Effects and Factors Related to Adherence to A Diabetes Pay-for-Performance Program: Analyses of a National Health Insurance Claims Database.
To compare the effects of a diabetes pay-for-performance (P4P) program on diabetes-related/nondiabetes-related healthcare utilization/expenses between participants who adhered to the program and those who did not, and explore factors related to program adherence. A secondary data analysis with a natural experimental design. Taiwan's National Health Insurance claims database (2001-2011) of newly diagnosed patients with diabetes in 2001 was used for the analyses. The database under analyses contained 119,970 patients who were newly diagnosed with diabetes in 2001. Longitudinal data from 2001 to 2011 were obtained. A sample of 5592 patients who were enrolled in the diabetes P4P program during 2003-2006 was identified. After a 3-year follow-up of the enrolled patients, 2647 (47.3%) of them adhered to the program. To minimize the differences between the characteristics of the patients who adhered to the program and those who did not, propensity score matching was adopted. A total of 5294 patients (adherence: 2647 vs nonadherence: 2647) were included for analyses. We estimated utilization/expenses of healthcare services for both groups at 6 time points and applied t tests to test each utilization and expense of healthcare services between the 2 groups. A repeated-measures analysis of variance was applied to examine changes in the annual diabetes-related healthcare service expenses and total annual expenses by group. Logistic regression models were used to examine factors related to program adherence. Covariates included participant age, gender, diabetes-related complications, Charlson Comorbidity Index, Continuity of Care Index, time since diagnosis of diabetes, hospitalization in the previous year, and location receiving healthcare services. Total annual healthcare expenses spent by the adherence group were significantly lower than those of the nonadherence group. Gender, continuity of care, time since diagnosis of diabetes, hospitalizations in the previous year, and location receiving healthcare services were factors related to program adherence. Long-term, beneficial effects of the diabetes P4P program might have been present if patients had adhered to the program. Interventions and strategies which could improve program adherence and continuity of care are suggested to achieve optimal disease control and clinical outcomes.


Weight gain, metabolic disturbances, and physical health care in a Brazilian sample of outpatients with schizophrenia.
In the last few decades, a large number of studies have produced compelling evidence that patients with schizophrenia are at increased risk for developing several medical conditions and diseases, including obesity, metabolic disturbances, and cardiovascular diseases. Several protocols have been designed with the aim of reducing such risk. To investigate current physical health status in a population of outpatients with schizophrenia. A cross-sectional study was conducted in our outpatient clinic, selecting subjects who met DSM-IV diagnosis criteria for schizophrenia. Data were collected regarding clinical characteristics, lifestyle, medication in use, and biometric and laboratory parameters. A total of 261 patients were included. We found a high prevalence of elevated body mass index (BMI . 25) (70%), dyslipidemia (73.2%), and metabolic syndrome (28.7%). Patients' ages were associated with worsened lipid profiles, but other variables, such as disorder duration or type of antipsychotic in use, were not associated with any metabolic disturbance. Despite the increased prevalence of these conditions, only a small portion of the sample was under regular medical treatment. Outpatients with schizophrenia show signs of poor physical health conditions. These findings reinforce the need for an intensive and appropriate approach to assure that these patients receive adequate clinical referral and treatment.


Barriers to accessing TB diagnosis for rural-to-urban migrants with chronic cough in Chongqing, China: a mixed methods study.
China is facing a significant tuberculosis epidemic among rural-to-urban migrants, which poses a threat to TB control. This study aimed to understand the health seeking behaviour of and health systems responses to migrants and permanent urban residents suffering from chronic cough, in order to identify the factors influencing delays for both groups in receiving a TB diagnosis in urban China. Combining a prospective cohort study of adult suspect TB patients and a qualitative study, the Piot model was used to analyze the health seeking behaviour of TB suspects among migrants and permanent urban residents, the factors influencing their decision and the responses by general health providers. Methods included a patient survey, focus group discussions with migrants in the general population, qualitative interviews with migrant and permanent resident TB suspects and TB patients as well as key stakeholders related to TB control and the management of migrants. Sixty eight percent of migrants delayed for more than two weeks before seeking care for symptoms suggestive of TB, compared to 54% of residents (p < 0.01). When they first decided to seek professional care, migrants were 1.5 times more likely than residents to use less expensive, community-level health services. Only 5% were ultimately referred to a TB dispensary. Major reasons for both patient and provider delay included lack of knowledge and mistrust of the TB control programme, lack of knowledge about TB (patients), and profit-seeking behaviour (providers). In the follow up survey, 61% of the migrants and 41% of the residents who still had symptoms gave up continuing to seek professional care, with a statistically significant difference between the two groups (p < 0.05). Rural-to-urban migrants are more likely than permanent residents to delay in seeking care for symptoms suggestive of TB in urban Chongqing. 'Patient-' and 'provider-' related factors interact to pose barriers to TB diagnosis for migrants, including: low awareness, and poor knowledge among both the general public and TB suspects about TB as a disease and about the TB control programme; low financial capacity to pay for care and diagnostic tests; and inadequate use of diagnostic tests and referral to TB dispensaries by general health providers.


Risk scoring in the assessment of cardiovascular risk.
Cardiovascular risk scoring is incorporated in guidelines and recommended for targeting preventive treatment. Evidence is required on the most appropriate method, its accuracy in a given population, and its effectiveness in favourably influencing clinical behaviour and health outcomes. Recent risk scores address inaccuracies that arise when methods are transferred between populations, and specific methods and recalibrations are described for use in low-risk populations. Ethnic and social differences in risk are also recognized in the context of cardiovascular risk scoring. More sensitive measures of known risk factors and numerous emerging risk factors are reported and new statistical methods and sources of data suggested. Little emphasis has been placed on evaluation of the clinical effectiveness of cardiovascular risk scores. Education in cardiovascular risk assessment may help improve uptake of methods by healthcare professionals. Numerous risk scoring methods are available to the healthcare professional but use is patchy. Accuracy varies between populations and methods have been developed to compensate for some of this variability. If risk scoring methods are to be widely used in general practice, evidence is required on both the accuracy of methods in appropriate populations and their effectiveness in improving health outcomes.


Virtual population pharmacokinetic using physiologically based pharmacokinetic model for evaluating bioequivalence of oral lacidipine formulations in dogs.
The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic (PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions (ASDs) capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study. In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions (ASDs) capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration (Cmax ), and the time (Tmax ) to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval (CI) for the Cmax , AUC0-24 h and AUC0-∞ of the ratio of the test drug to the referencedrug exceeded the acceptable bioequivalence (BE) limits (0.80-1.25). However, the 90% CI of the AUC0-24 h, AUC0-∞ and Cmax of the ratio of test to reference drug were within the BE limit, calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.


