Pax6 interactions with chromatin and identification of its novel direct target genes in lens and forebrain.
Pax6 encodes a specific DNA-binding transcription factor that regulates the development of multiple organs, including the eye, brain and pancreas. Previous studies have shown that Pax6 regulates the entire process of ocular lens development. In the developing forebrain, Pax6 is expressed in ventricular zone precursor cells and in specific populations of neurons; absence of Pax6 results in disrupted cell proliferation and cell fate specification in telencephalon. In the pancreas, Pax6 is essential for the differentiation of α-, β- and δ-islet cells. To elucidate molecular roles of Pax6, chromatin immunoprecipitation experiments combined with high-density oligonucleotide array hybridizations (ChIP-chip) were performed using three distinct sources of chromatin (lens, forebrain and β-cells). ChIP-chip studies, performed as biological triplicates, identified a total of 5,260 promoters occupied by Pax6. 1,001 (133) of these promoter regions were shared between at least two (three) distinct chromatin sources, respectively. In lens chromatin, 2,335 promoters were bound by Pax6. RNA expression profiling from Pax6⁺/⁻ lenses combined with in vivo Pax6-binding data yielded 76 putative Pax6-direct targets, including the Gaa, Isl1, Kif1b, Mtmr2, Pcsk1n, and Snca genes. RNA and ChIP data were validated for all these genes. In lens cells, reporter assays established Kib1b and Snca as Pax6 activated and repressed genes, respectively. In situ hybridization revealed reduced expression of these genes in E14 cerebral cortex. Moreover, we examined differentially expressed transcripts between E9.5 wild type and Pax6⁻/⁻ lens placodes that suggested Efnb2, Fat4, Has2, Nav1, and Trpm3 as novel Pax6-direct targets. Collectively, the present studies, through the identification of Pax6-direct target genes, provide novel insights into the molecular mechanisms of Pax6 gene control during mouse embryonic development. In addition, the present data demonstrate that Pax6 interacts preferentially with promoter regions in a tissue-specific fashion. Nevertheless, nearly 20% of the regions identified are accessible to Pax6 in multiple tissues.


Retreatment with lenalidomide is an effective option in heavily pretreated refractory multiple myeloma patients.
The combination of lenalidomide and dexamethasone is the current gold standard for treatment of relapsed multiple myeloma. This study analyzes the efficiency of repeated lenalidomide treatment in patients with relapsed and refractory multiple myeloma. A total of 41 patients were prospectively evaluated at the University Hospital Brno. Lenalidomide was administered at standard dosing and in combination with corticosteroids and/or chemotherapy. The maximum cumulative dose of lenalidomide was limited to 4,200 mg because of Czech health insurance rules. Before the second lenalidomide treatment, all patients were refractory to the last treatment; previously, 95% of patients had bortezomib treatment, 48% had autologous transplantation and the median number of prior therapy lines was three. A partial 14.2% or better response was achieved with the second lenalidomide treatment. The median progression-free survival was 4.8 months, and median overall survival was 11.9 months. Unfortunately, predicting risk factors in lenalidomide retreatment proved unsuccessful. Although our treatment results were significantly affected by limited Czech health care system coverage for lenalidomide, we established that its repeated treatment is an effective therapeutic alternative for heavily pretreated patients with relapsed and refractory multiple myeloma.


Fluoride and endosulfan together potentiate cytogenetic effects in Swiss albino mice bone marrow cells.
In this study, the cytotoxic potential of fluoride and endosulfan in combination was investigated in Swiss albino mice bone marrow cells using the chromosomal aberration (CA) and micronucleus (MN) test systems. Fluoride (25.1 mg kg-1 body weight [bw] in water) and endosulfan (1.8 mg kg-1 bw by oral intubation) were administered orally alone and in combination (fluoride 25.1 mg kg-1 bw + endosulfan 1.8 mg kg-1 bw) to male Swiss albino mice daily for 30 days. A significant (p < 0.01) increase in micronuclei (MNs) induction and decreased ratio (p < 0.01) of polychromatic to normonochromatic erythrocytes (indicators of cytotoxicity) were observed compared with saline controls when animals were given the combination of fluoride and endosulfan. A significant (p < 0.01) increase in MNs induction and no change in the polychromatic erythrocytes to erythrocyte ratio were also observed when endosulfan was given alone. CAs such as gaps, breaks, fragments, rings, exchanges, and polyploidy were recorded in the bone marrow cells. The mean percent frequency of CAs was increased (p < 0.01) in all the treated groups compared with the control saline group. In the combination group (F + E), the percent frequencies of CAs were significantly higher (13.875%) compared with those in the individual treatment groups of fluoride (4.375%) and endosulfan (6.25%). The mitotic index was calculated as percentage of dividing cells. A significant (p < 0.01) decrease in mitotic index was observed in all treated groups compared with controls. In the combination group (F + E), mitotic index was significantly less than (p < 0.01; 4.1 ± 0.49) the saline control (10.8 ± 0.98). These results indicated that repeated intake of endosulfan through various sources in fluoride affected areas resulted in increased cytotoxic effects. The greater effect in the combination group indicated additive interaction of fluoride and endosulfan in inducing cytotoxicity in Swiss albino mice.


Spherical DCB-spline surfaces with hierarchical and adaptive knot insertion.
This paper develops a novel surface fitting scheme for automatically reconstructing a genus-0 object into a continuous parametric spline surface. A key contribution for making such a fitting method both practical and accurate is our spherical generalization of the Delaunay configuration B-spline (DCB-spline), a new non-tensor-product spline. In this framework, we efficiently compute Delaunay configurations on sphere by the union of two planar Delaunay configurations. Also, we develop a hierarchical and adaptive method that progressively improves the fitting quality by new knot-insertion strategies guided by surface geometry and fitting error. Within our framework, a genus-0 model can be converted to a single spherical spline representation whose root mean square error is tightly bounded within a user-specified tolerance. The reconstructed continuous representation has many attractive properties such as global smoothness and no auxiliary knots. We conduct several experiments to demonstrate the efficacy of our new approach for reverse engineering and shape modeling.


Suture techniques during laparoscopic and robot-assisted partial nephrectomy: a systematic review and quantitative synthesis of peri-operative outcomes.
To summarize the available evidence on renorrhaphy techniques and to assess their impact on peri-operative outcomes after minimally invasive partial nephrectomy (MIPN). A systematic review of the literature was performed in January 2018 without time restrictions, using MEDLINE, Cochrane and Web of Science databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement recommendations. Studies providing sufficient details on renorrhaphy techniques during laparoscopic or robot-assisted partial nephrectomy and comparative studies focused on peri-operative outcomes were included in qualitative and quantitative analyses, respectively. Overall, 67 and 19 studies were included in the qualitative and quantitative analyses, respectively. The overall quality of evidence was low. Specific tumour features (i.e. size, hilar location, anatomical complexity, nearness to renal sinus and/or urinary collecting system), surgeon's experience, robot-assisted technology, as well as the aim of reducing warm ischaemia time and the amount of devascularized renal parenchyma preserved represented the key factors driving the evolution of the renorrhaphy techniques during MIPN over the past decade. Quantitative synthesis showed that running suture was associated with shorter operating and ischaemia time, and lower postoperative complication and transfusion rates than interrupted suture. Barbed suture had lower operating and ischaemia time and less blood loss than non-barbed suture. The single-layer suture technique was associated with shorter operating and ischaemia time than the double-layer technique. No comparisons were possible concerning renal functional outcomes because of non-homogeneous data reporting. Renorrhaphy techniques significantly evolved over the years, improving outcomes. Running suture, particularly using barbed wires, shortened the operating and ischaemia times. A further advantage could derive from avoiding a double-layer suture.


Period-prevalence and Publication Rate of Health Research Productivity in Seven Arabian Gulf Countries: Bibliometric Analysis from 1996 to 2018.
Despite the worldwide increase in health research, few studies have evaluated the health research productivity in member states of the Gulf Health Council (GHC). This study solicited the period-prevalence and publication rates of health research productivity in the seven GHC countries. We searched the Scopus database for publications between 1996 and 2018 and used the SCImago Journal and Country Rank portal to obtain the relevant information. We also recorded qualitative (citation-based) and quantitative (document recount) indicators. Overall and country-specific period-prevalence and publication rates were estimated and standardized to the corresponding overall Gulf Cooperation Council (GCC) population and country-specific population size. Overall, 112 409 articles were enumerated during the study period. The majority (59.8%) were from Saudi Arabia, followed by UAE (11.9%). The GCC publications were associated with 1 315 778 citations, which revealed a 46.0 Hirsch-index. The period-prevalence of health publications for the overall GCC region was 1320 publications per million population over 22 years, and the publication rate estimate was 13.2 (95% confidence interval (CI): 13.1-13.3) publication per 10 000 population. The highest publication rate estimate was noted in Qatar (36.5; 95% CI: 35.8-37.3), followed by Kuwait, Bahrain, Saudi Arabia, UAE, Oman, and Yemen. This study is the first study in the context of GCC to utilize period-prevalence and publication rates to chart health research productivity in the GCC region. Concerted efforts are required to improve the quality and quantity of the health research output in the GCC region.


