, and noninvasive method was developed for measuring metabolic rate in patients receiving assisted ventilation and increased concentrations of inspired O2. In nonseptic patients requiring assisted ventilation, metabolic rate was within the predicted normal range, but in septic patients it was increased by an average of 60 percent over the predicted normal. This level of resting hypermetabolism is greater than previously reported in septic patients not requiring assisted ventilation. The explanation of this difference is likely to be related to the greater severity of the illness in the present group. The potential clinical significance of these findings is discussed.


[Fetuses born lifeless: new representations and new rights].
A february-2008 rule about << children born lifeless >> stressed that << every fetus born lifeless >> could be registered at the General Register Office. This rule, which was followed in 2009 by the implementation of new procedures to deal with dead fetuses, highlighted that this topic is more and more becoming an important public issue. The rights for parents to choose has now been recognized, bringing about new questions for health professionals. Another point is which symbolism is to be given to dead fetuses to alleviate couples' suffering, without being too ideological, i.e. seeing fetuses as persons. This change also makes professionals reconsider public health system priorities, and this at a very particular time. Indeed, as parent mourning has now been made easier through registration at the General Register Office, there has not been any rule yet linking national epidemiological registration and fetal death in France. double dagger.


Reproductive decision making in women with medical comorbidities: a qualitative study.
A growing number of reproductive-age women in the U.S. have chronic medical conditions, increasing their risk of perinatal morbidity and mortality. Still, they experience unintended pregnancies at similar rates to low-risk mothers. We have limited understanding of how these individuals consider decisions about pregnancy and contraceptive use. The purpose of this study was to understand factors that influence reproductive decision-making among pregnant women with chronic medical conditions. We conducted 28 semi-structured interviews with pregnant women with pre-existing medical conditions admitted to a tertiary maternal hospital to examine factors influencing reproductive decision making. Maternal demographic characteristics, medical history, and pregnancy outcome data were obtained through participant surveys and abstraction from electronic health records. Interview transcripts were coded and analyzed using Dedoose® with both deductive and inductive content analysis. Out of 33 eligible participants, 30 consented to participate and 28 completed interviews. The majority of participants identified as black, Christian, made less than $23,000 yearly, and had a variety of preexisting medical conditions. Overarching themes included: 1) Perceived risks-benefits of pregnancy, 2) Perceived risks-benefits of birth control, 3) Determinants of contraceptive utilization, and 4) Perceived reproductive self-agency. Contraception was viewed as acceptable, but with concerning physical and psychological side effects. Although some considered pregnancy as a health threat, more experienced pregnancy as positive and empowering. Few planned their pregnancies. Preexisting health conditions did not significantly influence reproductive decision-making. Barriers to birth control use were generally based in patient value-systems instead of external factors. Interventions to improve uptake and use of birth control in this cohort should focus on improving care for chronic health conditions and influencing patient knowledge and attitudes toward contraception.


Non-enzymic phosphorylation of polyphosphoinositides and phosphatidic acid is catalysed by bivalent metal ions.
Phosphatidylinositol 4-phosphate, phosphatidylinositol 4,5-bisphosphate and phosphatidic acid undergo non-enzymic phosphorylation by ATP in the presence of bivalent metal ions. The non-enzymic reaction is more rapid in a mixture of water, chloroform and methanol than in water alone. Chemical evidence indicates that the product formed from phosphatidylinositol 4-phosphate is the corresponding 4-pyrophosphate. This product shows an RF value very close to that of phosphatidylinositol 4,5-bisphosphate on t.l.c. with an acidic solvent commonly used to characterize and measure the latter; however, it can be separated readily with an alkaline solvent. Chemical evidence indicates that the products formed from phosphatidylinositol 4,5-bisphosphate and phosphatidic acid are also pyrophosphates.


[The morphofunctional status of the isoperistaltic gastric transplant for esophagoplasty].
Thirteen patients with carcinomas of the esophagus underwent one-stage operations--extirpation of the esophagus without thoracotomy with simultaneous esophagoplasty using isoperistaltic gastric tube made of the greater curvature of the stomach, in posterior mediastinum with esophagogastrostomy in the neck. The morphofunctional state of the gastric transplants was investigated at early and late periods (for 8 months) after operations. The reduction of blood in the transplants to 40% of the initial, deterioration of acid production, depression of the motility, ischemic atrophy of mucosa and increased fibrosis in submucosa were revealed. Nevertheless satisfactory results of the isoperistaltic tubular esophagoplasty were obtained in 77% of patients in early periods and in 54% of the patients during the first year after operation.


Development of a High Performance Liquid Chromatography with Diode Array Detector (HPLC-DAD) Method for Determination of Biogenic Amines in Ripened Cheeses.
Biogenic amines (BAs) are organic, basic nitrogenous compounds formed during the decarboxylation of amino acids. A method for the determination of eight biogenic amines (tryptamine, 2-phenyletylamine, putrescine, cadaverine, histamine, tyramine, spermidine, spermine) in ripened cheeses was developed and validated. Cheese samples with the addition of internal standards were extracted with 0.2 M perchloric acid and pre-column derivatized with dansyl chloride at 60 °C for 15 min, purified with toluene and dried under a stream of nitrogen. The samples were analyzed using high performance liquid chromatography with diode array detector (HPLC-DAD). The method was validated with the BAs at three concentration levels: 50, 100, and 200 mg/kg, respectively. The obtained values of correlation coefficient (R2) ranged at 0.9997−0.9998 for all of compounds. The limits of detection (LOD) and quantification (LOQ) were in ranges 1.53−1.88 and 5.13−6.28 mg/kg, respectively. The recovery for all of biogenic amines ranged from 70 to 120% and the precision (RSDr) value were <20%. The validated method was applied to analysis of 35 real ripened cheese samples purchased in Poland.


Physician job satisfaction: developing a model using qualitative data. SGIM Career Satisfaction Study Group.
The purpose of this study was to develop a current and comprehensive model of physician job satisfaction. Information was gathered by (1) analysis of open-ended responses from a large group practice physician survey in 1988, and (2) analysis of focus group data of diverse physician subgroups from 1995. Participants were 302 physicians from large-group practices and 26 participants in six focus groups of HMO, women, minority, and inner-city physicians. Data were used to develop a comprehensive model of physician job satisfaction. The large group practice survey data supported the key importance of day-to-day practice environment and relationships with patients and physician peers. Future concerns focused on the effect of managed care on the physician-patient relationship and the ability of physicians to provide quality care. Focus groups provided contemporary data on physician job satisfaction, reinforcing the centrality of relationships as well as special issues for diverse physician subgroups of practicing physicians. New variables that relate to physician job satisfaction have emerged from economic and organizational changes in medicine and from increasing heterogeneity of physicians with respect to gender, ethnicity, and type of practice. A more comprehensive model of physician job satisfaction may enable individual physicians and health care organizations to better understand and improve physician work life.


Learning and knowledge-production for public health: a review of approaches to evidence-based public health.
Public health needs to be evidence-based if it is to be done correctly, which means that learning and knowledge-production for public health must be comprehensive and include knowledge from four different domains: distribution of health, determinants or causal web, consequences, and intervention methods. Specification of development trends in cardiovascular prevention points at four generations of preventive programs; these include a clinical, a bioepidemiological, a socioepidemiological, and an environmental and policy-oriented generation. Generations differ in focus and strategy, in knowledge base--the art of making an impact--and evaluation. Comprehensive public health programs often comprise components from different generations, leading to the need for an expanded model for research and evaluation. There is an urgent need for learning and knowledge-production using both quantitative and qualitative approaches for developing the evidence base for public health action. In addition, epidemiological knowledge is necessary for making appropriate priorities.