Small cell lung cancer.
Lung cancer is the predominant fatal neoplasm of our time, and SCLC, which accounts for about 25% of all lung cancer, if untreated results in death in about 3 months. Currently employed aggressive combination chemotherapy has allowed a 4- to 5-fold improvement in median survival over untreated patients. Ten to 20% of patients with limited disease can be expected to have a long-term (2-yr) survival. The majority of patients, however, have extensive disease. For these patients the median survival is about 7 months. Less than 2% survive 2 yr. During the last 10 yr, experience in the treatment of thousands of patients has been reported. These trials, using a large variety of drug combinations, doses, and schedules as well as multiple modalities including radiotherapy, surgery, and bone marrow transplantation, demonstrate that a plateau has been reached with our present therapeutic approach. The development of new effective therapeutic strategies as well as prevention of SCLC require a better basic understanding of the cellular pathophysiology of the disease. A consistent chromosomal abnormality has been associated with SCLC. This may provide new insight into predisposition and pathogenesis of SCLC. How this chromosomal abnormality relates to loss of control of cell growth is under intense investigation. Similarly, during the past 3 yr, the identification of growth regulatory oncogenes has greatly improved our understanding of malignancy. The discovery that metastatic cells escape immune surveillance has led to attempts at modulating antigenic expression. The modulation of cellular antigenic expression may facilitate the destruction of tumor cells by host defense mechanisms. The understanding of the genetic basis of drug resistance may lead to approaches that prevent or delay resistance. This century has witnessed the emergence of SCLC as an important fatal neoplasm. It has also been during this time that another, formerly dominant pulmonary condition, tuberculosis, has been controlled. The reduction of tuberculosis was accomplished by a combination of scientific understanding, beginning with the discovery of Koch's bacillus, and public health measures. Perhaps a similar parallel for SCLC as well as other forms of cancer will be written. Basic cellular investigations with the new tools of molecular biology as well as measures to control exposure to predisposing environmental factors such as component of cigarette smoke may one day lead to control of SCLC.


[Metastatic breast cancer in 28 years old man].
Male breast cancer only makes up about 1% of all malignancies in the male population; the median age at time of diagnosis is 68 years. The treatment procedures used in clinical practice are those confirmed by studies on women. Presented is a case of a 28-year-old man with breast cancer in the fourth clinical stage. The patient was treated with the addition of trastuzumab to chemotherapy, radiotherapy, hormone treatment, with disease progression with lapatinib added to chemotherapy. 18 months after initiation of therapy, the patient died. Despite the increase in incidence, male breast cancer remains a rare diagnosis and treatment data are not confirmed in prospective randomized studies.


Mucoadhesive vaginal tablets as veterinary delivery system for the controlled release of an antimicrobial drug, acriflavine.
The aim of the study was the development of mucoadhesive vaginal tablets designed for the local controlled release of acriflavine, an antimicrobial drug used as a model. The tablets were prepared using drug-loaded chitosan microspheres and additional excipients (methylcellulose, sodium alginate, sodium carboxymethylcellulose, or Carbopol 974). The microspheres were prepared by a spray-drying method, using the drug to polymer weight ratios 1:1 and 1:2 and were characterized in terms of morphology, encapsulation efficiency, and in vitro release behavior, as MIC (Minimum Inhibitory Concentration), MBC (Minimum Bacterial Concentration), and killing time (KT). The tablets were prepared by direct compression, characterized by in vitro drug release and in vitro mucoadhesive tests. The microparticles have sizes of 4 to 12 microm; the mean encapsulation yields are about 90%. Acriflavine, encapsulated into the polymer, maintains its antibacterial activity; killing time of the encapsulated drug is similar to that of the free drug. In vitro release profiles of tablets show differences depending on the excipient used. In particular Carbopol 974, which is highly cross-linked, is able to determine a drug-controlled release from the matrix tablets for more than 8 hours. The in vitro adhesion tests, carried out on the same formulation, show a good adhesive behavior. The formulation containing microspheres with drug to polymer weight ratios of 1:1 and Carbopol 974 is characterized by the best release behavior and shows good mucoadhesive properties. These preliminary data indicate that this formulation can be proposed as a mucoadhesive vaginal delivery system for the controlled release of acriflavine.


Observational stepped-wedge analysis of a community health worker-led intervention for diabetes and hypertension in rural Mexico.
There is emerging interest and data supporting the effectiveness of community health workers (CHWs) in non-communicable diseases (NCDs) in low/middle-income countries (LMICs). This study aimed to determine whether a CHW-led intervention targeting diabetes and hypertension could improve markers of clinical disease control in rural Mexico. A prospective observational stepped-wedge study was conducted across seven communities in rural Chiapas, Mexico from March 2014 to April 2018. 149 adults with hypertension and/or diabetes. This study was conducted in the context of the programmatic roll-out of an accompaniment-based CHW-led intervention designed to complement comprehensive primary care for adults with diabetes and/or hypertension. Implementation occurred sequentially at 3-month intervals with point-of-care data collected at baseline and every 3 months thereafter for 12 months following roll-out in all communities. Primary outcomes were glycated haemoglobin (HbA1c) and systolic blood pressure (SBP), overall and stratified by baseline disease control. We conducted an individual-level analysis using mixed effects regression, adjusting for time, cohort and clustering at the individual and community levels. Among patients with diabetes, the CHW-led intervention was associated with a decrease in HbA1c of 0.35%; however, CIs were wide (95% CI -0.90% to 0.20%). In patients with hypertension, there was a 4.7 mm Hg decrease in SBP (95% CI -8.9 to -0.6). In diabetic patients with HbA1c ≥9%, HbA1c decreased by 0.96% (95% CI -1.69% to -0.23%), and in patients with uncontrolled hypertension, SBP decreased by 10.2 mm Hg (95% CI -17.7 to -2.8). We found that a CHW-led intervention resulted in clinically meaningful improvement in disease markers for patients with diabetes and hypertension, most apparent among patients with hypertension and patients with uncontrolled disease at baseline. These findings suggest that CHWs can play a valuable role in supporting NCD management in LMICs. NCT02549495.


Association between extreme autistic traits and intellectual disability: insights from a general population twin study.
Autism is associated with intellectual disability. The strength and origin of this association is unclear. To investigate the association between extreme autistic traits and intellectual disability in children from a community-based sample and to examine whether the association can be explained by genetic factors. Children scoring in the extreme 5% on measures of autistic traits, IQ and academic achievement were selected from 7965 7/8-year-old and 3687 9-year-old twin pairs. Phenotypic associations between extreme autistic traits and intellectual disability were compared with associations among the full-range scores. Genetic correlations were estimated using bivariate DeFries-Fulker extremes analyses. Extreme autistic traits were modestly related to intellectual disability; this association was driven by communication problems characteristic of autism. Although this association was largely explained by genetic factors, the genetic correlation between autistic traits and intellectual disability was only modest. Extreme autistic traits are substantially genetically independent of intellectual disability.


Comparison of Bisulfite Pyrosequencing and Methylation-Specific qPCR for Methylation Assessment.
Different methodological approaches are available to assess DNA methylation biomarkers. In this study, we evaluated two sodium bisulfite conversion-dependent methods, namely pyrosequencing and methylation-specific qPCR (MS-qPCR), with the aim of measuring the closeness of agreement of methylation values between these two methods and its effect when setting a cut-off. Methylation of tumor suppressor gene p16/INK4A was evaluated in 80 lung cancer patients from which cytological lymph node samples were obtained. Cluster analyses were used to establish methylated and unmethylated groups for each method. Agreement and concordance between pyrosequencing and MS-qPCR was evaluated with Pearson's correlation, Bland-Altman, Cohen's kappa index and ROC curve analyses. Based on these analyses, cut-offs were derived for MS-qPCR. An acceptable correlation (Pearson's R2 = 0.738) was found between pyrosequencing (PYRmean) and MS-qPCR (NMP; normalized methylation percentage), providing similar clinical results when categorizing data as binary using cluster analysis. Compared to pyrosequencing, MS-qPCR tended to underestimate methylation for values between 0 and 15%, while for methylation >30% overestimation was observed. The estimated cut-off for MS-qPCR data based on cluster analysis, kappa-index agreement and ROC curve analysis were much lower than that derived from pyrosequencing. In conclusion, our results indicate that independently of the approach used for estimating the cut-off, the methylation percentage obtained through MS-qPCR is lower than that calculated for pyrosequencing. These differences in data and therefore in the cut-off should be examined when using methylation biomarkers in the clinical practice.