Polyamino-Isoprenic Derivatives Block Intrinsic Resistance of P. aeruginosa to Doxycycline and Chloramphenicol In Vitro.
Multidrug resistant bacteria have been a worldwide concern for decades. Though new molecules that effectively target Gram-positive bacteria are currently appearing on the market, a gap remains in the treatment of infections caused by Gram-negative bacteria. Therefore, new strategies must be developed against these pathogens. The aim of this study was to select an antibiotic for which a bacterium is naturally resistant and to use an escort molecule to restore susceptibility, similarly to the model of β-lactam/ β-lactamase inhibitors. High-content screening was performed on the reference strain PA01, allowing the selection of four polyamino-isoprenic compounds that acted synergistically with doxycycline. They were assayed against clinical isolates and Multi-Drug-Resistant strains. One of these compounds was able to decrease the MIC of doxycycline on the reference strain, efflux pump overproducers and clinical isolates of P. aeruginosa, to the susceptibility level. Similar results were obtained using chloramphenicol as the antibiotic. Membrane permeation assays and real-time efflux experiments were used to characterize the mechanism of doxycycline potentiation. The results showed that the selected compound strongly decreases the efficiency of glucose-triggered efflux associated with a slight destabilization of the outer membrane. According to these data, targeting natural resistance may become an interesting way to combat MDR pathogens and could represent an alternative to already devised strategies.


Structural and biochemical characterization of the oxidoreductase NmDsbA3 from Neisseria meningitidis.
DsbA is an enzyme found in the periplasm of Gram-negative bacteria that catalyzes the formation of disulfide bonds in a diverse array of protein substrates, many of which are involved in bacterial pathogenesis. Although most bacteria possess only a single essential DsbA, Neisseria meningitidis is unusual in that it possesses three DsbAs, although the reason for this additional redundancy is unclear. Two of these N. meningitidis enzymes (NmDsbA1 and NmDsbA2) play an important role in meningococcal attachment to human epithelial cells, whereas NmDsbA3 is considered to have a narrow substrate repertoire. To begin to address the role of DsbAs in the pathogenesis of N. meningitidis, we have determined the structure of NmDsbA3 to 2.3-A resolution. Although the sequence identity between NmDsbA3 and other DsbAs is low, the NmDsbA3 structure adopted a DsbA-like fold. Consistent with this finding, we demonstrated that NmDsbA3 acts as a thiol-disulfide oxidoreductase in vitro and is reoxidized by Escherichia coli DsbB (EcDsbB). However, pronounced differences in the structures between DsbA3 and EcDsbA, which are clustered around the active site of the enzyme, suggested a structural basis for the unusual substrate specificity that is observed for NmDsbA3.


Guidance from key organisations on exploring, confirming and interpreting subgroup effects of medical treatments: a scoping review.
With the increasing interest in personalised medicine, the use of subgroup analyses is likely to increase. Subgroup analyses are challenging and often misused, possibly leading to false interpretations of the effect. It remains unclear to what extent key organisations warn for such pitfalls and translate current methodological research to detect these effects into research guidelines. The aim of this scoping review is to determine and evaluate the current guidance used by organisations for exploring, confirming and interpreting subgroup effects. Scoping review. We identified four types of key stakeholder organisations: industry, health technology assessment organisations (HTA), academic/non-profit research organisations and regulatory bodies. After literature search and expert consultation, we identified international and national organisations of each type. For each organisation that was identified, we searched for official research guidance documents and contacted the organisation for additional guidance. Twenty-seven (45%) of the 60 organisations that we included had relevant research guidance documents. We observed large differences between organisation types: 18% (n=2) of the industry organisations, 64% (n=9) of the HTA organisations, 38% (n=8) of academic/non-profit research organisations and 57% (n=8) of regulatory bodies provided guidance documents. The majority of the documents (n=33, 63%) mentioned one or more challenges in subgroup analyses, such as false positive findings or ecological bias with variations across the organisation types. Statistical recommendations were less common (n=19, 37%) and often limited to a formal test of interaction. Almost half of the organisations included in this scoping review provided guidance on subgroup effect research in their guidelines. However, there were large differences between organisations in the amount and level of detail of their guidance. Effort is required to translate and integrate research findings on subgroup analysis to practical guidelines for decision making and to reduce the differences between organisations and organisation types.


The effectiveness of opioid substitution treatments for patients with opioid dependence: a systematic review and multiple treatment comparison protocol.
Opioids are psychoactive analgesic drugs prescribed for pain relief and palliative care. Due to their addictive potential, effort and vigilance in controlling prescriptions is needed to avoid misuse and dependence. Despite the effort, the prevalence of opioid use disorder continues to rise. Opioid substitution therapies are commonly used to treat opioid dependence; however, there is minimal consensus as to which therapy is most effective. Available treatments include methadone, heroin, buprenorphine, as well as naltrexone. This systematic review aims to assess and compare the effect of all available opioid substitution therapies on the treatment of opioid dependence. The authors will search Medline, EMBASE, PubMed, PsycINFO, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform Search Portal, and the National Institutes for Health Clinical Trials Registry. The title, abstract, and full-text screening will be completed in duplicate. When appropriate, multiple treatment comparison Bayesian meta-analytic methods will be performed to deduce summary statistics estimating the effectiveness of all opioid substitution therapies in terms of retention and response to treatment (as measured through continued opioid abuse). Using evidence gained from this systematic review, we anticipate disseminating an objective review of the current available literature on the effectiveness of all opioid substitution therapies for the treatment of opioid use disorder. The results of this systematic review are imperative to the further enhancement of clinical practice in addiction medicine. PROSPERO CRD42013006507.


The effectiveness of exercise interventions to prevent sports injuries: a systematic review and meta-analysis of randomised controlled trials.
Physical activity is important in both prevention and treatment of many common diseases, but sports injuries can pose serious problems. To determine whether physical activity exercises can reduce sports injuries and perform stratified analyses of strength training, stretching, proprioception and combinations of these, and provide separate acute and overuse injury estimates. PubMed, EMBASE, Web of Science and SPORTDiscus were searched and yielded 3462 results. Two independent authors selected relevant randomised, controlled trials and quality assessments were conducted by all authors of this paper using the Cochrane collaboration domain-based quality assessment tool. Twelve studies that neglected to account for clustering effects were adjusted. Quantitative analyses were performed in STATA V.12 and sensitivity analysed by intention-to-treat. Heterogeneity (I(2)) and publication bias (Harbord's small-study effects) were formally tested. 25 trials, including 26 610 participants with 3464 injuries, were analysed. The overall effect estimate on injury prevention was heterogeneous. Stratified exposure analyses proved no beneficial effect for stretching (RR 0.963 (0.846-1.095)), whereas studies with multiple exposures (RR 0.655 (0.520-0.826)), proprioception training (RR 0.550 (0.347-0.869)), and strength training (RR 0.315 (0.207-0.480)) showed a tendency towards increasing effect. Both acute injuries (RR 0.647 (0.502-0.836)) and overuse injuries (RR 0.527 (0.373-0.746)) could be reduced by physical activity programmes. Intention-to-treat sensitivity analyses consistently revealed even more robust effect estimates. Despite a few outlying studies, consistently favourable estimates were obtained for all injury prevention measures except for stretching. Strength training reduced sports injuries to less than 1/3 and overuse injuries could be almost halved.


Dynamic changes in corticospinal tracts after stroke detected by fibretracking.
The integrity of motor pathways and functional connectivity patterns are important in assessing plastic changes related to successful recovery, to obtain prognostic information and to monitor future therapeutic strategies of stroke patients. We tested the following hypotheses: (1) that changes in axonal integrity along the corticospinal tract after stroke can be detected as a reduction in fractional anisotropy; and (2) that sustained low fractional anisotropy is indicative of axonal loss and therefore is correlated with poor motor outcome, as measured by specific neurological motor scores. We developed a segmentation tool based on magnetic resonance diffusion tensor imaging in conjunction with three dimensional fibretracking for longitudinal studies of the corticospinal tract, and used specific neurological motor scores to test the hypotheses in five stroke patients within the first week and 30 and 90 days after the stroke. Reduction in fractional anisotropy within the first weeks after stroke reflected a decline in axonal integrity, leading to Wallerian degeneration, and demonstrated a correlation between the temporal evolution of fractional anisotropy and motor function in patients with poor motor outcome. The study demonstrated the feasibility of fibretracking as a segmentation tool for mapping distal parts of the corticospinal motor pathways and showed that fractional anisotropy in the segmented corticospinal tract is a sensitive measure of structural changes after stroke.


Instilling hope and respecting patient autonomy: reconciling apparently conflicting duties.
In contemporary American medical practice, certain physicians are critical and wary of the current emphasis on patient autonomy in medicine, questioning whether it really serves the complex needs of severely ill patients. Physicians such as Eric Cassell and Thomas Duffy argue that the duty of beneficence should override the duty to respect autonomy when conflicts arise in clinical situations. After evaluating their claim that severe illness robs patients of their autonomy, I will argue that this perceived conflict between beneficence and autonomy is ill-conceived, resting on misperceptions about both the capacity for autonomy and the meaning of hope. Considering insights on hope from phenomenologist Gabriel Marcel and theologian William Lynch, as well as drawing upon a case study involving a bone marrow patient, I claim that respecting and nurturing patients' capacity for autonomy is a necessary condition for acting beneficently and fostering authentic hope.