Dual action of retinoic acid on human embryonic/fetal hematopoiesis: blockade of primitive progenitor proliferation and shift from multipotent/erythroid/monocytic to granulocytic differentiation program.
In preliminary studies, we have analyzed the hematopoietic growth factor (HGF) requirement of hematopoietic progenitor cells (HPCs) purified from embryonic-fetal liver (FL) and grown in fetal calf serum-supplemented (FCS+) clonogenic culture. The key role of erythropoietin (Epo) for colony formation by early erythroid progenitors (burst-forming units-erythroid [BFU-E]) has been confirmed. Furthermore, in the absence of exogenous HGFs, FL monocytic progenitors (colony-forming unit monocyte [CFU-M]) generate large colonies exclusively composed of monocytes-macrophages; these colonies are absent in FCS- clonogenic culture. On this basis, we have investigated the role of all-trans retinoic acid (ATRA) and its isomer 9-cis RA in FL hematopoiesis. Both compounds modulate the growth of purified FL HPCs, which show a dose-dependent shift from mixed/erythroid/ monocytic to granulocytic colony formation. Studies on unicellular and paired daughter cell culture unequivocally indicate that the shift is mediated by modulation of the HPC differentiation program to the granulopoietic pathway (rather than RA-induced down-modulation of multipotent/ erythroid/monocytic HPC growth coupled with recruitment of granulocytic HPCs). ATRA and 9-cis RA also exert their effect on the proliferation of primitive HPCs (high-proliferative potential colony-forming cells [HPP-CFCs]) and putative hematopoietic stem cells (HSCs; assayed in Dexter-type long-term culture). High concentrations of either compound (1) drastically reduced the number of primary HPP-CFC colonies and totally abolished their recloning capacity and (2) inhibited HSC proliferation. It is crucial that these results mirror recent observations indicating that murine adult HPCs transduced with dominant negative ATRA receptor (RAR) gene are immortalized and show a selective blockade of granulocytic differentiation. Altogether, these results suggest that ATRA/9-cis RA may play a key role in FL hematopoiesis via a dual effect hypothetically mediated by interaction with the RAR/RXR heterodimer, ie, inhibition of HSC/ primitive HPC proliferation and induction of CFU-GEMM/ BFU-E/CFU-M shift from the multipotent/erythroid/monocytic to the granulocytic-neutrophilic differentiation program.


Sperm telomere length is positively associated with the quality of early embryonic development.
What is the relationship between telomere length in sperm and early embryonic development in in vitro fertilization (IVF)? Sperm telomere length (STL) is positively associated with embryo quality in IVF. Previous studies have shown that STL differs among human males. In order to determine the associations between STL, fertilization laboratory parameters and clinical pregnancy in IVF, 418 couples were recruited from August 2013 to August 2014. We collected semen samples and used quantitative PCR technique to detect the mean STL for each patient. These data were compared with the IVF outcomes. The mean STL was positively correlated with the age of patient (rP = 0.100; P = 0.041) and total sperm count/ejaculate (rp = 0.28; P < 0.001). Analysis of the age-adjusted mean STL in relation to the male patient's paternal and maternal ages at the time of his conception showed significant positive relationships between STL and both paternal (r = 0.16; P = 0.003) and maternal (r = 0.19; P < 0.001) ages at the time of conception. In addition, significant correlations were found between STL and good quality embryo (regression coefficient: 1.63; P < 0.001) and transplantable embryo rates (regression coefficient: 1.57; P < 0.001), but clinical pregnancy rates were not affected (odds ratio = 1.00 [95% CI: 0.93-1.07]; P = 0.90). This study showed that STL was positively associated with embryo quality in IVF. Additional studies are needed to confirm these observations. STL has the potential to be used as a marker for the prediction of embryonic quality. This work was supported by the National Natural Science Foundation of China (Grants 31271605 and 31471404), and the National Science Foundation for Young Scientists of China (Grant 31401274), and Science Foundation of First Affiliated Hospital of Zhengzhou University for Yong Scientists. The authors have declared that no competing interests exist.


Cross-sectional study to evaluate the associated factors with differences between city and districts secondary school students of the southeast of Spain (Murcia) for their adherence to the Mediterranean diet.
The "Mediterranean diet" is recognized as one of the healthiest dietary patterns but, even in Mediterranean countries it is gradually being lost. Adolescence is a crucial period for changes in dietary patterns. The purpose of this study was to evaluate the Adherence to Mediterranean diet (AMD) of secondary school students and evaluate possible variations between those residents in the city or in the districts. A cross-sectional study was designed with 379 secondary school students. To assess the AMD a self-administered questionnaire KIDMED was used. They were classified according to sex and residence (city or districts). The body mass index (BMI) for the whole sample was 22.34 in boys and 20.79 in girls (p<0.05). Students from the city resulted more physically active than those from the districts (p<0.05). The average AMD score was 5.8, with 20.3% of students showing good adherence. In general, there was a low consumption of fruits, vegetables and pasta or rice, all foods included in the bottom of the dietary pyramid and the consumption of olive oil and legumes was very positive. Around 25% of students skip breakfast regularly. Although BMI was in general in the range of normality, AMD of secondary school students is lower than expected attending to previous studies. Consume of fruits and vegetables several times per day, having breakfast daily and regular physical activity should be promoted. Educational and informative activities should be designed for adolescents and also for their parents since in these stages menus at home are usually established by them.


Complications of reamed intramedullary nailing of the tibia.
A retrospective review of 60 acute fractures of the tibia treated with reamed intramedullary nailing was undertaken to document the spectrum of complications associated with this procedure. Forty-five tibial fractures were followed to radiographic union; follow-up averaged 25 months (range, 10-63 months). Complications were categorized into intraoperative, early postoperative, and late postoperative groups. Intraoperative complications occurred in 6 of the 60 (10%) fractures and included propagation of the tibial fracture into the insertion site of the nail in four cases. In each of two other fractures, at least one of the proximal interlocking screws was documented to have poor bony purchase. These complications did not affect final fracture alignment or clinical result. Early complications included soft-tissue complications, complications of fixation, and neurologic complications. Four patients developed hematomas at the nail insertion site. Eight fractures were stabilized in greater than 5 degrees of varus or valgus. Neurologic deficits directly related to the procedure were documented in 18 patients (30%). The majority were minor sensory neuropraxias of the peroneal nerve. Sixteen (89%) of these nerve palsies were transient, resolving within 3-6 months. Two patients had persistent nerve deficits at 1-year follow-up. In the late complications group, 10 of the 45 (22%) tibial fractures followed to union developed patellar tendinitis. Nonunion developed in two fractures, both of which required additional surgical procedures to obtain fracture union. Two deep infections occurred, both of which resolved after local wound care, fracture union, and nail removal. Overall, 26 of the 45 tibial fractures available for follow-up (58%) developed some complication attributable to the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)


Improving the biological nitrogen removal process in pharmaceutical wastewater treatment plants: a case study.
The Biological Nitrogen Removal (BNR) process of some pharmaceutical wastewater treatment plants has important operational problems. This study shows that, in order to solve these problems, the design of industrial BNR processes should start by analysing three key parameters: the characteristics of the wastewater load, the determination of the maximum TKN removal rate and the detection of toxic or inhibitory compounds in the wastewater. A case study of this analysis in pharmaceutical wastewater is presented here. In this case, the conventional TKN analytical method does not make an accurate characterisation of the wastewater load because it measures a concentration of 100 mg TKN l(-1) whereas the real concentration, determined with a modified TKN analytical method, is 150-500 mg TKN l(-1). Also, the TKN removal of the treatment system is insufficient in some periods because it falls below legal requirements. This problem might be a consequence of the wrong characterisation of wastewater during the design process. The maximum TKN removal at 27 degrees C (24 mg N g VSS(-1) d(-1) or 197 mg N l(-1) d(-1)) was evaluated in a pilot-scale plant. This value is six times greater than the average NLR applied in the full-scale plant. Finally, some of the components of the wastewater, such as p-phenylenediamine, might have inhibitory or toxic effects on the biological process. P-phenylenediamine causes a large decrease in the nitrification rate. This effect was determined by respirometry. This methodology shows that the effect is mainly inhibitory with a contact time of 30 min and if the contact time is longer, 14 hours, a toxic effect is observed.


Evaluation of a Pomegranate Peel Extract as an Alternative Means to Control Olive Anthracnose.
Olive anthracnose is caused by different species of Colletotrichum spp. and may be regarded as the most damaging disease of olive fruit worldwide, greatly affecting quality and quantity of the productions. A pomegranate peel extract (PGE) proved very effective in controlling the disease. The extract had a strong in vitro fungicidal activity against Colletotrichum acutatum sensu stricto, was very effective in both preventive and curative trials with artificially inoculated fruit, and induced resistance in treated olive tissues. In field trials, PGE was significantly more effective than copper, which is traditionally used to control the disease. The highest level of protection was achieved by applying the extract in the early ascending phase of the disease outbreaks because natural rots were completely inhibited with PGE at 12 g/liter and were reduced by 98.6 and by 93.0% on plants treated with PGE at 6 and 3 g/liter, respectively. Two treatments carried out 30 and 15 days before the expected epidemic outbreak reduced the incidence of the disease by 77.6, 57.0, and 51.8%, depending on the PGE concentration. The analysis of epiphytic populations showed a strong antimicrobial activity of PGE, which sharply reduced both fungal and bacterial populations. Because PGE was obtained from a natural matrix using safe chemicals and did not have any apparent phytotoxic effect on treated olive fruit, it may be regarded as a safe and effective natural antifungal preparation to control olive anthracnose and improve olive productions.