[Three-dimensional-segmentation of the spine with specially adapted tools].
Segmented 3-D data of the spine form the basis for various modern clinical applications. Among these, multisegmental image fusion, image registration and finite element modeling for biomechanical analysis are promising innovative tools capable of facilitating treatment decisions and optimization of individual therapy in the future. However, the complex anatomy of the spine and the often extensive degenerative deformation presenting in clinical practice, generally limit the application of fully automated segmentation. A newly developed software system is presented that meets the complex requirements for image segmentation of the spine through the use of specially adapted interactive tools that take account of its axial skeletal structure. Furthermore, a standardized protocol is introduced that combines the newly developed interactive tools (rotation transformation, warped dissection plane) and standard segmentation tools to permit rapid and accurate segmentation. To date, the software environment presented herein has been applied with success to the segmentation of cervical, thoracic and lumbar spine.


Transcranial Doppler Systolic Flow Index and ICP-Derived Cerebrovascular Reactivity Indices in Traumatic Brain Injury.
The purpose of our study was to explore relationships between transcranial Doppler (TCD) indices of cerebrovascular reactivity and those derived from intracranial pressure (ICP). Goals included: A) confirming previously described co-variance patterns of TCD/ICP indices, and B) describing thresholds for systolic flow index (Sx; correlation between systolic flow velocity [FVs] and cerebral perfusion pressure [CPP]) associated with outcome. In a retrospective cohort of traumatic brain injury (TBI) patients: with TCD and ICP monitoring, we calculated various continuous indices of cerebrovascular reactivity: A) ICP (pressure reactivity index [PRx]: correlation between ICP and mean arterial pressure [MAP]; PAx: correlation between pulse amplitude of ICP [AMP] and MAP; RAC: correlation between AMP and CPP) and B) TCD (mean flow index [Mx]: correlation between mean flow velocity [FVm] and CPP; Mx_a: correlation between FVm and MAP; Sx: correlation between FVs and CPP; Sx_a: correlation between FVs and MAP; Dx: correlation between diastolic flow velocity [FVd] and CPP; Dx_a: correlation between FVd and MAP). We assessed the relationships via various statistical techniques, including: principal component analysis, agglomerative hierarchal clustering, and k-means cluster analysis (KMCA). We performed sequential χ2 testing to define thresholds associated with outcome for Sx/Sx_a. Outcome was assessed at 6 months via dichotomized Glasgow Outcome Score (GOS): A) Favorable (GOS 4 or 5) versus Unfavorable (GOS 3 or less), B) Alive versus Dead. We analyzed 410 recordings in 347 patients. All analyses confirmed our previously described co-variance of Sx/Sx_a with ICP-derived indices. Sx displayed thresholds of -0.15 for unfavorable outcome (p < 0.0001) and -0.20 for mortality (p < 0.0001). Sx_a displayed thresholds of +0.05 (p = 0.019) and -0.10 (p = 0.0001) for alive/dead and favorable/unfavorable outcomes. TCD systolic indices are most closely associated with ICP indices. Sx and Sx_a likely provide better approximation of ICP indices, compared with Mx/Mx_a/Dx/Dx_a. Sx provides superior outcome prediction, versus Mx, with defined thresholds.


Gel-forming antagonist provides a lasting effect on CGRP-induced vasodilation.
Migraine affects ∼15% of the adult population, and the standard treatment includes the use of triptans, ergotamines, and analgesics. Recently, CGRP and its receptor, the CLR/RAMP1 receptor complex, have been targeted for migraine treatment due to their critical roles in mediating migraine headaches. The effort has led to the approval of several anti-CGRP antibodies for chronic migraine treatment. However, many patients still suffer continuous struggles with migraine, perhaps due to the limited ability of anti-CGRP therapeutics to fully reduce CGRP levels or reach target cells. An alternative anti-CGRP strategy may help address the medical need of patients who do not respond to existing therapeutics. By serendipity, we have recently found that several chimeric adrenomedullin/adrenomedullin 2 peptides are potent CLR/RAMP receptor antagonists and self-assemble to form liquid gels. Among these analogs, the ADE651 analog, which potently inhibits CLR/RAMP1 receptor signaling, forms gels at a 6-20% level. Screening of ADE651 variants indicated that residues at the junctional region of this chimeric peptide are important for gaining the gel-forming capability. Gel-formation significantly slowed the passage of ADE651 molecules through Centricon filters. Consistently, subcutaneous injection of ADE651 gel in rats led to the sustained presence of ADE651 in circulation for >1 week. In addition, analysis of vascular blood flow in rat hindlimbs showed ADE651 significantly reduces CGRP-induced vasodilation. Because gel-forming antagonists could have direct and sustained access to target cells, ADE651 and related antagonists for CLR/RAMP receptors may represent promising candidates for targeting CGRP- and/or adrenomedullin-mediated headaches in migraine patients.


Screening for renal cell carcinoma using ultrasonography: a feasibility study.
To assess the practicability and efficacy of systematic screening for renal cell carcinoma (RCC) by ultrasonography (US), as more small RCCs are being detected incidentally by US. A 2-year screening programme for RCC was established for the general population (aged >or= 40 years) in two German cities, Mainz and Wuppertal. In cooperation with different health insurers, the organisers recruited general practitioners, internists and urologists in private practice who were experienced in and equipped to conduct renal US. The screening was offered in the form of cost-free renal US in the first year and a re-examination in the second. For any equivocal or positive renal mass, a reference ultrasonogram was provided by the urology departments at the two university hospitals. In all, 9959 volunteers participated in the screening programme (49% men, 51% women, mean age 61 years, range 40-94) in the first year. Of these participants, 79% returned for re-examination in the second year. Thirteen (0.1%) subjects were found to have a renal mass, of which nine were RCC. The sensitivity of the programme was 82% (at the 1-year follow-up), and the predictive value 2% for equivocal findings on initial examination and 50% for positive findings. The incidence of other abnormal findings was 12%. The screening programme was well accepted by physicians in private practice and by the eligible population. The method was effective, especially if equivocal findings were re-assessed by reference US before using further imaging studies, e.g. computed tomography or magnetic resonance imaging.


Physical and functional follow-up of tuberculosis patients in initial intensive phase of treatment in Cameroon using the 6-min walk test.
This study aimed to evaluate functional capacities of Cameroonian tuberculosis (TB) patients in initial intensive phase of treatment using the 6-min walk test (6MWT) and to compare them to an age-matched healthy group. Twenty-eight TB patients newly diagnosed and 19 healthy age-matched peoples participated in the study. Performance parameters were determined using the 6MWT. Anthropometric and cardiorespiratory parameters were measured at baseline and after 6MWT. Two months later, TB patients were submitted to the same evaluation. We found significant differences in anthropometric parameters between the two groups. The baseline cardiorespiratory parameters and performance characteristics of TB patients were lower than control group (571.7±121.0 m vs 841.6±53.0 m, P<0.0001 for 6-min walk distance (6MWD) and 18.1±2.8 mL/kg/min vs 24.3±1.2 mL/kg/min, P<0.001 for mean VO2 peak (peak oxygen consumption). Two months after, significant improvements were noted in anthropometric, cardiorespiratory and performance parameters except for bone mass and FEV1/FEV6 (forced expiratory volumes in 1 second/6 seconds) ratio. Significant correlations were found between the 2-min walked distance (P<0.0001, r=0.95), 4-min walked distance (P<0.0001, r=0.97) and 6MWD. In conclusion, TB patients have impaired physical functional capacity but they improved after 2 months of treatment. 6MWT can be a useful tool in the assessment of physical parameters and cardiorespiratory functional capacity rehabilitation of TB patients during the treatment.