Domestic abuse in the emergency department: can a risk profile be defined?
The main purpose of this study was to determine whether any clinical or demographic characteristics could identify adult female patients presenting to the emergency department (ED) with a history of domestic abuse. A second objective was to describe the frequency, types, and severity of this abuse. This study was a crosssectional survey of 611 women conducted in an academically-affiliated, urban ED. Domestic abuse was described as "recent" (within the preceding 12 months) or "lifetime" (recent or past). This included emotional, physical, and sexual abuse. Recent (7.9%, n = 48) and lifetime (38%, n = 232) domestic abuse was reported. For recently abused women, violence had been severe (87.5%, n = 42) and was associated with 1) trauma (OR 5.4, 95% CI = 2.6 to 11.6), 2) obstetrical and gynecological syndromes (OR 5.6, 95% CI = 2.4 to 13.2), and 3) psychiatric symptoms and substance use (OR 7.3, 95% CI = 2.4 to 22.0). The sensitivities and positive predictive values of these risk factors individually (<27.1% and <25.0%, respectively) and in aggregate (56.3% and 20.9%, respectively) were low. These indicators predicted only 27 (56.3%) of recently abused women. Lifetime domestic violence was more likely in homeless women (OR 5.8, 95% CI = 2.2 to 15.0), although less likely in immigrants (OR 0.4, 95% CI = 0.3 to 0.7). Clinical presentations and demographic characteristics of women presenting to the ED may not be sensitive or predictive indicators of domestic abuse. In the absence of typical clinical or demographic findings, asking all women in the ED about domestic abuse remains a necessary priority.


Robust surgical approach for cutaneous neurofibroma in neurofibromatosis type 1.
Cutaneous neurofibromas (cNF) are physically disfiguring, painful, and cause extensive psychologic harm in patients with neurofibromatosis type 1 (NF1). There is currently no effective medical treatment and surgical procedures are inaccessible to most NF1 patients globally. While research is underway to find an effective medical treatment for cNF, there is an urgent need to develop surgical approach that is accessible to all NF1 patients in the world with the skill set and equipment found in most general medical office settings. Here, we present a robust surgical approach to remove cNF that does not require sterile surgical field, utilizes accessible clinical equipment, and can be performed by any health care providers including family practitioners, and physician assistants. In a prospective case-series, patients with NF1 underwent this surgical procedure which removes multiple cutaneous neurofibromas. The Dermatology Life Quality Index was given to subjects before and after the procedure as surrogate for patient satisfaction. 83 tumors were removed throughout the body from twelve individuals. Examination at follow-up visits revealed well-healed scars without infection or adverse events including aberrant scarring. Patient satisfaction with the procedure was high with significant improvements in symptoms, daily activities, leisure, personal relationships, and treatment experience (P = 0.00062). This study demonstrates a robust surgical approach to management cutaneous neurofibromas which can be accessed world-wide to individuals with NF1 and performed by a wide-variety of medical specialists with high clinical efficacy and patient satisfaction.


Cryoactivation of plasma renin.
1. The mechanism of increased renin activity after human plasma had been kept at -5 degrees C for 4 days (cryoactivation) was investigated. 2. The increase in renin activity of human plasma by cryoactivation was closely correlated to the increase obtained by incubation with trypsin (r = 0.88, P less than 0.001, n = 10). 3. An inhibitor of thiol enzyme, N-ethylmaleimide did not inhibit cryoactivation. 4. Soyabean trypsin inhibitor and di-isopropylflurophosphate (DFP) inhibited cryoactivation, suggesting that the cryoactivation may be due to the action of a trypsin-like serine enzyme. 5. In an experiment in the rat haemorrhagic shock caused parallel and cryoactivated plasma, the renin activity being about two times higher in the latter. No significant differences were found in the concentrations of renin and renin substrate between the non-cryoactivated and cryoactivated plasma samples. 6. The results may indicate that a destruction of an inhibitor of the renin-renin substrate reaction is responsible for the increase of renin activity after exposure of rat plasma to low temperature. A trypsin-like enzyme in plasma might have destroyed the inhibitor during this procedure.


The bovine chemokine receptors and their mRNA abundance in mononuclear phagocytes.
The chemokine and chemokine receptor families play critical roles in both the healthy and diseased organism mediating the migration of cells. The chemokine system is complex in that multiple chemokines can bind to one chemokine receptor and vice versa. Although chemokine receptors have been well characterised in humans, the chemokine receptor repertoire of cattle is not well characterised and many sequences are yet to be experimentally validated. We have identified and sequenced bovine homologs to all identified functional human chemokine receptors. The bovine chemokine receptors show high levels of similarity to their human counterparts and similar genome arrangements. We have also characterised an additional bovine chemokine receptor, not present in the available genome sequence of humans or the more closely related pigs or horses. This receptor shows the highest level of similarity to CCR1 but shows significant differences in regions of the protein that are likely to be involved in ligand binding and signalling. We have also examined the mRNA abundance levels of all identified bovine chemokine receptors in mononuclear phagocytic cells. Considerable differences were observed in the mRNA abundance levels of the receptors, and interestingly the identified novel chemokine receptor showed differing levels of mRNA abundance to its closest homolog CCR1. The chemokine receptor repertoire was shown to differ between monocytes, macrophages and dendritic cells. This may reflect the differing roles of these cells in the immune response and may have functional consequences for the trafficking of these cells in vivo. In summary, we have provided the first characterisation of the complete bovine chemokine receptor gene repertoire including a gene that is potentially unique to cattle. Further study of this receptor and its ligands may reveal a specific role of this receptor in cattle. The availability of the bovine chemokine receptor sequences will allow further characterisation of the function of these genes and will confer wide-reaching benefits to the study of this important aspect of the bovine immune response.


Surveillance after initial surgery for pediatric and adolescent girls with stage I ovarian germ cell tumors: report from the Children's Oncology Group.
To determine whether overall survival (OS) can be preserved for patients with stage I pediatric malignant ovarian germ cell tumor (MOGCT) with an initial strategy of surveillance after surgical resection. Between November 2003 and July 2011, girls age 0 to 16 years with stage I MOGCT were enrolled onto Children's Oncology Group study AGCT0132. Required histology included yolk sac, embryonal carcinoma, or choriocarcinoma. Surveillance included measurement of serum tumor markers and radiologic imaging at defined intervals. In those with residual or recurrent disease, chemotherapy with compressed PEB (cisplatin, etoposide, and bleomycin) was initiated every 3 weeks for three cycles (cisplatin 33 mg/m(2) on days 1 to 3, etoposide 167 mg/m(2) on days 1 to 3, bleomycin 15 U/m(2) on day 1). Survivor functions for event-free survival (EFS) and OS were estimated using the Kaplan-Meier method. Twenty-five girls (median age, 12 years) with stage I MOGCT were enrolled onto AGCT0132. Twenty-three patients had elevated alpha-fetoprotein (AFP) at diagnosis. Predominant histology was yolk sac. After a median follow-up of 42 months, 12 patients had evidence of persistent or recurrent disease (4-year EFS, 52%; 95% CI, 31% to 69%). Median time to recurrence was 2 months. All patients had elevated AFP at recurrence; six had localized disease, two had metastatic disease, and four had tumor marker elevation only. Eleven of 12 patients experiencing relapse received successful salvage chemotherapy (4-year OS, 96%; 95% CI, 74% to 99%). Fifty percent of patients with stage I pediatric MOGCT can be spared chemotherapy; treatment for those who experience recurrence preserves OS. Further study is needed to identify the factors that predict recurrence and whether this strategy can be extended successfully to older adolescents and young adults.


Progesterone and the premenstrual syndrome: a double blind crossover trial.
A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Moos's menstrual distress questionnaire, Beck et al's depression inventory, Spielberger et al's state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.


Post-traumatic stress disorder diagnosis in children: challenges and promises.
Children and adolescents experience high rates of potentially traumatic experiences. Many children subsequently develop mental health problems, including post-traumatic stress disorder (PTSD) symptoms. Accurately diagnosing PTSD in children is challenging. This paper reviews the following important issues: (i) the specificity of the PTSD diagnosis; (ii) children who are symptomatic and impaired but do not have enough symptoms for the diagnosis of PTSD; (iii) developmental considerations for preschool and school-age children; and (iv) a variety of assessment challenges that reflect the difficulty and complexity of interviewing children and caregivers about these symptoms. Despite these challenges, PTSD remains the best construct for clinical and research work with trauma survivors. Pediatric PTSD criteria are valuable for identifying children at risk and in need of treatment, and can be even more helpful when developmentally modified in ways that are discussed.


Sidelobe suppression in chiral optical filters by apodization of the local form birefringence.
Chiral optical filters are characterized by circular Bragg effects, including the preferential reflection and transmission of circular polarization states. The selective response to circularly polarized light is caused by stratified birefringent plates twisted into a helical arrangement, as seen in cholesteric liquid crystals and columnar thin films produced by oblique-angle physical vapor deposition. A refinement of the latter, glancing angle deposition employs substrate rotation to control the optical anisotropy of columnar thin films, and was used in this study to suppress the reflection sidelobes of chiral optical filters by modulating the local birefringence of helically structured thin films using an apodization function. Both theoretical simulations based on Berreman formalism, and experimental results involving evaporated TiO(2) thin films are presented and compared.


Both encouraging feeding style and high energy density may increase energy intakes from fermented millet gruels eaten by infants and toddlers in Ouagadougou.
Traditional fermented millet gruel is frequently eaten by children in Burkina Faso as a complementary food or for breakfast. The effects of gruel energy density and feeding style on intakes (amounts and energy) were assessed in children in Ouagadougou. Twenty-three young children (11 infants and 12 toddlers) were given two meals of gruel per day for two periods of 11 consecutive days, first, the traditional fermented gruel (TFG), and second, an improved high energy density fermented gruel (IFG). On the first 10 days of each period, the children were fed as usual, while on the 11th day, the mothers were asked to use encouraging feeding. Intakes of TFG and IFG were also measured once a day for nine days in 25 preschoolers (2-5 years-old). After adjustment for the subject effect, IFG intakes did not significantly differ from TFG intakes in the groups of infants and toddlers, meaning there was a significant increase in energy intakes, which almost doubled. Encouraging feeding increased TFG intakes in both age groups, but IFG intakes only increased in toddlers, whose energy intake tripled compared to that from TFG with the usual feeding style. In preschoolers, mean IFG intakes were lower than TFG intakes and there were no increase in mean energy intakes. Improving fermented gruel and training the mothers to encourage their young children during feeding are two possible strategies to improve food intakes, and hence to better satisfy the children's nutritional needs.