High-Throughput Screening of Type III Secretion Determinants Reveals a Major Chaperone-Independent Pathway.
Numerous Gram-negative bacterial pathogens utilize type III secretion systems (T3SSs) to inject tens of effector proteins directly into the cytosol of host cells. Through interactions with cognate chaperones, type III effectors are defined and recruited to the sorting platform, a cytoplasmic component of these membrane-embedded nanomachines. However, notably, a comprehensive review of the literature reveals that the secretion of most type III effectors has not yet been linked to a chaperone, raising questions regarding the existence of unknown chaperones as well as the universality of chaperones in effector secretion. Here, we describe the development of the first high-throughput type III secretion (T3S) assay, a semiautomated solid-plate-based assay, which enables the side-by-side comparison of secretion of over 20 Shigella effectors under a multitude of conditions. Strikingly, we found that the majority of Shigella effectors are secreted at equivalent levels by wild-type and variants of Shigella that no longer encode one or all known Shigella T3S effector chaperones. In addition, we found that Shigella effectors are efficiently secreted from a laboratory strain of Escherichia coli expressing the core Shigella type III secretion apparatus (T3SA) but no other Shigella-specific proteins. Furthermore, we observed that the sequences necessary and sufficient to define chaperone-dependent and -independent effectors are fundamentally different. Together, these findings support the existence of a major, previously unrecognized, noncanonical chaperone-independent secretion pathway that is likely common to many T3SSs.IMPORTANCE Many bacterial pathogens use specialized nanomachines, including type III secretion systems, to directly inject virulence proteins (effectors) into host cells. Here, we present the first extensive analysis of chaperone dependence in the process of type III effector secretion, providing strong evidence for the existence of a previously unrecognized chaperone-independent pathway. This noncanonical pathway is likely common to many bacteria, as an extensive review of the literature reveals that the secretion of multiple type III effectors has not yet been knowingly linked to a chaperone. While additional studies will be required to discern the molecular details of this pathway, its prevalence suggests that it can likely serve as a new target for the development of antimicrobial agents.


Apoptosis resistance increases with metastatic potential in cells of the human LNCaP prostate carcinoma line.
The aim of this study was to determine whether stable differences in apoptosis sensitivity were selected for in nonmetastatic and metastatic variants of the LNCaP human prostate carcinoma line that had been isolated from tumors grown orthotopically in the prostate glands and regional lymph nodes of nude mice. The nonmetastatic LNCaP-Pro5 cells were significantly more sensitive to thapsigargin-induced apoptosis than were the metastatic LNCaP-LN3 cells, as measured by viability, DNA fragmentation, and interleukin 1beta-converting enzyme family-mediated cleavage of the DNA repair enzyme, poly(ADP-ribose) polymerase. Apoptosis resistance in the metastatic cells was associated with higher levels of expression of the cell death suppressor BCL-2 and lower levels of the death promoters BAX and BAK than were detected in the nonmetastatic LNCaP-Pro5 cells, whereas levels of two other BCL-2 family members (BCL-X(L) and BAD) were indistinguishable. Our data support the hypothesis that apoptosis resistance contributes to prostate cancer metastasis and that elevated expression of BCL-2 is involved.


Selective actions of mitochondrial fission/fusion genes on metabolism-secretion coupling in insulin-releasing cells.
Mitochondria form filamentous networks that undergo continuous fission/fusion. In the pancreatic beta-cells, mitochondria are essential for the transduction of signals linking nutrient metabolism to insulin granule exocytosis. Here we have studied mitochondrial networks in the insulinoma cell line INS-1E, primary rat and human beta-cells. We have further investigated the impact of mitochondrial fission/fusion on metabolism-secretion coupling in INS-1E cells. Overexpression of hFis1 caused dramatic mitochondrial fragmentation, whereas Mfn1 evoked hyperfusion and the aggregation of mitochondria. Cells overexpressing hFis1 or Mfn1 showed reduced mitochondrial volume, lowered cellular ATP levels, and as a consequence, impaired glucose-stimulated insulin secretion. Decreased mitochondrial ATP generation was partially compensated for by enhanced glycolysis as indicated by increased lactate production in these cells. Dominant-negative Mfn1 elicited mitochondrial shortening and fragmentation of INS-1E cell mitochondria, similar to hFis1. However, the mitochondrial volume, cytosolic ATP levels, and glucose-stimulated insulin secretion were little affected. We conclude that mitochondrial fragmentation per se does not impair metabolism-secretion coupling. Through their impact on mitochondrial bioenergetics and distribution, hFis1 and Mfn1 activities influence mitochondrial signal generation thereby insulin exocytosis.


Computation of deregressed proofs for genomic selection when own phenotypes exist with an application in French show-jumping horses.
Genomic evaluations often use as pseudo-phenotypes corrected means of progeny performances, like daughter yield deviations (DYD) in dairy species. In horse breeding, own performances are also available and performances from other relatives (as half sibs) may play an important part in the EBV because the number of progeny remains low, even for stallions. The first step for genomic selection in horses is therefore to generate pseudo-phenotypes for genomic analysis when parental or own information is considered. This work presents an easy method to compute deregressed EBV from regular pedigree-based genetic evaluations (EBV, reliabilities) to be used in genomic evaluations. The proposed methodology builds deregressed proofs so that they combine own performances (from genotyped individuals) and performances of relatives (outside of the genotyped sample). An application to show jumping horse data is presented. A sample of 908 stallions specialized in show jumping [71% Selle Français (SF), 17% foreign sport horses (FH), 13% Anglo Arab (AA)] were genotyped. Genotyping was performed using the Illumina Equine SNP50 BeadChip, and after quality tests, 44,444 SNP were retained. Two methods were used for genomic evaluation: GBLUP and BayesCπ, and 6 validation data sets were compared, chosen according to breeds SF + FH + AA or SF + FH, family structure (more than 3 half sibs), reliability of sires (>0.97) or sons (>0.72). In spite of a favorable genetic structure [linkage disequilibrium equal to 0.24 at 50 kb pairs], results showed low advantage of genomic evaluation. On the validation sample SF + FH + AA, the correlation between deregressed proofs and GBLUP or BayesCπ predictions was 0.39, 0.37, 0.51 according to the different validation data sets, compared with 0.36, 0.33, 0.53 obtained with BLUP predictions. Correlations were much lower on the SF + FH sample. Research is pursued to understand this low advantage of genomic selection and to improve the methodology for genomic evaluation in this context, which is less favorable than dairy cattle breeding.


Controlling speed and direction during interception: an affordance-based approach.
The coordination of direction and speed of self-motion when intercepting a target moving parallel to the ground plane was examined. Subjects viewed a computer-generated environment comprised of a textured ground plane and a moving target. Turning rate was controlled using a steering wheel and speed was controlled using a foot pedal. It was hypothesized that these two degrees of freedom would be coordinated such that the speed required to intercept the target (i.e., the ideal speed) would be maintained below the subject's maximum possible speed. As predicted, subjects turned toward the target when ideal speed was less than maximum speed and ahead of the target when ideal speed was greater than maximum speed. When behavior was compared across groups with different maximum speed capabilities, it was found that the ratio of ideal to maximum speed was invariant across groups at critical points of both steering and speed adjustments. Finally, subjects rapidly recalibrated to a sudden increase or decrease in maximum speed. The results suggest that actors coordinate steering and speed during interception in a way that takes into account the limits on their action capabilities. Discussion focuses on the role of calibration and the implications of the present findings for existing models of visually guided interception.


Introducing health sciences librarians to the Internet.
The Internet is no longer just for the adventurous explorers or the technical experts--it has found its way into the mainstream of librarianship. New users are coming onto "the net" in droves. A wealth of information is currently available dealing with the mechanics of the Internet and there are general guides to the available resources. More work needs to be done, however, in developing subject specific materials. This paper will report on the strategy that Scott Memorial Library, Thomas Jefferson University, has employed to develop staff skills and awareness and to take advantage of the resources and opportunities that the network provides for the health sciences community.