Monocyte-conditioned medium, interleukin-1, and tumor necrosis factor stimulate the acute phase response in human hepatoma cells in vitro.
Human hepatoma cells mimic the acute phase response after treatment with monocyte-conditioned medium. Levels of secreted fibrinogen, alpha-1 acid glycoprotein, C-reactive protein, haptoglobin, and the third component of complement were elevated compared with control levels after 48 h of incubation with conditioned supernatant medium from an enriched fraction of normal peripheral monocytes. Albumin levels declined and alpha-1 antitrypsin remained unchanged. Levels of specific mRNA were measured by hybridization to slot blots and Northern blots and changed in correspondence with protein alterations. Interleukin-1 and tumor necrosis factor stimulated the third component of complement, but did not elevate any other member of the acute phase group and were therefore only partially active in this system. The identification of an in vitro model of the human acute phase response will permit analysis of the molecular basis for coordinate regulation of this group of facultative genes.


[Treatment of bipolar II disorder with lamotrigine].
This study analyzes the effectiveness and safety of lamotrigine in the treatment of bipolar II disorder. Patients and methods. Seventeen patients with DSM-IV bipolar II disorder with a history of poor response to lithium or other mood-stabilizers gave their consent to be treated with lamotrigine. Th ey we re followed-up for 6 months and assessed with the Young Mania Scale (YMRS), Hamilton Depression Rating Scale (HDRS-17) and the modified version of the Global Clinic Impresion Scale for Bipolar Disorder ( CG I-BP-M). Twelve patients completed the study. Three patients dropped out due to side effects (two because of mild rash, which vanished after treatment was discontinued and one because of vomiting) and two due to lack of efficacy. The mean dose of lamotrigine for patients completing the study was 202.1 64.4 mg/day. There was a significant improvement in HDRS-17 scores (p= 0.004) and the depressive (p=0.002) and overall (p= 0.002) subscales of the CGI-BP-M. This study confirms previous findings concerning the antidepressant profile of lamotrigine and its potential effectiveness in bipolar II disorder.


Genetic variation of apolipoproteins, diet and other environmental interactions; an updated review.
This paper summarizes the recent findings from studies investigating the potential environmental modulation of the genetic variation of apolipoprotein genes on metabolic traits. We reviewed nutrigenetic studies evaluating variations on apolipoproteins-related genes and its associated response to nutrients (mostly dietary fatty acids) or any other dietary or environmental component. Most revised research studied single nucleotide polymorphism (SNP) and specific nutrients through small intervention studies, and only few interactions have been replicated in large and independent populations (as in the case of -265T > C SNP in APOA2 gene). Although current knowledge shows that variations on apolipoprotein genes may contribute to the different response on metabolic traits due to dietary interventions, evidence is still scarce and results are inconsistent. Success in this area will require going beyond the limitations of current experimental designs and explore the hypotheses within large populations. Some of these limitations are being covered by the rapidly advance in high-throughput technologies and large scale-genome wide association studies.


Involvement of galanin receptors 1 and 2 in the modulation of mouse vagal afferent mechanosensitivity.
It is established that the gut peptide galanin reduces neuronal excitability via galanin receptor subtypes GALR1 and GALR3 and increases excitability via subtype GALR2. We have previously shown that galanin potently reduces mechanosensitivity in the majority of gastro-oesophageal vagal afferents, and potentiates sensitivity in a minority. These actions may have implications for therapeutic inhibition of gut afferent signalling. Here we investigated which galanin receptors are likely to mediate these effects. We performed quantitative RT-PCR on RNA from vagal (nodose) sensory ganglia, which indicated that all three GALR subtypes were expressed at similar levels. The responses of mouse gastro-oesophageal vagal afferents to graded mechanical stimuli were investigated before and during application of galanin receptor ligands to their peripheral endings. Two types of vagal afferents were tested: tension receptors, which respond to circumferential tension, and mucosal receptors which respond only to mucosal stroking. Galanin induced potent inhibition of mechanosensitivity in both types of afferents. This effect was totally lost in mice with targeted deletion of Galr1. The GALR1/2 agonist AR-M961 caused inhibition of mechanosensitivity in Galr1+/+ mice, but this was reversed to potentiation in Galr1-/- mice, indicating a minor role for GALR2 in potentiation of vagal afferents. We observed no functional evidence of GALR3 involvement, despite its expression in nodose ganglia. The current study highlights the complex actions of galanin at different receptor subtypes exhibiting parallels with the function of galanin in other systems.


Toll-Like Receptor-4 Is Involved in Mediating Intestinal and Extra-Intestinal Inflammation in Campylobacter coli-Infected Secondary Abiotic IL-10-/- Mice.
Human Campylobacter infections are emerging worldwide and constitute significant health burdens. We recently showed that the immunopathological sequelae in Campylobacter jejuni-infected mice were due to Toll-like receptor (TLR)-4 dependent immune responses induced by bacterial lipooligosaccharide (LOS). Information regarding the molecular mechanisms underlying Campylobacter coli-host interactions are scarce, however. Therefore, we analyzed C. coli-induced campylobacteriosis in secondary abiotic IL-10-/- mice with and without TLR4. Mice were infected perorally with a human C. coli isolate or with a murine commensal Escherichia coli as apathogenic, non-invasive control. Independent from TLR4, C. coli and E. coli stably colonized the gastrointestinal tract, but only C. coli induced clinical signs of campylobacteriosis. TLR4-/- IL-10-/- mice, however, displayed less frequently fecal blood and less distinct histopathological and apoptotic sequelae in the colon versus IL-10-/- counterparts on day 28 following C. coli infection. Furthermore, C. coli-induced colonic immune cell responses were less pronounced in TLR4-/- IL-10-/- as compared to IL-10-/- mice and accompanied by lower pro-inflammatory mediator concentrations in the intestines and the liver of the former versus the latter. In conclusion, our study provides evidence that TLR4 is involved in mediating C. coli-LOS-induced immune responses in intestinal and extra-intestinal compartments during murine campylobacteriosis.


Spatial Heterogeneity of Carbon Emissions and Its Influencing Factors in China: Evidence from 286 Prefecture-Level Cities.
In the face of the severe challenge of global warming, promoting low-carbon emission reductions is an important measure to cope with global climate change and achieve a green cycle of sustainable development. The purpose of this study was to reveal the spatial heterogeneity of carbon emissions and the influencing factors in 286 prefecture-level-and-above cities in China, and to provide an empirical basis for the formulation of low-carbon emission reduction policies in China. This study used a combination of comparative analysis, regional difference analysis, correlation analysis, principal component analysis, and stepwise regression analysis to analyze the spatial differences in carbon emissions and their influencing factors in 286 prefecture-level-and-above cities in China, and draws the following main conclusions: (1) From 2005 to 2015, regional differences in six sectors, including household carbon emissions, widened in the 286 prefecture-level-and-above cities in China, while regional differences in 14 sectors, including rural household carbon emissions, narrowed. (2) There were significant intra-group differences in urban household carbon emissions, and the contributions to intra-group differences in carbon emissions differed across the six sectors in the northeast, east, central, and west regions. (3) Although the total and average carbon emissions of each sector increased from 2005 to 2015, China's carbon emission intensity was decreasing, and carbon productivity is increasing. (4) Carbon emissions per capita (CCE) were positively correlated with GRP per capita, industrial SO2 emissions per capita, and the proportion of employees in the secondary sector, and negatively correlated with population density and the proportion of employees in the tertiary sector. (5) Resident savings and consumption factors, pollution emission factors, and economic structure factors had a facilitating effect on CCE, while population density factors and economic growth factors have a weakening effect on CCE.