Clinically Significant Fibrosis Is Associated With Longitudinal Increases in Fibrosis-4 and Nonalcoholic Fatty Liver Disease Fibrosis Scores.
There is limited knowledge regarding the longitudinal utility of biomarkers of fibrosis, such as the nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) or the fibrosis-4 score (FIB-4) score. We examined longitudinal changes in the NFS and the FIB-4 score in patients with NAFLD, with and without clinically significant fibrosis (CSF). We performed a retrospective study of 230 patients with NAFLD, collecting clinical and laboratory records to calculate NFS and FIB-4 scores at 6 monthly intervals for 5 years before hepatology assessment of fibrosis. Linear mixed models with random intercept and slope and adjusted for age at baseline were used to assess the progression of NFS and log-transformed FIB-4 scores over time in subjects with and without CSF, determined by liver stiffness measurements of 8.2 kPa or greater. Patients had a median of 11 (minimum, 10; maximum, 11) retrospective observations over a median time period of 5 years (minimum, 4.5 y; maximum, 5 y). Of patients with low baseline NFS and FIB-4 scores, 31.11% and 37.76%, respectively, had CSF at the time of hepatology assessment. There was a correlation between NFS and log10 FIB-4 over time (repeated measure r = 0.55; 95% CI, 0.52-0.59). The rate of increase in NFS and log10 FIB-4 was significantly higher in patients with than without CSF (both P < .001). Predicted NFS increased by 0.17 and 0.06 units per year in subjects with and without CSF, respectively. Predicted log10 FIB-4 score increased by 0.032 and 0.0003 units per year in subjects with and without CSF, respectively. Noninvasively measured fibrosis scores increase progressively in patients with NAFLD and CSF. Further studies are needed to determine whether repeated measurements can identify patients at risk for CSF.


Absorbent products for incontinence: 'treatment effects' and impact on quality of life.
This study aimed to determine how the use and characteristics of absorbent products for incontinence impact on women's quality of life, and to examine the concept of 'treatment effects' in the context of pad use. Key pad performance characteristics were identified from the literature and focus group work. Semi-structured interviews with 99 women with light incontinence were used to investigate the impact of pad use on women's quality of life, including both positive and negative 'treatment effects', and to rank pad characteristics by their importance. Achieving effective and discrete containment of urine was the dominant factor impacting on women's lives. Sub-themes embraced physical effects, psychological impact and social functioning. The five pad characteristics ranked most important for day time use were: 'to hold urine, to contain smell, to stay in place, discreteness, and comfort when wet. For night use discreteness was replaced by to keep skin dry'. High levels of reported anxiety were associated with perceived risk of poor pad performance, lack of discreteness and need for complex regimes for pad management. Insufficient attention has been paid to the balance between the beneficial and negative treatment effects of absorbent pads to date. Existing continence-related quality of life measures are not designed for conditions where change in symptoms is not an outcome measure. The study findings provide the basis for developing a more sensitive, patient-oriented, quality of life measure for pad-users which can aid product selection, new product development and inform future evaluative comparisons between products/products and treatments. This paper illustrates the complex influence on quality of life caused by using absorbent pads to contain incontinence. It raises awareness of the importance of careful selection of the most appropriate pad for each individual to minimize unfavourable side effects, and the need for a new quality of life measure designed for pad-users.


Reliability and relevance evaluations of REACH data.
Regulatory authorities rely on hazard and risk assessments performed under REACH for identifying chemicals of concern and to take action. Therefore, these assessments must be systematic and transparent. This study investigates how registrants evaluate and report data evaluations under REACH and the procedures established by the European Chemicals Agency (ECHA) to support these data evaluations. Data on the endpoint repeated dose toxicity were retrieved from the REACH registration database for 60 substances. An analysis of these data shows that the system for registrants to evaluate data and report these evaluations is neither systematic nor transparent. First, the current framework focuses on reliability, but overlooks the equally important aspect of relevance, as well as how reliability and relevance are combined for determining the adequacy of individual studies. Reliability and relevance aspects are also confused in the ECHA guidance for read-across. Second, justifications for reliability evaluations were mainly based on studies complying with GLP and test guidelines, following the Klimisch method. This may result in GLP and guideline studies being considered reliable by default and discounting non-GLP and non-test guideline data. Third, the reported rationales for reliability were frequently vague, confusing and lacking information necessary for transparency. Fourth, insufficient documentation of a study was sometimes used as a reason for judging data unreliable. Poor reporting merely affects the possibility to evaluate reliability and should be distinguished from methodological deficiencies. Consequently, ECHA is urged to improve the procedures and guidance for registrants to evaluate data under REACH to achieve systematic and transparent risk assessments.


ADAP-GC 4.0: Application of Clustering-Assisted Multivariate Curve Resolution to Spectral Deconvolution of Gas Chromatography-Mass Spectrometry Metabolomics Data.
We report a multivariate curve resolution (MCR)-based spectral deconvolution workflow for untargeted gas chromatography-mass spectrometry metabolomics. As an essential step in preprocessing such data, spectral deconvolution computationally separates ions that are in the same mass spectrum but belong to coeluting compounds that are not resolved completely by chromatography. As a result of this computational separation, spectral deconvolution produces pure fragmentation mass spectra. Traditionally, spectral deconvolution has been achieved by using a model peak approach. We describe the fundamental differences between the model peak-based and the MCR-based spectral deconvolution and report ADAP-GC 4.0 that employs the latter approach while overcoming the associated computational complexity. ADAP-GC 4.0 has been evaluated using GC-TOF data sets from a 27-standards mixture at different dilutions and urine with the mixture spiked in, and GC Orbitrap data sets from mixtures of different standards. It produced the average matching scores 960, 959, and 926 respectively. Moreover, its performance has been compared against MS-DIAL, eRah, and ADAP-GC 3.2, and ADAP-GC 4.0 demonstrated a higher number of matched compounds and up to 6% increase of the average matching score.


LTR_FINDER: an efficient tool for the prediction of full-length LTR retrotransposons.
Long terminal repeat retrotransposons (LTR elements) are ubiquitous eukaryotic transposable elements. They play important roles in the evolution of genes and genomes. Ever-growing amount of genomic sequences of many organisms present a great challenge to fast identifying them. That is the first and indispensable step to study their structure, distribution, functions and other biological impacts. However, until today, tools for efficient LTR retrotransposon discovery are very limited. Thus, we developed LTR_FINDER web server. Given DNA sequences, it predicts locations and structure of full-length LTR retrotransposons accurately by considering common structural features. LTR_FINDER is a system capable of scanning large-scale sequences rapidly and the first web server for ab initio LTR retrotransposon finding. We illustrate its usage and performance on the genome of Saccharomyces cerevisiae. The web server is freely accessible at http://tlife.fudan.edu.cn/ltr_finder/.


Recurrence following treatment of ductal carcinoma in situ with skin-sparing mastectomy and immediate breast reconstruction.
Skin-sparing mastectomy with immediate breast reconstruction can provide an excellent cosmetic result. Despite its increasing popularity, few studies have assessed the risk of recurrence when the procedure is used for the treatment of ductal carcinoma in situ. To evaluate the oncologic safety of skin-sparing mastectomy used for the treatment of ductal carcinoma in situ, the recurrence rate was analyzed. Patients with ductal carcinoma in situ or invasive carcinoma or both who underwent skin-sparing mastectomy with immediate breast reconstruction between 1985 and 1994 and had a follow-up period of at least 6 years were included in this retrospective analysis. The recurrence rates were determined for invasive carcinoma (with or without foci of ductal carcinoma in situ) and ductal carcinoma in situ alone. A total of 221 patients were included, 177 patients with invasive carcinoma and 44 patients with ductal carcinoma in situ alone. The immediate breast reconstructions were performed with transverse rectus abdominis muscle (TRAM) flaps in 62 percent of patients, implants in 34 percent of patients, and latissimus dorsi myocutaneous flaps (with or without implants) in 4 percent of patients. The local recurrence rate was zero of 44 for patients with ductal carcinoma in situ and 5.6 percent (10 of 177) for patients with invasive carcinoma during a mean follow-up period of 9.8 years. There was a 6.8 percent (12 of 177) metastatic recurrence rate in the invasive carcinoma group. All recurrences were invasive ductal carcinoma. Of the patients with ductal carcinoma in situ alone, none developed metastatic disease. The combined metastatic and local recurrence rates for the invasive carcinoma group (n = 177) with each type of reconstruction were 13 percent (14 of 110), 12 percent (seven of 60), and 14 percent (one of seven) for TRAM flaps, implants, and latissimus dorsi flaps, respectively. The risk of recurrence following skin-sparing mastectomy and immediate breast reconstruction for ductal carcinoma in situ is low during this follow-up period. Therefore, skin-sparing mastectomy with immediate breast reconstruction seems to be a safe oncologic treatment option for ductal carcinoma in situ; however, a longer follow-up period is important to determine the long-term risk of recurrence.


Substantial health and economic returns from delayed aging may warrant a new focus for medical research.
Recent scientific advances suggest that slowing the aging process (senescence) is now a realistic goal. Yet most medical research remains focused on combating individual diseases. Using the Future Elderly Model--a microsimulation of the future health and spending of older Americans--we compared optimistic "disease specific" scenarios with a hypothetical "delayed aging" scenario in terms of the scenarios' impact on longevity, disability, and major entitlement program costs. Delayed aging could increase life expectancy by an additional 2.2 years, most of which would be spent in good health. The economic value of delayed aging is estimated to be $7.1 trillion over fifty years. In contrast, addressing heart disease and cancer separately would yield diminishing improvements in health and longevity by 2060--mainly due to competing risks. Delayed aging would greatly increase entitlement outlays, especially for Social Security. However, these changes could be offset by increasing the Medicare eligibility age and the normal retirement age for Social Security. Overall, greater investment in research to delay aging appears to be a highly efficient way to forestall disease, extend healthy life, and improve public health.