Computer generated holograms for testing aspheric lenses.
For the purpose of measuring aspheric surfaces, an improved type of computer generated hologram, named the inclined bar type hologram, is proposed. This hologram is characterized by inclined bars. The inclination angle for each bar is obtained from the calculated wavefront aberration of the test lens. A few problems with these computer generated holograms are analyzed, and the advantage of the inclined bar type hologram over the conventional one is demonstrated by experiment.


Improving access to noninstitutional long-term care for American Indian veterans.
Home-based primary care (HBPC) is an effective model of noninstitutional long-term care developed in the Department of Veterans Affairs (VA) to provide ongoing care to homebound persons. Significant rural populations of American Indians have limited access to services designed for frail older adults. Fourteen Veterans Affairs Medical Centers (VAMCs) initiated efforts to expand access to HBPC in concert with local tribes and Indian Health Service (IHS) facilities. This study characterizes the resulting emerging models of HBPC and co-management. Using an observational design, key respondent telephone interviews (n = 37) were conducted with stakeholders representing the 14 VAMCs to describe these HBPC programs, and HBPC models were evaluated in relation to VAMC organizational culture as revealed on the annual VA All Employee Survey. Twelve VAMCs independently developed HBPC expansion programs for American Indian veterans, and six different program models were implemented. Two models were unique to collaborations between VAMCs and tribes; in these collaborations, the tribes retained primary care responsibilities. VAMC used the other four models for delivery of care in remote rural areas to all veteran populations, American Indians and non-Indians alike. Strategies to improve access by reducing geographic barriers occur in all models. Comparing mean VAMC organizational culture ratings, as defined in the Competing Values Framework, revealed significant group differences for one of these six models. Findings from this study illustrate the flexibility of the HBPC program and opportunities for co-management and expansion of healthcare access for American Indians and non-Indians, particularly in rural areas.


Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm.
Expression of the natural killer (NK) cell antigen CD56 is uncommon among lymphomas, and those that do are almost exclusively of non-B-cell lineage and show a predilection for the nasal and nasopharyngeal region. This study analyzes 49 cases of nonnasal CD56+ lymphomas, the largest series to date, to characterize the clinicopathologic spectrum of these rare neoplasms. All patients were Chinese. Four categories could be delineated. (1) Nasal-type NK/T cell lymphoma (n = 34) patients were adults 21 to 76 years of age (median, 50 years), including 25 men and 9 women. They presented with extranodal disease, usually in multiple sites. The commonest sites of involvement were skin, upper aerodigestive tract, testis, soft tissue, gastrointestinal tract, and spleen. Only 7 cases (21%) apparently had stage I disease. The neoplastic cells were often pleomorphic, with irregular nuclei and granular chromatin, and angiocentric growth was common. The characteristic immunophenotype was CD2+ CD3/Leu4- CD3epsilon+ CD56+, and 32 cases (94%) harbored Epstein-Barr virus (EBV). Follow-up information was available in 29 cases: 24 died at a median of 3.5 months; 3 were alive with relapse at 5 months to 2.5 years; and 2 were alive and well at 3 and 5 years, respectively. (2) Aggressive NK cell leukemia/lymphoma (n = 5) patients presented with hepatomegaly and blood/marrow involvement, sometimes accompanied by splenomegaly or lymphadenopathy. The neoplastic cells often had round nuclei and azurophilic granules in the pale cytoplasm. All cases exhibited an immunophenotype of CD2+ CD3/Leu4- CD56+ CD16- CD57- and all were EBV+. All of these patients died within 6 weeks. (3) In blastoid NK cell lymphoma (n = 2), the lymphoma cells resembled those of lymphoblastic or myeloid leukemia. One case studied for CD2 was negative and both cases were EBV-. One patient was alive with disease at 10 months and one was a recent case. (4) Other specific lymphoma types with CD56 expression (n = 8) included one case each of hepatosplenic gammadelta T-cell lymphoma and S100 protein+ T-cell lymphoproliferative disease and two cases each of T-chronic lymphocytic/prolymphocytic leukemia, lymphoblastic lymphoma, and true histiocytic lymphoma. All of these cases were EBV-. Six patients died at a median of 6.5 months. Nonnasal CD56+ lymphomas are heterogeneous, but all pursue a highly aggressive clinical course. The nasal-type NK/T-cell lymphoma and aggressive NK cell leukemia/lymphoma show distinctive clinicopathologic features and a very strong association with EBV. Blastoid NK cell lymphoma appears to be a different entity and shows no association with EBV.


[Value of radical lymph node dissection (compartment I and II) in stomach carcinoma].
In a prospective multicentre study of 2394 patients with gastric carcinoma the prognostic relevance of systematic lymph node dissection was evaluated. Of 1654 patients undergoing resection, 558 had a standard lymph node dissection, defined as fewer than 26 nodes in the specimen, and 1096 underwent radical lymphadenectomy, i.e. 26 or more nodes in the specimen. Radical dissection significantly improved the survival rate in patients with Union Internacional Contra la Cancrum (UICC) stages II and IIIA tumors. Multivariate analysis identified radical dissection as an independent prognostic factor in the subgroups of patients with UICC tumor stages II and IIIA. Radical dissection conferred no survival advantage in patients with pN2 tumors. There was no significant difference in morbidity and mortality rates between radical and standard lymph node dissection. Radical lymphadenectomy improves survival in patients with UICC gastric cancer stages II and IIIA, and should be the recommended treatment for such patients.


cDNA and derived amino acid sequence of rabbit nasal cytochrome P450NMb (P450IIG1), a unique isozyme possibly involved in olfaction.
Olfactory-specific cytochrome P450NMb was previously purified to electrophoretic homogeneity from microsomes of rabbit nasal mucosa in this laboratory. In the present study, a cDNA library made from poly(A)+ RNA from rabbit nasal mucosa was screened with antibodies to this P450, and eight immunopositive clones were isolated and characterized. The sequence determined from two overlapping clones contained an open reading frame of 1446 nucleotides, with the predicted first 39 amino acids corresponding to residues 12 to 50 of purified NMb, except for position 46, where Leu was encoded instead of the Glu residue that was found earlier by Edman degradation analysis. The complete polypeptide, including residues 1 to 11, contains 494 amino acid residues and has a molecular weight of 56,640. Sequence comparisons indicated that NMb is more than 50% identical to members of the rabbit P450 gene II family, including IIB4, IIC3, IIC5, IIE1, and IIE2, and 83% identical to rat P450olf1 (IIG1). Hybridization of NMb to electrophoretically fractionated rabbit nasal poly(A)+ RNA revealed 3.6- and 2.1-kb species, but with a probe derived from the 3'-nontranslated portion of the cDNA only the 3.6-kb band was observed, suggesting the use of alternate polyadenylation sites or splicing. In agreement with the known tissue-specific distribution of NMb protein, NMb transcripts were found in olfactory mucosa, but not in liver, lung, intestine, or kidney. Genomic hybridization analysis indicated that there may be only one copy of the NMb gene present in the rabbit genome.


Self-healing of space-time light sheets.
Space-time (ST) wave packets are diffraction-free, dispersion-free pulsed beams whose propagation invariance stems from correlations introduced into their spatio-temporal spectra. We demonstrate here experimentally and computationally that ST light sheets exhibit self-healing properties upon traversing obstacles in the form of opaque obstructions. The unscattered fraction of the wave packet retains the spatio-temporal correlations and, thus, propagation invariance is maintained. The scattered component does not satisfy the requisite correlation and thus, undergoes diffractive spreading. These results indicate the robustness of ST wave packets and their potential utility for deep illumination and imaging in scattering media, such as biological tissues.