Was fine-needle vasography an obsolete diagnostic method to evaluate ejaculatory duct obstruction? Report of 37 cases.
Based on comparative analyses of the precision as well as reliability of the diagnostic results on fine-needle vasography (FNV) and transrectal ultrasonography (TRUS) in the diagnosis of patients who were suspected of having ejaculatory duct obstruction (EDO), this paper aims to demonstrate whether or not FNV techniques still constitute the backbone of diagnostic imaging used in obstructive azoospermia of EDO. From July 2005 to December 2008, opening fine-needle punctuation and vasography were performed under local anesthesia in 37 infertile male patients in our center, all of whom were suspected of having bilateral EDO. The diagnostic criteria of these infertile males included characteristic changes of TRUS and/or characteristic changes of semen analysis. Comparative analyses were made of the diagnostic results of the two methods. In the 37 male patients, 19 (51.35%) had been confirmed with pathognomonic findings of both semen analyses and TRUS on complete EDO. Of the others, 18 patients (48.65%) testified with only pathognomonic findings of TRUS but not the typical characteristics on semen analyses. When compared with diagnostic results via FNV however, there were only 5 patients (13.51%) who could be confirmed as having bilateral EDO, 16/37 showed obstruction of the epididymis and proximal vas deferens, 7/37 showed bilateral vasal multiple obstruction, 2 showed unilateral EDO and multiple obstruction of the contralateral vas deferens, and the other 6 patients showed unilateral vasal multiple obstruction and obstruction on the contralateral epididymis and proximal vas deferens. Free flow of the contrast medium could be defined into the bladder by vasography in 23 patients. Of the 23 patients, 12 were suspected of having delayed evacuation based on more than 50% contrast medium remaining inside their seminal vesicles after exhaustion of urine. Our analyses suggest that despite its advantages of being non-invasive, the diagnostic effect of TRUS is limited by both accuracy and reliability. In contrast, although an invasive radiographic imaging method, FNV has been proven as being informative when providing preoperative details about obstruction and other symptoms. After 3 years of research we came to the conclusion that opening fine-needle punctuation and vasography have not become outdated, at least recently, and will remain a necessary and effective method to identify diseases and to provide a strictly defined morphology of the seminal vesicle and ductal system for more comprehensive diagnosis of obstructive azoospermia of EDO.


Analysis of histology and long noncoding RNAs involved in the rabbit hair follicle density using RNA sequencing.
Hair follicle density influences wool fibre production, which is one of the most important traits of the Wan Strain Angora rabbit. However, molecular mechanisms regulating hair follicle density have remained elusive. In this study, hair follicle density at different body sites of Wan Strain Angora rabbits with high and low wool production (HWP and LWP) was investigated by histological analysis. Haematoxylin-eosin staining showed a higher hair follicle density in the skin of the HWP rabbits. The long noncoding RNA (lncRNA) profile was investigated by RNA sequencing, and 50 and 38 differentially expressed (DE) lncRNAs and genes, respectively, were screened between the HWP and LWP groups. A gene ontology analysis revealed that phospholipid, lipid metabolic, apoptotic, lipid biosynthetic, and lipid and fatty acid transport processes were significantly enriched. Potential functional lncRNAs that regulate lipid metabolism, amino acid synthesis, as well as the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and hedgehog signalling pathways, were identified. Consequently, five lncRNAs (LNC_002171, LNC_000797, LNC_005567, LNC_013595, and LNC_020367) were considered to be potential regulators of hair follicle density and development. Three DE lncRNAs and genes were validated by quantitative real-time polymerase chain reaction (q-PCR). LncRNA profiles provide information on lncRNA expression to improve the understanding of molecular mechanisms involved in the regulation of hair follicle density.


Differential activation of the clustered homeobox genes CNOT2 and CNOT1 during notogenesis in the chick.
CNOT2, a newly identified homeobox gene, is physically linked to the CNOT1 gene in the chicken genome. The two chicken genes represent two different subgroups of the Not gene family, the first including CNOT1 and the Xenopus genes XNot1 and XNot2, and the second CNOT2 and the zebrafish floating head gene. The overall expression pattern of CNOT2 in Hensen's node, notochord, neural plate, tailbud, and epiphysis resembled the CNOT1 pattern. However, several significant differences occurred: CNOT2 expression was much stronger and more widespread in the pregastrulation embryo, it showed an additional, transient domain on the anterior intestinal portal, and lacked expression on the early anterior neural folds and the anterodistal limb bud. We studied CNOT expression by transplanting parts of the primitive streak into growing embryos or by explanting them into tissue culture. CNOT gene expression from young nodes was maintained in vivo, but required in vitro the addition of retinoic acid. The generation of differentiated notochord structures could only be obtained, if either older node grafts were used in vitro or young node grafts were transplanted close to the primary axis in vivo. We conclude that CNOT expression in the anterior streak is not enough for notochord differentiation, but further influences are necessary. A Not-related gene has previously been isolated from Drosophila melanogaster and its expression was detected in the posterior brain and the neuroblasts (Dessain and McGinnis, 1993. Adv. Dev. Biochem. 2, 1-55). The correspondence between Not gene-expressing cells in the nervous system of Drosophila and the early neuroectoderm in the chick and its implication for a phylogenetic relationship between neuroectoderm and the notochord is discussed.


Epilepsy surgery for children with tuberous sclerosis complex.
Tuberous sclerosis complex is associated with medically refractory seizures and developmental delay in children. These epilepsies are often resistant to antiepileptic drugs, can be quite severe, and usually have a negative impact on the child's neurologic and cognitive development. It is believed that functional outcome is improved if seizures can be controlled at an early age. The surgical treatment of intractable epilepsy in children and adults with tuberous sclerosis complex has gained significant interest in recent years. Previously published studies have shown a potential benefit from resection of single tubers, with most of the results noted in relatively older children. All of these reports support the idea that if a single primary epileptogenic tuber or region can be identified, then a surgical approach is appropriate. However, most children with tuberous sclerosis complex have multiple potentially epileptogenic tubers, rendering localization challenging, and they are therefore rejected as possible surgical candidates. We have used a novel surgical approach using invasive intracranial monitoring, which is typically multistaged and bilateral. This multistage surgical approach has been useful in identifying both primary and secondary epileptogenic zones in patients with tuberous sclerosis complex with multiple tubers. Multiple or bilateral seizure foci are not necessarily a contraindication to surgery in selected patients. Long-term follow-up will determine whether this approach has durable effects. We await better methods for identifying the epileptogenic zone, both noninvasive and invasive.