Intracranial and extracranial complications of acute mastoiditis: evaluation with computed tomography.
The incidence of acute mastoiditis has decreased significantly because we can effectively treat otitis media with oral antibiotics. Inadequate or delayed treatment of otitis predisposes to the development of mastoiditis and more serious, life-threatening complications. Extension of the infectious process beyond the mastoid system can lead to a variety of intracranial and extracranial complications including meningitis, epidural and intracerebral abscesses, vascular thrombosis, osteomyelitis, and abscesses deep within the neck. Signs of clinical deterioration in a patient with otitis media should indicate to the general practitioner that a more serious condition is evolving and surgical intervention may be necessary. Computed tomography is considered the imaging modality of choice for patients with acute mastoiditis because it can define clearly the regional anatomy and provide important diagnostic information.


The 'pH optimum anomaly' of intracellular enzymes of Ferroplasma acidiphilum.
A wide range of microorganisms, the so-called acidophiles, inhabit acidic environments and grow optimally at pH values between 0 and 3. The intracellular pH of these organisms is, however, close to neutrality or slightly acidic. It is to be expected that enzymatic activities dedicated to extracellular functions would be adapted to the prevailing low pH of the environment (0-3), whereas intracellular enzymes would be optimally active at the near-neutral pH of the cytoplasm (4.6-7.0). The genes of several intracellular or cell-bound enzymes, a carboxylesterase and three alpha-glucosidases, from Ferroplasma acidiphilum, a cell wall-lacking acidophilic archaeon with a growth optimum at pH 1.7, were cloned and expressed in Escherichia coli, and their products purified and characterized. The Ferroplasmaalpha-glucosidases exhibited no sequence similarity to known glycosyl hydrolases. All enzymes functioned and were stable in vitro in the pH range 1.7-4.0, and had pH optima much lower than the mean intracellular pH of 5.6. This 'pH optimum anomaly' suggests the existence of yet-undetected cellular compartmentalization providing cytoplasmic pH patchiness and low pH environments for the enzymes we have analysed.


Anion-dependent thermo-responsive supramolecular superstructures of Cu(ii) macrocycles.
This investigation highlights the role of counter anion towards the formation of thermo-responsive supramolecular assemblies of pre-defined discrete molecular Cu(ii) macrocycles. A new heteroditopic ligand (L) composed of two terminal triazolyl-pyridine units and a central pyridine-2,6-carboxamide unit connected via ethylene spacers predominantly forms dinuclear Cu(ii) macrocycles [L2Cu2]X4 (X = ClO4-, NO3-, Cl-) in the presence of respective monoanion-based Cu2+ salts. In contrast, dianionic SO42--based Cu2+ salt produces a mixture of both dinuclear [L2Cu2(SO4)2] and mononuclear [LCu(SO4)] Cu(ii) macrocycles. Importantly, detailed molecular structure determinations revealed the presence of multiple secondary interactions of the different counter anions with the corresponding macrocycles. The field emission scanning electron microscopy (FESEM) studies confirmed the ability of the individual macrocycles to further assemble upon slow evaporation of the solvent. Morphologically pure rod, sphere, and sheet-like superstructures were obtained for ClO4-, NO3-, and Cl- monoanion-based macrocycles, respectively. In contrast, a mixture of linear ribbon and microflower-like assemblies were obtained for SO42--based macrocycles. Moreover, it was found that upon heating, the rod-like assembly of [L2Cu2](ClO4)4 was gradually transformed into nanoparticles through a microparticle formation, which regenerated the rod-like assembly upon standing at room temperature. This was established from the FESEM, atomic force microscopy (AFM), and dynamic light scattering (DLS) studies.


Formate adsorption on Pt nanoparticles during formic acid electro-oxidation: insights from in situ infrared spectroscopy.
Adsorbed formate is observed on a supported Pt nanoparticle for the first time during formic acid electro-oxidation. Bands assigned to OCO stretching and CH bending reveal some OCO but little CH bond weakening on adsorption compared to the free anion. The formate potential dependence is similar to polycrystalline electrodes while adsorbed CO persists up to +1.2 V, 0.5 V higher than on polycrystalline Pt.


The Epstein-Barr virus nuclear antigen-1 reprograms transcription by mimicry of high mobility group A proteins.
Viral proteins reprogram their host cells by hijacking regulatory components of protein networks. Here we describe a novel property of the Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA1) that may underlie the capacity of the virus to promote a global remodeling of chromatin architecture and cellular transcription. We found that the expression of EBNA1 in transfected human and mouse cells is associated with decreased prevalence of heterochromatin foci, enhanced accessibility of cellular DNA to micrococcal nuclease digestion and decreased average length of nucleosome repeats, suggesting de-protection of the nucleosome linker regions. This is a direct effect of EBNA1 because targeting the viral protein to heterochromatin promotes large-scale chromatin decondensation with slow kinetics and independent of the recruitment of adenosine triphosphate-dependent chromatin remodelers. The remodeling function is mediated by a bipartite Gly-Arg rich domain of EBNA1 that resembles the AT-hook of High Mobility Group A (HMGA) architectural transcription factors. Similar to HMGAs, EBNA1 is highly mobile in interphase nuclei and promotes the mobility of linker histone H1, which counteracts chromatin condensation and alters the transcription of numerous cellular genes. Thus, by regulating chromatin compaction, EBNA1 may reset cellular transcription during infection and prime the infected cells for malignant transformation.


Band heterotopia.
Band heterotopias are one of the rarest groups of congenital disorder that result in variable degree of structural abnormality of brain parenchyma. Band of heterotopic neurons result from a congenital or acquired deficiency of the neuronal migration. MRI is the examination of choice for demonstrating these abnormalities because of the superb gray vs. white matter differentiation, detail of cortical anatomy and ease of multiplanar imaging. We report a case of band heterotopia that showed a bilateral band of gray matter in deep white matter best demonstrated on T2 Wt. and FLAIR images.


Fibromyalgia: Moderate and substantial pain intensity reduction predicts improvement in other outcomes and substantial quality of life gain.
Chronic pain is associated with a range of other problems, including disturbed sleep, depression, anxiety, fatigue, reduced quality of life, and an inability to work or socialise. We investigated whether good symptom control of pain (using definitions of moderate and substantial benefit) is associated with improvement in other symptoms. Individual patient data from four randomised trials in fibromyalgia (2575 patients) lasting 8-14weeks were used to calculate percentage pain reduction for each completing patient (1858), divided into one of five groups according to pain reduction, irrespective of treatment: substantial benefit - 50% pain reduction; moderate - 30% to <50%; minimal - 15% to <30%; marginal - 0% to <15%; worse - <0% (increased pain intensity). We then calculated change from baseline to end of trial for measures of fatigue, function, sleep, depression, anxiety, ability to work, general health status, and quality-adjusted life year (QALY) gain over a 12-month period. Substantial and moderate pain intensity reductions were associated with statistically significant reduction from baseline by end of trial in all measures, with values by trial end at or approaching normative values. Substantial pain intensity reduction resulted in 0.11 QALYs gained, and moderate pain intensity reduction in 0.07 QALYs gained over a 12-month period. Substantial and moderate pain intensity reduction predicts broad beneficial outcomes and improved quality of life that do not occur without pain relief. Pain intensity reduction is a simple and effective predictor of which patients should continue treatment, and which should discontinue and try an alternative therapy.


Identifying neural correlates of visual consciousness with ALE meta-analyses.
Neural correlates of consciousness (NCC) have been a topic of study for nearly two decades. In functional imaging studies, several regions have been proposed to constitute possible candidates for NCC, but as of yet, no quantitative summary of the literature on NCC has been done. The question whether single (striate or extrastriate) regions or a network consisting of extrastriate areas that project directly to fronto-parietal regions are necessary and sufficient neural correlates for visual consciousness is still highly debated [e.g., Rees et al., 2002, Nat Rev. Neurosci 3, 261-270; Tong, 2003, Nat Rev. Neurosci 4, 219-229]. The aim of this work was to elucidate this issue and give a synopsis of the present state of the art by conducting systematic and quantitative meta-analyses across functional magnetic resonance imaging (fMRI) studies using several standard paradigms for conscious visual perception. In these paradigms, consciousness is operationalized via perceptual changes, while the visual stimulus remains invariant. An activation likelihood estimation (ALE) meta-analysis was performed, representing the best approach for voxel-wise meta-analyses to date. In addition to computing a meta-analysis across all paradigms, separate meta-analyses on bistable perception and masking paradigms were conducted to assess whether these paradigms show common or different NCC. For the overall meta-analysis, we found significant clusters of activation in inferior and middle occipital gyrus; fusiform gyrus; inferior temporal gyrus; caudate nucleus; insula; inferior, middle, and superior frontal gyri; precuneus; as well as in inferior and superior parietal lobules. These results suggest a subcortical-extrastriate-fronto-parietal network rather than a single region that constitutes the necessary NCC. The results of our exploratory paradigm-specific meta-analyses suggest that this subcortical-extrastriate-fronto-parietal network might be differentially activated as a function of the paradigms used to probe for NCC.