Adult-onset asthma becomes the dominant phenotype among women by age 40 years. the longitudinal CARDIA study.
Although asthma is usually considered to originate in childhood, adult-onset disease is being increasingly reported. To contrast the proportion and natural history of adult-onset versus pediatric-onset asthma in a community-based cohort. We hypothesized that asthma in women is predominantly of adult onset rather than of pediatric onset. This study used data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort in the United States over a 25-year period. Adult- and pediatric-onset asthma phenotypes were studied, as defined by age at onset of 18 years or older. Subjects with asthma were categorized by sex, obesity, atopy, smoking, and race by mean age/examination year, using a three-way analysis of covariance model. Natural history of disease was examined using probabilities derived from a Markov chain model. Asthma of adult onset became the dominant (i.e., exceeded 50%) phenotype in women by age 40 years. The age by which adult-onset asthma became the dominant phenotype was further lowered for obese, nonatopic, ever-smoking, or white women. The prevalence trend with increasing time for adult-onset disease was greater among subjects with nonatopic than atopic asthma among both sexes. Furthermore, adult-onset asthma had remarkable sex-related differences in risk factors. In both sexes, the quiescent state for adult-onset asthma was less frequent and also "less stable" over time than for pediatric-onset asthma. Using a large national cohort, this study challenges the dictum that most asthma in adults originates in childhood. Studies of the differences between pediatric- and adult-onset asthma may provide greater insight into the phenotypic heterogeneity of asthma.


The roles and mechanism of IFIT5 in bladder cancer epithelial-mesenchymal transition and progression.
The prognosis of bladder cancer (BCa) depends on several key factors including anatomical site, tumor grade, and stage. In general, muscle-invasive bladder cancer (MIBC) is associated with higher incidence of distant metastasis compared with Non-muscle-invasive bladder cancer (NMIBC). Treatment outcome of the patients with metastatic BCa has been very poor with ~15% of overall survival rate. Thus, it is apparently important to understand the underlying biology for metastatic progression of BCa. Although epithelial-mesenchymal transition (EMT) has long been implicated in BCa metastasis and treatment resistance, the underlying mechanism is not fully understood. In this study, we have identified that the expression of interferon induced protein with tetratricopeptide repeats 5 (IFIT5) is positively correlated with pathological characteristics, and predicts a poor prognosis of BCa patients. Since the function of IFIT5 in BCa has not yet been characterized, we demonstrate that IFIT5 can induce EMT, promote cell migration and invasion, and increase the expression of ICAM1 in BCa via down-regulation of mature miR-99a. Moreover, ICAM1 is shown as a direct target of miR-99a. Overall, we conclude that IFIT5 is a new oncogene in BCa.


Developing institutional capacity of health service system management at the district level in rural Cambodia.
The implementation of decentralization policies in the health sector of many developing countries has been a major issue in international health. The objectives were to focus on health sector reform, health financing system, and human resource development. However, less attention has been paid to the institutional capacity development of health systems. In this paper, institutional capacity refers to the abilities of organizations to make effective management in order to build local capacity and to achieve goals with local ownership. The aims of this paper were to explore the developmental process of districts institutional capacity by assistance of an NGO in Cambodia, and to identify the key factors influencing this development. We chose five operational districts (ODs) and two of them were contracted to NGO for management assistance. We conducted semi-structured in-depth interview to 17 managers and 16 key informant interviews. For analysis, we used qualitative analysis based on a grounded theory approach to clarify a conceptual framework for understanding management practices at district health institutions. There is a 4-stage capacity developmental process at the district-level institution. Supportive supervision and widening of decision-making authority were identified as key factors for sustainable institutional capacity development. They have complementary function each other. External agencies such as NGOs can use these key factors to develop local management capacities, and also this capacity development can be done internally within institutions such as OD health offices and by upper authorities such as the PHD.


Chagas Disease Drug Discovery: Multiparametric Lead Optimization against Trypanosoma cruzi in Acylaminobenzothiazole Series.
Acylaminobenzothiazole hits were identified as potential inhibitors of Trypanosoma cruzi replication, a parasite responsible for Chagas disease. We selected compound 1 for lead optimization, aiming to improve in parallel its anti-T. cruzi activity (IC50 = 0.63 μM) and its human metabolic stability (human clearance = 9.57 mL/min/g). A total of 39 analogues of 1 were synthesized and tested in vitro. We established a multiparametric structure-activity relationship, allowing optimization of antiparasite activity, physicochemical parameters, and ADME properties. We identified compound 50 as an advanced lead with an improved anti-T. cruzi activity in vitro (IC50 = 0.079 μM) and an enhanced metabolic stability (human clearance = 0.41 mL/min/g) and opportunity for the oral route of administration. After tolerability assessment, 50 demonstrated a promising in vivo efficacy.


Safety profile of raloxifene as used in general practice in England: results of a prescription-event monitoring study.
Raloxifene, a selective estrogen receptor modulator (SERM) licensed for the prevention of non-traumatic vertebral fractures in postmenopausal women at increased risk of osteoporosis, was launched in the UK in August 1998. The aim of the study was to monitor the safety of raloxifene prescribed in the primary care setting in England using prescription-event monitoring (PEM). Patients were identified by means of prescription data supplied by the Prescription Pricing Authority between September 1998 and November 2000. Demographic and clinical event data were collected from questionnaires posted to primary care physicians (GPs) at least 6 months after the date of the first prescription for each patient. Information on medical events, suspected adverse drug reactions (ADRs), reasons for stopping treatment, pregnancies, and causes of death was requested. Event rates [Incidence Densities (IDs): no. first reports /1000 patient-months of treatment] were calculated. Differences between IDs for events reported in month one (ID(1)) and months 2-6 (ID(2-6)) of treatment were examined. The cohort comprised 13,987 patients [median age 62 years (IQR 55,69); 99.8% female]. The major indication was osteoporosis (40.9%, n=5725). Flushing was the event with the highest ID in month 1 (22.8), reported most frequently by GPs as an ADR to raloxifene (67/461 reports) and as the reason for stopping (700/4592 reports). Events associated with starting treatment included flushing, malaise/lassitude, headache/migraine, nausea/vomiting, sweating, cramp, pain abdomen, dizziness, diarrhea, mastalgia and vaginal hemorrhage. Less common events reported during treatment included deep vein thrombosis (n=13), pulmonary embolism (n=13), thrombophlebitis (n=31) and visual disturbance (n=29). In this study, there were 122 (0.9%) confirmed deaths, of which 32 causes of death were unknown. This study shows that raloxifene is generally well tolerated when used in general practice in England. Potential signals of unrecognised ADRs requiring further evaluation included gastrointestinal adverse symptoms and vaginal hemorrhage. There were also a small number of reports of events associated with venous thromboembolism and visual disorders that require further investigation.


Venous Thromboembolism after Allogeneic Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Study.
Venous thromboembolism (VTE) in children who undergo hematopoietic stem cell transplantation (HSCT) has high morbidity. The aim of this study is to assess the incidence of VTE in allogeneic pediatric HSCT recipients and the contribution of pretransplant prothrombotic risk factors to thrombosis. We retrospectively evaluated 92 patients between April 2010 and November 2012 undergoing allogeneic HSCT who had completed 100 days post-HSCT. Before HSCT, coagulation profiles; acquired and inherited prothrombotic risk factors including factor V Leiden, prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations; and serum homocysteine and lipoprotein(a), plasma antithrombin III, protein C, and protein S levels were obtained from all patients. In the screening of thrombophilia, 8 patients (9%) were heterozygous for factor V Leiden, 5 (6%) were homozygous for MTHFR 677TT, 12 (14%) were homozygous for MTHFR 1298CC, and 2 (2%) were heterozygous for prothrombin G20210A mutation. We observed VTE in 5 patients (5.4%); a prothrombotic risk factor was found in 3 out of these 5 patients, while 4 out of 5 patients had central venous catheters. It was determined there was no significant relationship between VTE and inherited prothrombotic risk factors. VTE after HSCT seems to be a low-frequency event that may be due to low-dose, low-molecular-weight heparin prophylaxis, and the role of inherited prothrombotic risk factors cannot be entirely excluded without a prospective study.


Results from the first English stool bank using faecal microbiota transplant as a medicinal product for the treatment of Clostridioides difficile infection.
Faecal Microbiota Transplant (FMT) has improved outcomes for the treatment of Clostridioides difficile infection (CDI) compared to antibiotic therapy. FMT is classified as a medicinal product in the United Kingdom, similar to the USA and Canada, limiting supply via stool banks without appropriate licencing. In the largest UK cohort to date, we describe the clinical outcomes for 124 patients receiving FMT for recurrent or refractory CDI and present a framework to produce FMT as a licenced medicinal product. Anonymous unrelated healthy donors, screened via health assessment and microbiological testing donated stool. In aerobic conditions FMT aliquots were prepared for immediate use or frozen storage, following a production framework developed to comply with Good Manufacturing Practice. Outcome measures were clinical response to FMT defined as resolution of diarrhoea within seven days and clinical cure defined as response without diarrhoea recurrence at 90 days. Clinical response was 83·9% (95% CI 76·0%-90·0%) after one treatment. Clinical cure was 78·2% (95% CI 67·4%-89·0%) across the cohort. Refractory cases appeared to have a lower initial clinical response rate compared to recurrent cases, however at day 90 there were no differences observed between these groups. The methodology developed here enabled successful licencing of FMT by The Medicines and Healthcare products Regulatory Agency as a medicinal product. This has widened the availability of FMT in the National Health Service via a stool bank and can be applied in other centres across the world to improve access to safe and quality assured treatments.