Additive impacts of deoxygenation and acidification threaten marine biota.
Deoxygenation in coastal and open-ocean ecosystems rarely exists in isolation but occurs concomitantly with acidification. Here, we first combine meta-data of experimental assessments from across the globe to investigate the potential interactive impacts of deoxygenation and acidification on a broad range of marine taxa. We then characterize the differing degrees of deoxygenation and acidification tested in our dataset using a ratio between the partial pressure of oxygen and carbon dioxide (pO2 /pCO2 ) to assess how biological processes change under an extensive, yet diverse range of pO2 and pCO2 conditions. The dataset comprised 375 experimental comparisons and revealed predominantly additive but variable effects (91.7%, additive; 6.0%, synergistic; and 2.3%, antagonistic) of the dual stressors, yielding negative impacts across almost all responses examined. Our data indicate that the pO2 /pCO2 -ratio offers a simplified metric to characterize the extremity of the concurrent stressors and shows that more severe impacts occurred when ratios represented more extreme deoxygenation and acidification conditions. Importantly, our analysis highlights the need to assess the concurrent impacts of deoxygenation and acidification on marine taxa and that assessments considering the impact of O2 depletion alone will likely underestimate the impacts of deoxygenation events and their ecosystem-wide consequences.


Smoking Behavior in Low- and High-Income Adults Immediately Following California Proposition 56 Tobacco Tax Increase.
Objectives. To compare the association of California Proposition 56 (Prop 56), which increased the cigarette tax by $2 per pack beginning on April 1, 2017, with smoking behavior among low- and high-income adults.Methods. Drawing on a sample of 17 206 low-income and 21 324 high-income adults aged 21 years or older from the 2012 to 2018 California Behavioral Risk Factor Surveillance System data, we explored 2 outcomes: current smoking prevalence and smoking intensity (average number of cigarettes per day among current smokers). For each income group, we estimated a multivariable logistic regression to analyze the association of Prop 56 with smoking prevalence and a multivariable linear regression to analyze the association of Prop 56 with smoking intensity.Results. Although we observed no association between smoking intensity and Prop 56, we found a statistically significant decline in smoking prevalence among low-income adults following Prop 56. No such association was found among the high-income group.Conclusions. Given that low-income Californians smoke cigarettes at greater rates than those with higher incomes, our results provide evidence that Prop 56 is likely to reduce income disparities in cigarette smoking in California.


Interaction between ellagic acid and calf thymus DNA studied with flow linear dichroism UV-VIS spectroscopy.
The interaction between ellagic acid and DNA has been characterized with respect to the geometry of the ellagic acid-DNA complex, and the active form of ellagic acid has been identified. Optical spectroscopic methods have been employed to examine the interaction between double-stranded calf thymus DNA and ellagic acid in low-ionic-strength aqueous solutions at pH values of 5.5, 7.0, and 8. 8. Based on normal absorption titration and flow linear dichroism experiments, it is confirmed that the neutral form of ellagic acid present at pH 5.5 binds to double-stranded DNA. It is found that the plane of the ellagic acid chromophore is positioned at an angle relative to the DNA helix axis, which is in accordance with intercalation of ellagic acid in DNA. It is concluded that at higher values of pH no or a very limited amount of ellagic acid binds to DNA. These results prove that the direct interaction between ellagic acid and DNA must be taken into account when evaluating the mechanism underlying the observed biological effects of this plant phenol.


Roles of p97-associated deubiquitinases in protein quality control at the endoplasmic reticulum.
To maintain protein homeostasis in the ER, an ER protein quality control system retains unfolded polypeptides and misassembled membrane proteins, allowing only properly folded proteins to exit the ER. Misfolded proteins held in the ER are retrotranslocated into the cytosol, ubiquitinated, and degraded by the proteasome through the ER-associated degradation pathway (ERAD). By timely eliminating misfolded proteins, the ERAD system alleviates cytotoxic stress imposed by protein misfolding. It is well established that ER-associated ubiquitin ligases play pivotal roles in ERAD by assembling ubiquitin conjugates on retrotranslocation substrates, which serve as degradation signals for the proteasome. Surprisingly, recent studies have revealed an equally important function for deubiquitinases (DUBs), enzymes that disassemble ubiquitin chains, in ERAD. Intriguingly, many ERAD specific DUBs are physically associated with the retrotranslocation- driving ATPase p97. Here we discuss the potential functions of p97-associated DUBs including ataxin-3 and YOD1. Our goal is to integrate the emerging evidence into models that may explain how protein quality control could benefit from deubiquitination, a process previously deemed destructive for proteasomal degradation.


A high plasma concentration of TNF-alpha is associated with dementia in centenarians.
Inflammatory mechanisms and immune activation have been hypothesized to play a role in the pathogenesis of age-associated diseases such as dementia and atherosclerosis. The purpose of this study was to evaluate the plasma concentration of tumor necrosis factor (TNF)-alpha in a large cohort of centenarians and to look for its possible associations with cognitive function, atherosclerosis, and general health status. Furthermore, we investigated whether the concentration of TNF-alpha was correlated with the blood concentration of leucocyte subsets or the plasma concentrations of interleukin (IL)-6, soluble TNF receptor 11 (sTNFR-H) (75 kDa) and C-reactive protein (CRP). Plasma TNF-alpha was measured by ELISA in 126 centenarians, 45 subjects aged 81 years, 23 subjects aged 55-65 years, and 38 subjects aged 18-30 years. Atherosclerosis was evaluated by the ankle-brachial blood pressure index, and general health status was evaluated by the body mass index and the number of diagnoses present. The concentration of TNF-alpha was significantly increased in 126 centenarians compared to younger control groups, and a high concentration of TNF-alpha was associated with both Alzheimer's disease and generalized atherosclerosis in the centenarians. The concentration of TNF-alpha was positively correlated with the concentrations of plasma IL-6, sTNFR-II, and CRP. No associations were found with increased leucocyte subsets or the body mass index. This study demonstrates that, even in apparently healthy subjects, age-associated immune activation indicated by raised levels of pro-inflammatory cytokines may reflect age-associated pathological processes that develop over decades.


The prophylactic effect of date palm (Phoenix dactylifera L.) fruit extract on testicular toxicity induced by formaldehyde: An experimental study.
Formaldehyde (FA) is one of the most widely used materials in industries and in sciences. Prolonged contact with FA might have harmful effects on fertility due to the increase in the reactive oxygen species level. On the other hand, date palm (Phoenix Dactilifera L.) fruit extract (DPFE) contains a high concentration of natural antioxidants that could scavenge free radicals. Objective: The aim was to investigate the prophylactic effects of DPFE, with strong antioxidant properties, on FA-induced testicular toxicity in male mice. Thirty-two adult NMRI male mice with a weight range of 25-35 gr (9-10 wk old) were randomly divided into four groups: control group (distilled water, orally for 35 days), FA group (FA; 0.25 mg/kg intraperitoneally (i.p.) for 20 days), treatment group (Date (DT) + FA; DPFE, 4 mg/kg for 35 days followed by FA administration, 0.25 mg/kg, i.p., for 20 days), date fruit extract group (DT; DPFE, 4 mg/kg, orally for 35 days). After this, blood was collected and left epididymis and testis tissues were isolated to evaluate the sperm parameters and histological examination, respectively. The FA administration increased the sperm morphological anomalies and reduced the sperm count, viability and motility, and also testosterone compared to the control group (p ≤ 0.001). In addition, histological studies of the testes showed that FA causes changes in the testis seminiferous tubules such as destruction of germinal epithelium and vacuolization of the tubules. The DPFE consumption before FA administration could partially ameliorate the reduced testosterone, sperm, and testicular parameters due to FA. The DPFE use might have discount effects on FA-induced testicular toxicity.


Triploidy in human cell line.
Cytogenetic studies of a human amnion cell line (strain RA) indicate that the major stem cell was triploid. Consistently present in the triploid cells were two marker chromosomes, a small centric fragment, and an apparently telocentric D. At various times triploid cells constituted 40 to 80 percent of the cell population. The possible origin of the triplaid cell is a diploid/ triploid mosaic amnion.