Oocyst excretion in dogs fed mouse brains containing tissue cysts of a cloned line of Neospora caninum.
Neospora caninum is an apicomplexan parasite that causes neonatal neuromuscular disease in dogs and abortions in cattle. Bovine neosporosis is a major production problem worldwide. The parasite is transmitted to cattle via oocysts excreted by dogs or by transplacental transmission. Dogs are the only proven definitive host for N. caninum. One of 3 dogs fed mouse brains containing tissue cysts of a wild-type N. caninum strain CK0160SC3B (CKO) excreted oocysts in its feces. Two of 3 dogs fed mouse brains containing tissue cysts from a cloned line of the CKO strain excreted N. caninum oocysts in their feces. The results indicate that a single N. caninum tachyzoite contains all the genetic information needed to produce the asexual and sexual cycles in the canine intestine.


ESR1 PvuII (rs2234693 T>C) polymorphism and cancer susceptibility: Evidence from 80 studies.
Emerging epidemiological researches have been performed to assess the association of ESR1 PvuII (rs2234693 T>C) polymorphism with the risk of cancer, yet with conflicting conclusions. Therefore, this updated meta-analysis was performed to make a more accurate evaluation of such relationship. We adopted EMBASE, PubMed, CNKI, and WANFANG database to search relevant literature before January 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were employed to estimate the relationship strengths. In final, 80 studies (69 publications) involving 26428 cases and 43381 controls were enrolled. Our results failed to provide significant association between overall cancer risk and PvuII polymorphism under homozygous (TT vs. CC) and heterozygous (TT vs. CT) models. Statistically significant relationship was only observed for PvuII polymorphism in allele model T vs. C (OR=0.95, 95% CI=0.91-0.99). Stratification analysis by cancer type suggested that T genotype significantly decreased prostate cancer risk (TT vs. CC: OR=0.79, 95% CI=0.66-0.94; T vs. C: OR=0.89, 95% CI=0.82-0.98), Leiomyoma risk (T vs. C: OR=0.82, 95% CI=0.68-0.98), and HCC risk (TT vs. CC: OR=0.45, 95% CI=0.28-0.71; T vs. C: OR=0.67, 95% CI=0.47-0.95). Furthermore, significantly decreased risk was also found for Africans, population-based and hospital-based studies in the stratified analyses. These results suggest that ESR1 PvuII (rs2234693 T>C) polymorphism may only have little impact on cancer susceptibility. In the future, large-scale epidemical studies are warranted to verify these results.


Supervising dentists' perspectives on the effectiveness of community-based dental education.
The Commission on Dental Accreditation recently implemented new predoctoral standards that require dental schools in the United States to provide students with community-based dental education (CBDE) experiences. The objective of this study was to examine the perspectives of supervising dentists (also known as dental preceptors) at rural CBDE sites regarding the University of Nebraska Medical Center program's effectiveness in improving the competencies of dental students. Surveys were sent to all forty-three preceptors in two subsequent years: nineteen responded to all questions in 2012 and sixteen in 2013, for a total of thirty-five participants. These preceptors evaluated the effectiveness of the program based on the American Dental Education Association (ADEA) Competencies for the New General Dentist. Overall, these preceptors rated the CBDE program as effective (excellent or very good) in improving the students' competence in five of the six ADEA domains: Critical Thinking, Professionalism, Communication and Interpersonal Skills, Health Promotion, Patient Care: Assessment, Diagnosis, and Treatment Planning, and Patient Care: Establishment and Maintenance of Oral Health. Practice Management and Informatics was found to be the least effective domain of competence. CBDE provides a unique opportunity to develop a competent dental workforce with an appreciation for the value of community service. Applying a competency-based framework to program evaluation can provide valuable information on program effectiveness to program administrators, educators, and the dental preceptors.


Effects of 3,4-methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats.
The cardiovascular effects produced by 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats. Radiotelemetry was employed to evaluate the effects of s.c. administration of racemic MDMA and its phase I metabolites on BP, heart rate (HR) and locomotor activity in conscious male rats. MDMA (1-20 mg·kg(-1)) produced dose-related increases in BP, HR and activity. The peak effects on HR occurred at a lower dose than peak effects on BP or activity. The N-demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), produced effects that mimicked those of MDMA. The metabolite 3,4-dihydroxymethamphetamine (HHMA; 1-10 mg·kg(-1)) increased HR more potently and to a greater extent than MDMA, whereas 3,4-dihydroxyamphetamine (HHA) increased HR, but to a lesser extent than HHMA. Neither dihydroxy metabolite altered motor activity. The metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA) and 4-hydroxy-3-methoxyamphetamine (HMA) did not affect any of the parameters measured. The tachycardia produced by MDMA and HHMA was blocked by the β-adrenoceptor antagonist propranolol. Our results demonstrate that HHMA may contribute significantly to the cardiovascular effects of MDMA in vivo. As such, determining the molecular mechanism of action of HHMA and the other hydroxyl metabolites of MDMA warrants further study.


Influence of neighbourhood purchasing power on breastfeeding at four months of age: a Swedish population-based cohort study.
Parental socioeconomic status (SES) is an important determinant in child health, influencing beneficial factors such as breastfeeding. A better understanding of the influence of neighbourhood-level SES measures, relating to spatial determinants, might lead to targeted actions to promote breastfeeding during infancy. A cross-sectional study analysis the association between breastfeeding at four months of age and neighbourhood purchasing power, taking account of individual-level variables including maternal age, smoking and parental level of education. Data were obtained from a prospective population- based cohort study recruited from birth in 2007-2008 in the Halland region, southwestern Sweden. Questionnaire data on the individual-level variables and the outcome variable of breastfeeding at four months (yes/no) were used (n=2,407). Each mother was geo-coded with respect to her residential parish (there are 61 parishes in the region) and then stratified by parish-level household purchasing power. It emerged that four neighbourhood characteristics were reasonable to use, viz. <10%, 10-19%, 20-29% and ≥ 30% of the resident families with low purchasing power. The proportion of mothers not breastfeeding at four months of age showed a highly significant trend across the neighbourhood strata (p=0.00004): from 16.3% (< 10% with low purchasing power) to 29.4% (≥ 30% with low purchasing power), yielding an OR of 2.24 (95% confidence interval: 1.45-3.16). After adjusting for the individual-level variables, the corresponding OR=1.63 (1.07-2.56) was significant and the trend across the strata was still evident (p=0.05). A multi-level analysis estimated that, in the neighbourhoods with ≥ 30% of the families with low purchasing power, 20% more mothers than expected, taking account of the individual-level factors, reported no breastfeeding at four months of age (≥ 95% posterior probability of an elevated observed-to-expected ratio). The neighbourhood purchasing power provided a spatial determinant of low numbers of mothers breastfeeding at four months of age, which could be relevant to consider for targeted actions. The elevated observed-to-expected ratio in the neighbourhoods with the lowest purchasing power points toward a possible contextual influence.


[Advances of rice bacterial blight disease resistance gene Xa21].
Gene Xa21 is the first disease resistance gene cloned from rice (Oryza sativa L.), which encodes a receptor-like kinase and confers broad spectrum resistance against Xanthomonas oryzae pv. oryzae (Xoo). In this paper, the discovery, mapping and cloning of Xa21 were reviewed briefly. The molecular mechanism of resistance and its breeding application, including biochemical properties of the kinase domain of XA21, AvrXa21 identification, the disease resistance pathway mediated by Xa21, and the mechanism of disease resistance were summarized. Future perspective on Xa21-related research is also discussed.


Until programmed death do us tolerant.
Healthy individuals are generally immunologically tolerant to proteins derived from one's self (termed self proteins). However, patients with monogenic clotting disorders, like hemophilia A (HemA), lack central tolerance to the absent self protein. Thus, when exposed to replacement therapy, such as procoagulant factor VIII, they may mount an immune response against the very self protein that is missing. In the current issue of the JCI, Becker-Gotot, Meissner, et al. present data on a possible mechanism for tolerance to factor VIII in healthy individuals and the immune response in patients, involving a role of PD-1 and T regulatory cells. The findings suggest that treatment with PD-1- and PD-1L-specific reagents may induce tolerance in patients with autoimmune disease, especially those with HemA who also possess inhibiting antibodies.


Cardiorespiratory responses during the 6-minute walk and ramp cycle ergometer tests and their relationship to physical activity in stroke.
The 6-minute walk test (6MWT) is used to measure exercise capacity after stroke. We sought to compare cardiorespiratory responses during the 6MWT with responses to a ramp cycle ergometer test (CET) in community-dwelling individuals with stroke. A secondary objective was to determine the relationship between cardiorespiratory responses during each test and daily physical activity. Participants completed 3 evaluation sessions. The CET and 6MWT were conducted in 2 separate sessions at least 72 hours apart. Participants wore a portable gas analysis unit (Cosmed K4b2), which also measured heart rate (HR) during the 6MWT. A uniaxial accelerometer (activPAL) was used to measure time spent upright (standing and stepping) over 5 days as an estimate of daily physical activity. Complete CET and 6MWT data were obtained for 16 participants (14 men), a mean ± standard deviation of 2.0 ± 1.1 years after stroke and 71.1 ± 9.7 years of age. Compared with the 6MWT, the CET elicited a higher VO(2peak) (P = .032), VCO(2peak) (P = .005), respiratory exchange ratio (P = .015), and self-reported perceived breathing (P < .0001) and leg heaviness (P < .0001) at test completion and a lower HR(peak) (P = .029). Except for the first minute, VO(2) during the 6MWT was, on average, 80% to 85% of VO(2peak) from the CET. Among 15 participants, average time spent upright per day was not significantly associated with 6MWT distance (r = 0.447, P = .096) or VO(2peak) from the CET (r = 0.388, P = .153). Exercise intensity achieved during the 6MWT appeared sufficiently high for aerobic training, assuming CET VO(2peak) accurately reflects aerobic capacity. The 6MWT may be useful for prescribing aerobic exercise poststroke.