The hyalectan degrading ADAMTS-1 enzyme is expressed by osteoblasts and up-regulated at regions of new bone formation.
During bone formation, there are numerous pivotal changes in the interrelationships between osteoblasts and molecules of the extracellular matrix (ECM). Consequently, the mechanisms that underlie the temporal and spatial distribution of ECM molecules in bone are of considerable interest in understanding its formation. A subfamily of a disintegrin and metalloproteinase (ADAMs) has been identified, which contain thrombospondin-like motifs (ADAMTS), and can break down several ECM molecules. Using reversed transcribed PCR, we identified ADAMTS-1, -4 and -5 mRNA expression in cultures of rat osteoblasts treated with ascorbic acid, beta-glycerophosphate and dexamethasone, molecules known to drive osteoblast differentiation. Of these, ADAMTS-1 followed most closely the osteogenic marker osteocalcin during in vitro mineralisation. Consequently, we studied, in detail, protein expression of ADAMTS-1 during in vitro osteogenesis together with ADAMTS-1 immunohistochemistry staining of sections from 2- and 10-day-old rat femur. Western analysis of osteoblast proteins showed ADAMTS-1 products that correspond well with both full-length and furin-processed species. In the ECM laid down by osteoblasts, only the mature secreted protein (approximately 90 kDa) and its accumulation during the later stages of osteogenesis in vitro were noticed. Furthermore, immunostaining with an antibody recognising ADAMTS-1 demonstrated strong expression around mineralised nodules and intense focal staining of putative new areas of nodule formation in vitro. Finally, immunohistochemistry of 2- and 10-day-old rat femur localised ADAMTS-1 protein to regions associated with osteogenesis. These data show that ADAMTS-1 protein accumulates in osteoblast ECM during differentiation. Furthermore, the focalised expression of ADAMTS-1 in regions of osteogenesis, both in vitro and in vivo, implicates this multifunctional protein to be involved in mineralised nodule and bone formation.


[Electron-microscope study of ribonucleoprotein particles in the cerebral cortex neurons during the posthypoxia period].
As demonstrate the experiments performed in rats, during the postanoxic period in the cerebral cortex neurons, the content of nuclear and cytoplasmic ribonucleoproteids changes essentially. The most labile and highly sensitive components of the protein-synthesizing system in the neuron are the perichromatin fibrillae. Then the perichromatin and interchromatin granules disappear. An increased formation of the perichromatin fibrillae in the nucleus precedes the activation of the reparative processes.


Inhibition of the specific binding of human lactotransferrin to human peripheral-blood phytohaemagglutinin-stimulated lymphocytes by fluorescein labelling and location of the binding site.
Labelling of human lactotransferrin with fluorescein 5'-isothiocyanate (FITC) in an equimolar ratio inhibits the binding of the protein to phytohaemagglutinin-activated human peripheral-blood lymphocytes. Therefore it can be assumed that FITC reacts at, or near, the receptor-binding site. Three FITC-labelled peptides have been purified from a tryptic digest of the FITC-labelled lactotransferrin. The determination of their amino acid sequence and their localization on the primary structure of the protein permitted the identification of two FITC-accessible areas in the N-terminal lobe and one in the C-terminal lobe. In fact, only 10% of the total FITC was conjugated to one lysine residue (Lys579) of the C-terminal lobe, whereas most (80%) of the FITC was conjugated to three close lysine residues [Lys263 (65% of total fluorescence), Lys280 and Lys282 (15% of total fluorescence)] located in beta-turn structures, of the N-terminal domain I of human lactotransferrin. The results obtained show that the receptor-binding site should be located in the vicinity of the FITC-accessible Lys263, Lys280 and Lys282, and corroborate our preliminary results reporting the involvement of the N-terminal domain I in the binding of human lactotransferrin to mitogen-stimulated lymphocytes [Rochard, Legrand, Mazurier, Montreuil & Spik (1989) FEBS Lett. 255, 201-204]. In any case, FITC labelling is not suitable for studying the binding of lactotransferrin to activated lymphocytes and its use may lead to erroneous interpretations of cell binding experiments.


Chromosomal passenger complex hydrodynamics suggests chaperoning of the inactive state by nucleoplasmin/nucleophosmin.
The chromosomal passenger complex (CPC) is a conserved, essential regulator of cell division. As such, significant anti-cancer drug development efforts have been focused on targeting it, most notably by inhibiting its AURKB kinase subunit. The CPC is activated by AURKB-catalyzed autophosphorylation on multiple subunits, but how this regulates CPC interactions with other mitotic proteins remains unclear. We investigated the hydrodynamic behavior of the CPC in Xenopus laevis egg cytosol using sucrose gradient sedimentation and in HeLa cells using fluorescence correlation spectroscopy. We found that autophosphorylation of the CPC decreases its sedimentation coefficient in egg cytosol and increases its diffusion coefficient in live cells, indicating a decrease in mass. Using immunoprecipitation coupled with mass spectrometry and immunoblots, we discovered that inactive, unphosphorylated CPC interacts with nucleophosmin/nucleoplasmin proteins, which are known to oligomerize into pentamers and decamers. Autophosphorylation of the CPC causes it to dissociate from nucleophosmin/nucleoplasmin. We propose that nucleophosmin/nucleoplasmin complexes serve as chaperones that negatively regulate the CPC and/or stabilize its inactive form, preventing CPC autophosphorylation and recruitment to chromatin and microtubules in mitosis.


Impacts of COVID-19 on sexual risk behaviors, safe injection practices, and access to HIV services among key populations in Zambia: Findings from a rapid qualitative formative assessment.
Despite achievements in the HIV response, social and structural barriers impede access to HIV services for key populations (KP) including men who have sex with men (MSM), transgender women (TGW), and people who inject drugs (PWID). This may be worsened by the COVID-19 pandemic or future pandemic threats. We explored the impact of COVID-19 on HIV services and sexual and substance use behaviors among MSM/TGW and PWID in Zambia as part of a formative assessment for two biobehavioral surveys. From November-December 2020, 3 focus groups and 15 in-depth interviews (IDIs) with KP were conducted in Lusaka, Livingstone, Ndola, Solwezi, and Kitwe, Zambia. Overall, 45 PWID and 60 MSM/TGW participated in IDIs and 70 PWID and 89 MSM/TGW participated in focus groups. Qualitative data were analyzed using framework matrices according to deductive themes outlined in interview guides. KP reported barriers to HIV testing and HIV treatment due to COVID-19-related disruptions and fear of SARS-CoV-2 exposure at the health facility. MSM/TGW participants reported limited supply of condoms and lubricants at health facilities; limited access to condoms led to increased engagements in condomless sex. Restrictions in movement and closure of meet-up spots due to COVID-19 impeded opportunities to meet sex partners for MSM/TGW and clients for those who sold sex. COVID-19 restrictions led to unemployment and loss of income as well as to shortages and increased price of drugs, needles, and syringes for PWID. Due to COVID-19 economic effects, PWID reported increased needle-sharing and re-use of needles. Participants experienced barriers accessing HIV services due to COVID-19 and PWID attributed unsafe needle use and sharing to loss of income and lack of affordable needles during pandemic-related restrictions. To maintain gains in the HIV response in this context, strengthening harm reduction strategies and improvements in access to HIV services are necessary.