Another critical region for deletion of 22q11: a study of 100 patients.
Deletions at 22q11.1-q11.2 present with variable manifestations usually referred to as DiGeorge or velo-cardio-facial syndrome. We previously reported that deletions observed in patients with the syndrome can be subgrouped into three types (common large deletion, proximal deletion, and distal deletion) and demonstrated the presence of a second critical region for the syndrome. In order to characterize further the second critical region, a 22q11 deletion map was constructed from the data of 100 patients, using 12 DNA markers scattered in the common large deletion, and then a phenotype-genotype correlation was analyzed. The second critical region was found to correspond to the distal deletion encompassing the HCF2, cHKAD26, and D22S935 loci, and the proximal and distal deletions do not overlap each other. Although it seems that this condition is a contiguous gene syndrome, the phenotype of patients with these two types of deletion was indistinguishable from that of patients with the common large deletion. Thus, it is plausible that several genes located in the two segments corresponding to the two deleted regions are involved in the same developmental pathway or in an extremely long-range position effect.


Preparation, characterization, and theoretical analysis of group 14 element(I) dimers: a case study of magnesium(I) compounds as reducing agents in inorganic synthesis.
A synthetic route to the new amidine (DipNH)(DipN)C(C(6)H(4)Bu(t)-4) (ButisoH; Dip = C(6)H(3)Pr(i)(2)-2,6) has been developed. Its deprotonation with either LiBu(n) or KN(SiMe(3))(2) yields the amidinate complexes [M(Butiso)] (M = Li or K). Their reactions with group 14 element halides/pseudohalides afford the heteroleptic group 14 complexes [(Butiso)SiCl(3)], [(Butiso)ECl] (E = Ge or Sn), and [{(Butiso)Pb(μ-O(3)SCF(3))(THF)}(∞)], all of which have been crystallographically characterized. In addition, the synthesis and spectroscopic characterization of the homoleptic complex [Pb(Butiso)(2)] is reported. Reductions of the heteroleptic complexes with a soluble magnesium(I) dimer, [{((Mes)Nacnac)Mg}(2)] ((Mes)Nacnac = [(MesNCMe)(2)CH](-); Mes = mesityl), have given moderate-to-high yields of the group 14 element(I) dimers [{(Butiso)E}(2)] (E = Si, Ge, or Sn), the X-ray crystallographic studies of which reveal trans-bent structures. The corresponding lead(I) complex could not be prepared. Comprehensive spectroscopic and theoretical analyses of [{(Butiso)E}(2)] have allowed their properties to be compared. All complexes possess E-E single bonds and can be considered as intramolecularly base-stabilized examples of ditetrelynes, REER. Taken as a whole, this study highlights the synthetic utility of soluble and easy to prepare magnesium(I) dimers as valuable alternatives to the harsh, and often insoluble, alkali-metal reducing agents that are currently widely employed in the synthesis of low-oxidation-state organometallic/inorganic complexes.


Time-dependent association between STOPP and START criteria and gastrointestinal bleeding in older patients using routinely collected primary care data.
Only few studies have assessed the preventive effect of the STOPP/START criteria on adverse events. We aim to quantify 1) the association between nonadherence to STOPP/START criteria and gastrointestinal bleedings, and 2) the association between exposure to the potentially harmful START-medications and gastrointestinal bleedings. A retrospective cohort study using routinely collected data of patients aged ≥ 65 years from the electronic health records (EHR) of 49 general practitioners (GPs) in 6 GP practices, from 2007 to 2014. The database is maintained in the academic research network database (AHA) of Amsterdam UMC, the Netherlands. Gastrointestinal bleedings were identified using ICPC codes and free text inspections. Three STOPP and six START criteria pertaining to gastrointestinal bleedings were selected. Cox proportional hazards regression with time-dependent covariate analysis was performed to assess the independent association between nonadherence to the STOPP/START criteria and gastrointestinal bleedings. The analysis was performed with all criteria as a composite outcome, as well as separately for the individual criteria. Out of 26,576 participants, we identified 19,070 Potential Inappropriate Medications (PIM)/Potential Prescribing Omission (PPO) instances for 3,193 participants and 146 gastrointestinal bleedings in 143 participants. The hazard ratio for gastrointestinal bleedings of STOPP/STARTs, taken as composite outcome, was 5.45 (95% CI 3.62-8.21). When analysed separately, two out of nine STOPP/STARTs showed significant associations. This study demonstrates a significant positive association between nonadherence to the STOPP/START criteria and gastrointestinal bleeding. We emphasize the importance of adherence to the relevant criteria for gastrointestinal bleeding, which may be endorsed by decision support systems.


Clearing the air: a review of the effects of particulate matter air pollution on human health.
The World Health Organization estimates that particulate matter (PM) air pollution contributes to approximately 800,000 premature deaths each year, ranking it the 13th leading cause of mortality worldwide. However, many studies show that the relationship is deeper and far more complicated than originally thought. PM is a portion of air pollution that is made up of extremely small particles and liquid droplets containing acids, organic chemicals, metals, and soil or dust particles. PM is categorized by size and continues to be the fraction of air pollution that is most reliably associated with human disease. PM is thought to contribute to cardiovascular and cerebrovascular disease by the mechanisms of systemic inflammation, direct and indirect coagulation activation, and direct translocation into systemic circulation. The data demonstrating PM's effect on the cardiovascular system are strong. Populations subjected to long-term exposure to PM have a significantly higher cardiovascular incident and mortality rate. Short-term acute exposures subtly increase the rate of cardiovascular events within days of a pollution spike. The data are not as strong for PM's effects on cerebrovascular disease, though some data and similar mechanisms suggest a lesser result with smaller amplitude. Respiratory diseases are also exacerbated by exposure to PM. PM causes respiratory morbidity and mortality by creating oxidative stress and inflammation that leads to pulmonary anatomic and physiologic remodeling. The literature shows PM causes worsening respiratory symptoms, more frequent medication use, decreased lung function, recurrent health care utilization, and increased mortality. PM exposure has been shown to have a small but significant adverse effect on cardiovascular, respiratory, and to a lesser extent, cerebrovascular disease. These consistent results are shown by multiple studies with varying populations, protocols, and regions. The data demonstrate a dose-dependent relationship between PM and human disease, and that removal from a PM-rich environment decreases the prevalence of these diseases. While further study is needed to elucidate the effects of composition, chemistry, and the PM effect on susceptible populations, the preponderance of data shows that PM exposure causes a small but significant increase in human morbidity and mortality. Most sources agree on certain "common sense" recommendations, although there are lonely limited data to support them. Indoor PM exposure can be reduced by the usage of air conditioning and particulate filters, decreasing indoor combustion for heating and cooking, and smoking cessation. Susceptible populations, such as the elderly or asthmatics, may benefit from limiting their outdoor activity during peak traffic periods or poor air quality days. These simple changes may benefit individual patients in both short-term symptomatic control and long-term cardiovascular and respiratory complications.