Age-specific CUGBP1-eIF2 complex increases translation of CCAAT/enhancer-binding protein beta in old liver.
The RNA-binding protein CUGBP1 regulates translation of proteins in a variety of biological processes. In this study, we show that aging liver increases CUGBP1 translational activities by induction of a high molecular weight protein-protein complex of CUGBP1. The complex contains CUGBP1, subunits alpha, beta, and gamma of the initiation translation factor eIF2, and four proteins of the endoplasmic reticulum, eR90, CRT, eR60, and Grp78. The induction of the CUGBP1-eIF2 complex in old livers is associated with the elevation of protein levels of CUGBP1 and with the hyper-phosphorylation of CUGBP1 by a cyclin D3-cdk4 kinase, activity of which is increased with age. We have examined the role of the elevation of CUGBP1 and the role of cyclin D3-cdk4-mediated phosphorylation of CUGBP1 in the formation of the CUGBP1-eIF2 complex by using CUGBP1 transgenic mice and young animals expressing high levels of cyclin D3 after injection with cyclin D3 plasmid. These studies showed that both the increased levels of CUGBP1 and cdk4-mediated hyper-phosphorylation of CUGBP1 are involved in the age-associated induction of the CUGBP1-eIF2 complex. The CUGBP1-eIF2 complex is bound to C/EBPbeta mRNA in the liver of old animals, and this binding correlates with the increased amounts of liver-enriched activator protein and liver-enriched inhibitory protein. Consistent with these observations, the purified CUGBP1-eIF2 complex binds to the 5' region of C/EBPbeta mRNA and significantly increases translation of the three isoforms of C/EBPbeta in a cell-free translation system, in cultured cells, and in the liver. Thus, these studies demonstrated that age-mediated induction of the CUGBP1-eIF2 complex changes translation of C/EBPbeta in old livers.


Environmental and seasonal correlates of capercaillie movement traits in a Swedish wind farm.
Animals continuously interact with their environment through behavioral decisions, rendering the appropriate choice of movement speed and directionality an important phenotypic trait. Anthropogenic activities may alter animal behavior, including movement. A detailed understanding of movement decisions is therefore of great relevance for science and conservation alike. The study of movement decisions in relation to environmental and seasonal cues requires continuous observation of movement behavior, recently made possible by high-resolution telemetry. We studied movement traits of 13 capercaillie (Tetrao urogallus), a mainly ground-moving forest bird species of conservation interest, over two summer seasons in a Swedish windfarm using high-resolution GPS tracking data (5-min sampling interval). We filtered and removed unreliable movement steps using accelerometer data and step characteristics. We explored variation in movement speed and directionality in relation to environmental and seasonal covariates using generalized additive mixed models (GAMMs). We found evidence for clear daily and seasonal variation in speed and directionality of movement that reflected behavioral adjustments to biological and environmental seasonality. Capercaillie moved slower when more turbines were visible and faster close to turbine access roads. Movement speed and directionality were highest on open bogs, lowest on recent clear-cuts (<5 y.o.), and intermediate in all types of forest. Our results provide novel insights into the seasonal and environmental correlates of capercaillie movement patterns and supplement previous behavioral observations on lekking behavior and wind turbine avoidance with a more mechanistic understanding.


How and why party position estimates from manifestos, expert, and party elite surveys diverge: A comparative analysis of the 'left-right' and the 'European integration' dimensions.
This paper examines the validity of three approaches to estimate party positions on the general left-right and EU dimensions. We newly introduce party elite data from the comprehensive IntUne survey and cross-validate it with existing expert survey and manifesto data. The general left-right estimates generated by elites and experts show a higher congruence than those derived from party manifestos; neither measure clearly materializes as more valid regarding EU positions. We identify which factors explain diverging estimates. For instance, disagreement among experts has greater impact than their mere number. The substantial centrist bias of the manifesto estimates persists even when alternative documents are used to substitute manifestos. Low response rates among elites have no systematic detrimental effect on the validity of party position estimates.


Respiratory symptoms, lung function, and sensitisation to flour in a British bakery.
A survey of dust exposure, respiratory symptoms, lung function, and response to skin prick tests was conducted in a modern British bakery. Of the 318 bakery employees, 279 (88%) took part. Jobs were ranked from 0 to 10 by perceived dustiness and this ranking correlated well with total dust concentration measured in 79 personal dust samples. Nine samples had concentrations greater than 10 mg/m3, the exposure limit for nuisance dust. All participants completed a self administered questionnaire on symptoms and their relation to work. FEV1 and FVC were measured by a dry wedge spirometer and bronchial reactivity to methacholine was estimated. Skin prick tests were performed with three common allergens and with 11 allergens likely to be found in bakery dust, including mites and moulds. Of the participants in the main exposure group, 35% reported chest symptoms which in 13% were work related. The corresponding figures for nasal symptoms were 38% and 19%. Symptoms, lung function, bronchial reactivity, and response to skin prick tests were related to current or past exposure to dust using logistic or linear regression analysis as appropriate. Exposure rank was significantly associated with most of the response variables studied. The study shows that respiratory symptoms and sensitisation are common, even in a modern bakery.


Social and ecological structures supporting adolescent connectedness to school: a theoretical model.
Adolescence is a time of great change. For most young people, this is a healthy and happy experience; however, for some it is characterized by many health, social, and academic challenges. A student's feeling of connectedness to school helps meet these challenges. Little is known, however, about the school characteristics that promote this connection and, more importantly, how this connection occurs. This article reviews the connectedness literature and integrates health promotion, adolescent development, and ecological frameworks to describe how a school context fosters this connection. A systematic search and review process was used to retrieve scholarly articles pertaining to the research topic. Each retrieved article was summarized, and a subsequent model was developed to define a school ecology and describe how this ecology influences a student's need to feel connected to school and the positive influence this connection has on adolescent health and well-being. Integrating developmental, ecological, and health promotion intervention theories and frameworks assists in the identification of interpersonal and organizational aspects of a school environment, which satisfy an individual's needs to feel autonomous, competent, and connected, and to improve health and well-being outcomes for adolescents.


Antibiotic resistance ABCF proteins reset the peptidyl transferase centre of the ribosome to counter translational arrest.
Several ATPases in the ATP-binding cassette F (ABCF) family confer resistance to macrolides, lincosamides and streptogramins (MLS) antibiotics. MLS are structurally distinct classes, but inhibit a common target: the peptidyl transferase (PTC) active site of the ribosome. Antibiotic resistance (ARE) ABCFs have recently been shown to operate through direct ribosomal protection, but the mechanistic details of this resistance mechanism are lacking. Using a reconstituted translational system, we dissect the molecular mechanism of Staphylococcus haemolyticus VgaALC and Enterococcus faecalis LsaA on the ribosome. We demonstrate that VgaALC is an NTPase that operates as a molecular machine strictly requiring NTP hydrolysis (not just NTP binding) for antibiotic protection. Moreover, when bound to the ribosome in the NTP-bound form, hydrolytically inactive EQ2 ABCF ARE mutants inhibit peptidyl transferase activity, suggesting a direct interaction between the ABCF ARE and the PTC. The likely structural candidate responsible for antibiotic displacement by wild type ABCF AREs, and PTC inhibition by the EQ2 mutant, is the extended inter-ABC domain linker region. Deletion of the linker region renders wild type VgaALC inactive in antibiotic protection and the EQ2 mutant inactive in PTC inhibition.


Analysis of human-machine cooperation when driving with different degrees of haptic shared control.
This study investigated human-machine cooperation when driving with different degrees of a shared control system. By means of a direct intervention on the steering wheel, shared control systems partially correct the vehicle's trajectory and, at the same time, provide continuous haptic guidance to the driver. A crucial point is to determine the optimal level of steering assistance for effective cooperation between the two agents. Five system settings were compared with a condition in which no assistance was present. In addition, road visibility was manipulated by means of additional fog or self-controlled visual occlusions. Several performance indicators and subjective assessments were analyzed. The results show that the best repartition of control in terms of cooperation between human and machine can be identified through an analysis of the steering wheel reversal rate, the steering effort and the mean lateral position of the vehicle. The best cooperation was achieved with systems of relatively low-level haptic authority, although more intervention may be preferable in poor visibility conditions. Increasing haptic authority did not yield higher benefits in terms of steering behavior, visual demand or subjective feeling.


Energy dissipation of highly charged ions on Al oxide films.
Slow highly charged ions (HCIs) carry a large amount of potential energy that can be dissipated within femtoseconds upon interaction with a surface. HCI-insulator collisions result in high sputter yields and surface nanofeature creation due to strong coupling between the solid's electronic system and lattice. For HCIs interacting with Al oxide, combined experiments and theory indicate that defect mediated desorption can explain reasonably well preferential O atom removal and an observed threshold for sputtering due to potential energy. These studies have relied on measuring mass loss on the target substrate or probing craters left after desorption. Our approach is to extract highly charged ions onto the Al oxide barriers of metal-insulator-metal tunnel junctions and measure the increased conductance in a finished device after the irradiated interface is buried under the top metal layer. Such transport measurements constrain dynamic surface processes and provide large sets of statistics concerning the way individual HCI projectiles dissipate their potential energy. Results for Xe(q +) for q = 32, 40, 44 extracted onto Al oxide films are discussed in terms of postirradiation electrical device characteristics. Future work will elucidate the relationship between potential energy dissipation and tunneling phenomena through HCI modified oxides.


Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.