Laparotomy for Abdominal Injury Indication & Outcome of patients at a Teaching Hospital in Addis Ababa, Ethiopia.
Abdominal injury is among the major causes of trauma admissions. The aim was to determine etiology, commonly injured organs, indication and outcome of patients with abdominal injuries requiring laparotomy. A retrospective study of all adult patients who underwent laparotomy for abdominal injury at St. Paul's Hospital Millennium Medical College was conducted from January 2014 to December 2016. The factors associated with outcome were identified with bivariate and multivariate logistic regressions. Laparotomy for abdominal injury was performed for 145 patients. Of these, 129 (89%) case records were retrieved. The male to female ratio was 6.2:1. The mean age was 29 years, and most of them were unemployed. Penetrating trauma was the commonest injury, stab (46, 35.7%) and Road Traffic Accidents (RTA) (27, 20.9%) being the leading causes. Extra-abdominal injuries were seen in 33.3% (46) of the cases. Hollow organs were commonly injured than solid organs. Small intestine (35, 43.8%) and Spleen (17, 34.7%) were the leading injured organs in penetrating and blunt respectively. The main procedure performed was repair of hollow and solid organ laceration/perforation (70,54.3%). The negative laparotomy rate was 4.6% (6). Complications were seen in 23(17.8%) patients, the commonest being irreversible shock (7,30.4%). The mortality rate was 8.5 % (11), and it was significantly associated with blunt abdominal injury (AOR=7.25; 95% CI 1.09-48.37; p=0.041) and systolic blood pressure<90mmHg (AOR=8.66; 95% CI 1.1-68.41; p=0.041). Stab and RTA were the commonest indications of laparotomy. The mortality was significantly associated with blunt abdominal injury and hypotension (SBP<90mmHg).


Ionophore-Based Voltammetric Ion Activity Sensing with Thin Layer Membranes.
As shown in recent work, thin layer ion-selective multi-ionophore membranes can be interrogated by cyclic voltammetry to detect the ion activity of multiple species simultaneously and selectively. Additional fundamental evidence is put forward on ion discrimination with thin multi-ionophore-based membranes with thicknesses of 200 ± 25 nm and backside contacted with poly-3-octylthiophene (POT). An anodic potential scan partially oxidizes the POT film (to POT(+)), thereby initiating the release of hydrophilic cations from the membrane phase to the sample solution at a characteristic potential. Varying concentration of added cation-exchanger demonstrates that it limits the ion transfer charge and not the deposited POT film. Voltammograms with multiple peaks are observed with each associated with the transfer of one type of ion (lithium, potassium, and sodium). Experimental conditions (thickness and composition of the membrane and concentration of the sample) are chosen that allow one to describe the system by a thermodynamic rather than kinetic model. As a consequence, apparent stability constants for sodium, potassium, and lithium (assuming 1:1 stoichiometry) with their respective ionophores are calculated and agree well with the values obtained by the potentiometric sandwich membrane technique. As an analytical application, a membrane containing three ionophores was used to determine lithium, sodium, and potassium in artificial samples at the same location and within a single voltammetric scan. Lithium and potassium were also determined in undiluted human plasma in the therapeutic concentration range.


Practice Bulletin No. 166: Thrombocytopenia in Pregnancy.
Thrombocytopenia in pregnant women is diagnosed frequently by obstetricians because platelet counts are included with automated complete blood cell counts (CBCs) obtained during routine prenatal screening (). Although most U.S. health care providers are trained using U.S. Conventional Units, most scientists, journals, and countries use Système International (SI) units. The laboratory results reported in U.S. Conventional Units can be converted to SI Units or vice versa by using a conversion factor. The conversion factor for platelet count results is 1.0 (ie, to convert from x 103/µL, multiply by 1.0, to get x 109/L). Thrombocytopenia, defined as a platelet count of less than 150 x 109/L, is common and occurs in 7-12% of pregnancies (). Thrombocytopenia can result from a variety of physiologic or pathologic conditions, several of which are unique to pregnancy. Some causes of thrombocytopenia are serious medical disorders that have the potential for maternal and fetal morbidity. In contrast, other conditions, such as gestational thrombocytopenia, are benign and pose no maternal or fetal risks. Because of the increased recognition of maternal and fetal thrombocytopenia, there are numerous controversies about obstetric management of this condition. Clinicians must weigh the risks of maternal and fetal bleeding complications against the costs and morbidity of diagnostic tests and invasive interventions.


Sexual risk behaviour of street youths in south west Nigeria.
Previous studies have mainly focused on sexual behaviour of in-school Nigerian youths with little attention to those on the street. This survey was conducted to determine the sexual risk behaviours of young people on the streets of Ibadan, Nigeria. A cross sectional survey was conducted among youths aged 15-24 years in the major markets, motor parks and commercial areas in two local government areas in Ibadan. Participants in the study areas were identified in groups based on their occupational activity and all consenting young people were interviewed. A semi-structured questionnaire was used to obtain information on sexual behaviours, condom use and history of sexually transmitted infections. Data was managed using SPSS version 11. Most (68.8%) were males, 79.0%, were sexually experienced, the median age at sexual debut for males was 15 years and 16 years for females. More females (53.9%) compared to (34.5%) males reported that their first partners were five or more years older, p < 0.01. Condom use during the first sexual intercourse was reported by only 32.2%. Sex with a commercial sex worker or exchange of sex for money was reported by 18.2% (20.6% of males versus 12.2% of females, p = 0.01). Factors significantly associated with history of transactional sex were; male gender; older age (20-24 years); being out of school and regular alcohol use. Multiple sexual partnering was reported by 58.2%, the significant predictors were male gender; early age at sexual debut; regular alcohol use and history of transactional sex. Inconsistent condom use was reported by 44.8%, the predictors were female gender; regular alcohol use and history of transactional sex in the previous year. Majority of these young people on the streets are sexually active and many engage in high risk sexual behaviours. Development of appropriate sexual and reproductive health interventions is recommended.


Experiments in the EpiDerm 3D Skin In Vitro Model and Minipigs In Vivo Indicate Comparatively Lower In Vivo Skin Sensitivity of Topically Applied Aneugenic Compounds.
Risk management of in vitro aneugens for topically applied compounds is not clearly defined because there is no validated methodology to accurately measure compound concentration in proliferating stratum basale keratinocytes of the skin. Here, we experimentally tested several known aneugens in the EpiDerm reconstructed human skin in vitro micronucleus assay and compared the results to flow cytometric mechanistic biomarkers (phospho-H3; MPM2, DNA content). We then evaluated similar biomarkers (Ki-67, nuclear area) using immunohistochemistry in skin sections of minipigs following topical exposure the potent aneugens, colchicine, and hesperadin. Data from the EpiDerm model showed positive micronucleus responses for all aneugens tested following topical or direct media dosing with similar sensitivity when adjusted for applied dose. Quantitative benchmark dose-response analysis exhibited increases in the mitotic index biomarkers phospho-H3 and MPM2 for tubulin binders and polyploidy for aurora kinase inhibitors are at least as sensitive as the micronucleus endpoint. By comparison, the aneugens tested did not induce histopathological changes, increases in Ki-67 immunolabeling or nuclear area in skin sections from the in vivo minipig study at doses in significant excess of those eliciting a response in vitro. Results indicate the EpiDerm in vitro micronucleus assay is suitable for the hazard identification of aneugens. The lack of response in the minipig studies indicates that the barrier function of the minipig skin, which is comparable to human skin, protects from the effects of aneugens in vivo. These results provide a basis for conducting additional studies in the future to further refine this understanding.


Ponicidin-induced conformational changes of HSP90 regulates the MAPK pathway to relieve ulcerative colitis.
Ulcerative colitis (UC) is a recurring chronic intestinal disease that can be debilitating and in severe cases, may further lead to cancer. However, all these treatment techniques still suffer from drug dependence, adverse effects and poor patient compliance. Therefore, there is an urgent need to seek new therapeutic strategies. In traditional Chinese medicine, Rabdosia rubescens (Hemsl.) H.Hara has the effects of clearing heat-toxin and promoting blood circulation to relieve pain, it is wildly used for treating inflammatory diseases such as sore throats and tonsillitis. Ponicidin is an important molecule for the anti-inflammatory effects of Rabdosia rubescens, but it has not been studied in the treatment of colitis. HSP90 is the most critical regulator in the development and progression of inflammatory diseases such as UC. The aim of this study was to explore the anti-inflammatory activity of ponicidin and its mechanism of effect in vitro and in vivo, as well as to identify the target proteins on which ponicidin may interact. 2.5% (w/v) dextran sulfate sodium (DSS) was used to induce C57BL/6 mice to form an ulcerative colitis model, and then 5 mg/kg and 10 mg/kg ponicidin was given for treatment, while the Rabdosia rubescens extract group and Rabdosia rubescens diterpene extract group were set up for comparison of the efficacy of ponicidin. At the end of modeling and drug administration, mouse colon tissues were taken, and the length of colon was counted, inflammatory factors and inflammatory signaling pathways were detected. RAW264.7 cells were induced to form cell inflammation model with 1 μg/mL Lipopolysaccharide (LPS) for 24 h. 1 μM, 2 μM and 4 μM ponicidin were given at the same time, and after the end of the modeling and administration of the drug, the inflammatory factors and inflammatory signaling pathways were detected by qRT-PCR, western blotting, immunofluorescence and other methods. In vitro, target angling and combined with mass spectrometry were used to search for relevant targets of ponicidin, while isothermal titration calorimetry (ITC), protease degradation experiments and molecular dynamics simulations were used for further confirmation of the mode of action and site of action between ponicidin and target proteins. Ponicidin can alleviate DSS and LPS-induced inflammation by inhibiting the MAPK signaling pathway at the cellular and animal levels. In vitro, we confirmed that ponicidin can interact with the middle domain of HSP90 and induce the conformational changes in the N-terminal domain. These innovative efforts identified the molecular target of ponicidin in the treatment of UC and revealed the molecular mechanism of its interaction with HSP90.