Should sputum smear examination be carried out at the end of the intensive phase and end of treatment in sputum smear negative pulmonary TB patients?
The Indian guidelines on following up sputum smear-negative Pulmonary tuberculosis (PTB) patients differ from the current World Health Organization (WHO) guidelines in that the former recommends two follow up sputum examinations (once at the end of intensive phase and the other at the end of treatment) while the latter recommends only one follow up sputum smear microscopy examination, which is done at the end of the intensive phase. This study was conducted to examine if there was any added value in performing an additional sputum smear examination at the end of treatment within the context of a national TB program. This study was a descriptive record based review conducted in nine tuberculosis (TB) units in Delhi, India. All consecutive new sputum smear-negative PTB patients registered in these nine TB units from 1(st) January 2009 to 31(st) December 2009 were included in the study. Of 2567 new sputum smear-negative TB patients, 1973 (90%) had sputum specimens examined at the end of the intensive phase, of whom 36 (2%) were smear-positive: the majority (n = 28) successfully completed treatment with either the same or a re-treatment regimen. At treatment completion, 1766 (85%) patients had sputum specimens examined, of whom 16 (0.9%) were smear-positive: all these were changed to a re-treatment regimen. Amongst the sputum-positive patients identified as a result of follow up (n = 52), four were diagnosed with multi-drug resistant TB (MDR-TB), three of whom were detected after smear examination at the end of treatment. Given the high burden of TB in India, a 0.9% additional yield of smear-positive sputum smears at the end of treatment translates to 3,297 cases of smear-positive PTB. End-of-treatment smear is a low-yield strategy for detection of smear-positive TB cases, although further studies are needed to determine its population-level impact and cost, particularly in relation to other TB control interventions.


N-(3-oxododecanoyl)-L-homoserine lactone interactions in the breast tumor microenvironment: Implications for breast cancer viability and proliferation in vitro.
It is well documented that the tumor microenvironment profoundly impacts the etiology and progression of breast cancer, yet the contribution of the resident microbiome within breast tissue remains poorly understood. Tumor microenvironmental conditions, such as hypoxia and dense tumor stroma, predispose progressive phenotypes and therapy resistance, however the role of bacteria in this interplay remains uncharacterized. We hypothesized that the effect of individual bacterial secreted molecules on breast cancer viability and proliferation would be modulated by these tumor-relevant stressors differentially for cells at varying stages of progression. To test this, we incubated human breast adenocarcinoma cells (MDA-MB-231, MCF-DCIS.com) and non-malignant breast epithelial cells (MCF-10A) with N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), a quorum-sensing molecule from Pseudomonas aeruginosa that regulates bacterial stress responses. This molecule was selected because Pseudomonas was recently characterized as a significant fraction of the breast tissue microbiome and OdDHL is documented to impact mammalian cell viability. After OdDHL treatment, we demonstrated the greatest decrease in viability with the more malignant MDA-MB-231 cells and an intermediate MCF-DCIS.com (ductal carcinoma in situ) response. The responses were also culture condition (i.e. microenvironment) dependent. These results contrast the MCF-10A response, which demonstrated no change in viability in any culture condition. We further determined that the observed trends in breast cancer viability were due to modulation of proliferation for both cell types, as well as the induction of necrosis for MDA-MB-231 cells in all conditions. Our results provide evidence that bacterial quorum-sensing molecules interact with the host tissue environment to modulate breast cancer viability and proliferation, and that the effect of OdDHL is dependent on both cell type as well as microenvironment. Understanding the interactions between bacterial signaling molecules and the host tissue environment will allow for future studies that determine the contribution of bacteria to the onset, progression, and therapy response of breast cancer.


An algorithm to improve diagnostic accuracy in diabetes in computerised problem orientated medical records (POMR) compared with an established algorithm developed in episode orientated records (EOMR).
An algorithm that detects errors in diagnosis, classification or coding of diabetes in primary care computerised medial record (CMR) systems is currently available. However, this was developed on CMR systems that are episode orientated medical records (EOMR); and do not force the user to always code a problem or link data to an existing one. More strictly problem orientated medical record (POMR) systems mandate recording a problem and linking consultation data to them. To compare the rates of detection of diagnostic accuracy using an algorithm developed in EOMR with a new POMR specific algorithm. We used data from The Health Improvement Network (THIN) database (N = 2,466,364) to identify a population of 100,513 (4.08%) patients considered likely to have diabetes. We recalibrated algorithms designed to classify cases of diabetes to take account of that POMR enforced coding consistency in the computerised medical record systems [In Practice Systems (InPS) Vision] that contribute data to THIN. We explored the different proportions of people classified as having type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) and with diabetes unclassifiable as either T1DM or T2DM. We compared proportions using chi-square tests and used Tukey's test to compare the characteristics of the people in each group. The prevalence of T1DM using the original EOMR algorithm was 0.38% (9,264/2,466,364), and for T2DM 3.22% (79,417/2,466,364). The prevalence using the new POMR algorithm was 0.31% (7,750/2,466,364) T1DM and 3.65% (89,990/2,466,364) T2DM. The EOMR algorithms also left more people unclassified 11,439 (12%), as to their type of diabetes compared with 2,380 (2.4%), for the new algorithm. Those people who were only classified by the EOMR system differed in terms of older age, and apparently better glycaemic control, despite not being prescribed medication for their diabetes (p < 0.005). Increasing the degree of problem orientation of the medical record system can improve the accuracy of recording of diagnoses and, therefore, the accuracy of using routinely collected data from CMRs to determine the prevalence of diabetes mellitus; data processing strategies should reflect the degree of problem orientation.


A positive crosstalk between CXCR4 and CXCR2 promotes gastric cancer metastasis.
The molecular mechanism underlying gastric cancer (GC) invasion and metastasis is still poorly understood. In this study, we tried to investigate the roles of CXCR4 and CXCR2 signalings in gastric cancer metastasis. A highly invasive gastric cancer cell model was established. Chemokines receptors were profiled to search for the accountable ones. Then the underlying molecular mechanism was investigated using both in vitro and in vivo techniques, and the clinical relevance of CXCR4 and CXCR2 expression was studied in gastric cancer samples. CXCR4 and CXCR2 were highly expressed in a high invasive gastric cancer cell model and in gastric cancer tissues. Overexpression of CXCR4 and CXCR2 was associated with more advanced tumor stage and poorer survival for GC patients. CXCR4 and CXCR2 expression strongly correlated with each other in the way that CXCR2 expression changed accordingly with the activity of CXCR4 signaling and CXCR4 expression also changed in agreement with CXCR2 activity. Further studies demonstrated CXCR4 and CXCR2 can both activated NF-κB and STAT3 signaling, while NF-κBp65 can then transcriptionally activate CXCR4 and STAT3 can activate CXCR2 expression. This crosstalk between CXCR4 and CXCR2 contributed to EMT, migration and invasion of gastric cancer. Finally, Co-inhibition of CXCR4 and CXCR2 is more effective in reducing gastric cancer metastasis. Our results demonstrated that CXCR4 and CXCR2 cross-activate each other to promote the metastasis of gastric cancer.


Safety and side effects of cannabidiol, a Cannabis sativa constituent.
Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.


Survival disparities in non-small cell lung cancer by race, ethnicity, and socioeconomic status.
Non-small cell lung cancer (NSCLC) is among the leading causes of cancer death in the United States. Previous studies found mixed results regarding disparities in survival by race, ethnicity, and socioeconomic status (SES). However, race comparisons were usually limited, with comparisons made between black and white patients only or by merging race and ethnicity together as non-Hispanic black, non-Hispanic white, and Hispanic patients. Even fewer studies included race, ethnicity, and SES together while controlling for extensive confounding variables. Thus, because we have access to a large and unique population-based database that includes tumor characteristics and patient comorbidities, the purpose of this study was to explore disparities in NSCLC survival. We linked data from the 1996 to 2007 Florida Cancer Data System registry to the Florida's Agency for Health Care Administration and the US Census (n = 98,541). Survival time was from date of diagnosis to death or last contact. Race was white, black, Native American, Asian, Pacific Islander, Asian Indian/Pakistani, or other. Ethnicity was non-Hispanic or Hispanic. Socioeconomic status was measured as percentage of the participant's census tract living below the federal poverty line. Median survival and survival rates were calculated by Kaplan-Meier method. Cox proportional hazards regression models produced unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs). The majority of patients were white (91.9%) and non-Hispanic (94.1%). Blacks had the lowest median survival (8.4 months). At 5 years after diagnosis, survival rate was highest in whites (16.3%) and lowest for Pacific Islanders (6.4%). In the adjusted model, Asians had significantly improved survival compared with whites (HR, 0.85; 95% CI, 0.76-0.95). Patients in middle-low (HR, 0.96; 95% CI, 0.94-0.99), middle-high (HR, 0.92; 95% CI, 0.89-0.94), and highest (HR, 0.87; 95% CI, 0.84-0.91) SES areas had significantly improved survival compared with those in lowest areas. Significantly worse survival was found for patients with complicated diabetes (HR, 1.05; 95% CI, 1.01-1.08), weight loss (HR, 1.08; 95% CI, 1.06-1.11), fluid and electrolyte disorders (HR, 1.08; 95% CI, 1.06-1.11), and alcohol abuse (HR, 1.11; 95% CI, 1.07-1.14). We found strong evidence for racial and socioeconomic disparities in Floridian NSCLC survival. Asians had improved survival compared with whites, a novel finding. Our findings confirmed that patients living in lower socioeconomic neighborhoods have worse outcomes than their wealthier neighborhood counterparts. Finally, we found an association between some modifiable factors/comorbidities and worse survival. Clinicians may be able to use this information to improve patients' likelihood of better outcomes.