Characteristics of Infiltrating Immune Cells and a Predictive Immune Model for Cervical Cancer.
The role of infiltrating immune cells within the tumor microenvironment has received considerable attention, but their function in cervical cancer remains to be elucidated; thus, comprehensive evaluation of their predictive value is needed. Using cervical cancer samples from 406 patients, immune cell infiltration was evaluated via immunohistochemistry. CD3+, CD4+, CD8+, CD20+, CD57+, CD68+, and CD163+ cell infiltration was compared in samples from adjacent tissues and the tumor center. The associations between immune cell distributions in the tumor center, clinicopathological features, and prognosis were correlated among immune cell types. Using three immune features, an immune model was constructed based on a Cox regression analysis with the least absolute shrinkage and selection operator (lasso) penalty to derive immune risk scores. Immune cells that infiltrated the tumor center correlated with clinicopathological characteristics and prognosis. The immune risk scores were an independent prognostic indicator and were found to predict cervical cancer prognosis as well as the effects of chemoradiotherapy. We classified patients into either high- or low-risk subgroups (namely CD4+highCD163+highCD57+low and CD4+lowCD163+lowCD57+high, respectively) based on their immune scores. Significant differences were found in the 3-year overall survival of patients with high- and low-risk scores (83.0% vs. 96.6%; P < 0.001). High immune risk scores resulted in decreased overall survival for patients in stages IB1+IIA1, IB2+IIA2, and IIB-IV (P = 0.001, P = 0.008, and P = 0.044, respectively). Overall survival was significantly worse following chemoradiotherapy in high-scoring patients in stages IB1+IIA1 and IB2+IIA2 (P = 0.001 and P=0.008, respectively). Moreover, overall survival was significantly worse after radiotherapy or chemotherapy in high-scoring patients in stage IB1+IIA1 (P = 0.03). Our work reveals that the distribution of infiltrating immune cells affects their function in cervical cancer. Our tumor center-centric immune model effectively predicted survival, suggesting its potential use in identifying suitable candidates for chemoradiotherapy.


Antioxidant system status in threatened native fish Barbus meridionalis from the Osor River (Iberian Peninsula): I. Characterization and II. In vitro Zn assays.
The evaluation of antioxidant system capacity is important in aquatic toxicology. It was aimed to characterize the liver antioxidant enzymes (SOD, CAT, GPX, GR, and GST) and to test the in vitro Zn effect (200 and 400 ZnSO4 μg/L) in native fish Barbus meridionalis obtained from the Osor River (NE, Spain) influenced by Zn contamination. The maximal enzyme activities were at pH 7.0-7.5 and 100 mM phosphate buffer. Barbel showed high catalytic activity (high Vmax and low Km) indicating the efficient antioxidant detoxification ability. Direct Zn effect caused an antioxidant system imbalance. Mostly upon lower Zn concentration, GPX activity decreased (95-100 %) though CAT, GR, and GST increased (36-1543 %). GSH values either stimulated (290 %) or inhibited (85-93 %) due to tissue differences. The first record of barbel antioxidant enzyme characterization and in vitro data presenting an unbalanced antioxidant pattern could be significant to evaluate the metal pollution in the Osor River for further in vivo studies.


Tomato juice, chocolate drink, and other fluids suppress volitional drinking of alcohol in the female Syrian golden hamster.
Although the hamster generally prefers alcohol at a level similar to that of the rat or mouse selectively bred to consume alcohol, the drinking hamster demonstrates neither physical dependence on alcohol nor elevated blood levels of alcohol, which are two typical criteria characterizing an animal model of alcoholism. The present investigation was designed to determine whether a third criterion of an animal model (i.e., consumption of high levels of alcohol in the presence of a palatable fluid, fulfilled by the P rat) would be met by the female Syrian golden hamster (Mesocricetus auratus). A standard 3-bottle preference test was undertaken in 6 female hamsters over an 11 day period, in which water was presented in one tube and, in a second tube, a v/v solution of alcohol which was increased in concentration from 3% to 50% on each day as follows: 3%, 5%, 7%, 9%, 12%, 15%, 20%, 25%, 30%, 40%, and 50%. Then each hamster was offered its individually determined, maximally preferred concentration of alcohol for 4-8 days, which was 20%, 25%, or 30% alcohol. The mean absolute intake of alcohol during this period was 17.9 +/- 1.1 g/kg per day, whereas the mean proportion of alcohol to total fluid was 0.68 +/- 0.05. Then over a 4-day interval, a solution of tomato juice, peach juice, mango juice, dextrose and a chocolate beverage (Ensure Plus), all made isocaloric to the alcohol solutions with dextrose, was placed in the third tube simultaneously with water and the individually preferred concentration of alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevalences of intimate partner violence in a representative U.S. Air Force sample.
Intimate partner violence (IPV) is a serious health concern, but little is known about prevalence of IPV in the armed forces, as military members cope with the pressures of long-standing operations. Furthermore, previous prevalence studies have been plagued by definitional issues; most studies have focused on acts of aggression without consideration of impact (clinically significant [CS] IPV). This is the first large-scale study to examine prevalences of IPV, CS-IPV, and clinically significant emotional abuse (CS-EA) for men and women. A United States Air Force-wide anonymous survey was administered across 82 bases in 2006 (N = 42,744) to assess IPV, CS-IPV, and CS-EA. The adjusted prevalence of CS-IPV perpetration was 4.66% for men and 3.54% for women. Prevalences of IPV perpetration were 12.90% for men and 15.14% for women. CS-EA victimization was 6.00% for men and 8.50% for women. Sociodemographic differences in risk for violence were found for gender, race/ethnicity, pay grade, religious faith, marital status, and career type even after controlling for other demographic variables. Partner maltreatment is widespread in military (and civilian) samples. Men were more likely to perpetrate CS-IPV, whereas women were more likely to perpetrate IPV. Specific demographic risk factors were identified for different types of partner maltreatment (e.g., lower rank predicted higher risk for both perpetration and victimization across men and women). Other sociodemographic differences varied across severity (IPV vs. CS-IPV) and across gender.


TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by localized areas of demyelination. Although the etiology and pathogenesis of MS remain largely unknown, it is generally assumed that immune responses to myelin antigens contribute to the disease process. The exact sequence of events, as well as the molecular mediators that lead to myelin destruction, is yet to be defined. As a potent mediator of inflammation, the cytopathic cytokine, tumor necrosis factor (TNF) has been considered to be a strong candidate in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, its role in immune-mediated demyelination remains to be elucidated. To determine the contribution of TNF to the pathogenesis of the MS-like disease provoked by the myelin oligodendrocyte glycoprotein (MOG), we have tested mice with an homologous disruption of the gene encoding TNF. Here we report that upon immunization with MOG, mice lacking TNF develop severe neurological impairment with high mortality and extensive inflammation and demyelination. We show further that inactivation of the TNF gene converts MOG-resistant mice to a state of high susceptibility. Furthermore, treatment with TNF dramatically reduces disease severity in both TNF-/- mice and in other TNF+/+ mice highly susceptible to the MOG-induced disease. These findings indicate that TNF is not essential for the induction and expression of inflammatory and demyelinating lesions, and that it may limit the extent and duration of severe CNS pathology.