Prostacyclin modulates cholesteryl ester hydrolytic activity by its effect on cyclic adenosine monophosphate in rabbit aortic smooth muscle cells.
We tested the hypothesis that prostacyclin (PGI2), 6-keto-prostaglandinF1 alpha(6-keto-PGF1 alpha), and several E series prostaglandins (PG) may affect the activity of cholesteryl ester (CE) hydrolase since our previous experiments indicated that smooth muscle cells (SMC) in neointima of injured rabbit aorta (a) acquire the capacity to produce PGI2 and (b) have increased lysosomal CE hydrolytic (acid cholesteryl ester hydrolase [ACEH])activity. Using cultured SMC from rabbit thoracic aorta, we demonstrated that PGI2, 6-keto-PGF1 alpha, and 6-keto-PGE1 enhanced ACEH activity fourfold. No significant effects on ACEH activity were observed with PGE1 or PGE2. Preincubation of SMC with an inhibitor of adenylate cyclase activity (dideoxyadenosine) abolished the effect of these PG on CE hydrolytic activity. Addition of dibutyryl cAMP to these SMC significantly increased ACEH activity. Although concentrations of PGI2 used significantly increased cAMP levels, proliferation of these SMC was not observed. In related experiments, we determined if the addition of PGI2, 6-keto-PGF1 alpha, or 6-keto-PGE1 to cultured aortic SMC would enhance the egress of unesterified cholesterol and CE from these SMC. A significant loss of total cholesterol from PG-treated SMC was observed at the end of 14 d. Results suggest that increased synthesis of PGI2 by neointimal SMC in the injured aortic wall may, at least in part, explain the changes in CE catabolism and accumulation following injury. These PG may also be important in CE metabolism and accumulation in human arteries.


Human S100A3 tetramerization propagates Ca(2+)/Zn(2+) binding states.
The S100A3 homotetramer assembles upon citrullination of a specific symmetric Arg51 pair on its homodimer interface in human hair cuticular cells. Each S100A3 subunit contains two EF-hand-type Ca(2+)-binding motifs and one (Cys)3His-type Zn(2+)-binding site in the C-terminus. The C-terminal coiled domain is cross-linked to the presumed docking surface of the dimeric S100A3 via a disulfide bridge. The aim of this study was to determine the structural and functional role of the C-terminal Zn(2+)-binding domain, which is unique to S100A3, in homotetramer assembly. The binding of either Ca(2+) or Zn(2+) reduced the α-helix content of S100A3 and modulated its affinity for the other cation. The binding of a single Zn(2+) accelerated the Ca(2+)-dependent tetramerization of S100A3 while inducing an extensive unfolding of helix IV. The Ca(2+) and Zn(2+) binding affinities of S100A3 were enhanced when the other cation bound in concert with the tetramerization of S100A3. Small angle scattering analyses revealed that the overall structure of the S100A3 tetramer bound both Ca(2+) and Zn(2+) had a similar molecular shape to the Ca(2+)-bound form in solution. The binding states of the Ca(2+) or Zn(2+) to each S100A3 subunit within a homotetramer appear to be propagated by sensing the repositioning of helix III and the rearrangement of the C-terminal tail domain. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.


Radiation safety considerations for diagnostic radiology personnel.
In radiation protection, the guiding philosophy is ALARA (as low as reasonably achievable), and states have regulatory authority. Dose limits are in part based on effective dose equivalent and differences in tissue sensitivities. In diagnostic radiology, the main source of occupational dose is scattered radiation from the patient--particularly from fluoroscopically guided procedures. Personnel stand near patients for long times, and angulated geometries with C-arm equipment may result in high personnel doses from backscatter. For all procedures, judicious applications of time, distance, and shielding affect dose. Appropriate use includes collimating properly, optimizing beam-on time, minimizing distances between image intensifier and patient, ensuring sufficient distance between patient and x-ray tube, and optimizing exposure rates for image quality and dose. Although dose limits typically regulate maximum whole-body dose, protective clothing worn by fluoroscopists reduces personnel risks; weighting factors can be applied to estimate effective dose equivalent. Pregnant personnel have lower limits, which apply only with voluntary declaration of pregnancy. With appropriate precautions, fetal doses can typically remain within recommended limits without changes in occupational tasks. Radiation workers in each state must ensure that regulations are appropriate. Then, for protection of both employee and employers, the rules can and must be followed.


Ovarian Stromal Hyperplasia: A Rare Cause of Postmenopausal Hyperandrogenism.
Ovarian hyperthecosis and ovarian stromal hyperplasia (OSH) are two uncommon non-neoplastic causes of ovarian hyperandrogenism, whose etiology is still unknown. These conditions are characterized by obesity, hyperinsulinemia, acanthosis nigricans, and even virilization, mainly in postmenopausal women. Here we have reported the case of a 67-year-old patient with a diagnosis of OSH, which was resolved after bilateral laparoscopic oophorectomy. In this case report, we have discussed two different conditions posing a diagnostic challenge and requiring a high index of suspicion.


First-pass entry of nonionic contrast agent into the myocardial extravascular space. Effects on radiographic estimates of transit time and blood volume.
Almost all x-ray-based techniques intended to assess regional myocardial perfusion from myocardial concentration-time curves following the administration of soluble contrast agents assume that these agents behave as intravascular indicators and can therefore provide measurements of intravascular transit time and intramyocardial blood volume. We tested this assumption by comparing a conventional nonionic contrast agent (ioversol) to a particulate emulsion (ethiodol) that remained in the vascular space in closed-chest dogs during pharmacological vasodilation. Using fast computed tomography (CT), pairs of myocardial CT intensity-time curves were obtained following sequential bolus aortic administration of the two contrast agents. The emulsion (particle size less than 3 microns) was almost completely washed out of the myocardial region of interest within a few seconds, as would be anticipated for a vascular indicator. At the onset of recirculation, CT intensity for ethiodol fell to 5 +/- 1% (SEM) of peak values in normally perfused areas and to 10 +/- 4% of peak values in an area in which flow had been reduced by 50% by a chronically implanted coronary artery occluder (p = NS). In comparison, the diffusible nonionic contrast agent ioversol showed substantial intramyocardial retention at the onset of recirculation. At the time of recirculation, CT intensities for ioversol averaged 36 +/- 2% of peak values in normally perfused nonstenotic areas and 54 +/- 4% of peak values in stenotic areas (p less than 0.01). Using residue function analysis for a diffusible indicator, first-pass extractions of the conventional nonionic agent averaged 33 +/- 2% in normally perfused areas and 50 +/- 3% in stenotic areas (p less than 0.01). Because of the significant first-pass myocardial retention of ioversol, both mean myocardial appearance time and intramyocardial blood volume were consistently overestimated. Soluble radiographic contrast agents, like other small molecules, enter the interstitial space to a degree, which is important because it affects estimates of myocardial perfusion based on transit time and intramyocardial blood volume. Indicator dilution models intended to quantify myocardial perfusion with conventional radiographic contrast agents need to account for this extravascular exchange.


Oncogene-mediated transformation. An in vitro model for colon carcinogenesis.
Evaluation of molecular events in human colon polyps and tumors has revealed constitutive elevated expression of c-myc, activation of both ras and src proto-oncogenes, and allelic deletion events involving inactivation of putative regulatory genes, including p53. To evaluate the contribution of each of these events to colon carcinogenesis, it is desirable to establish epithelial cell lines representing different stages of neoplastic progression. Such in vitro models can be used to establish a primary role for different genes implicated in neoplastic transformation, identifying events involved in multistep carcinogenesis and delineating the factors modulating cellular transformation. We present herein a summary of such an in vitro model for colon carcinogenesis using the introduction of relevant genetic elements into normal mucosa to identify the molecular steps and accompanying cellular events underlying neoplastic progression in the colon.


Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: individual patient data meta-analysis of randomized controlled trials.
We conducted a meta-analysis of clinical trials of adults hospitalized with pneumonia outcomes research team (PORT) risk class 3-4 community-acquired pneumonia (CAP) receiving ceftaroline fosamil versus ceftriaxone. Three Phase III trials (clinicaltrials.gov registration numbers NCT00621504, NCT00509106 and NCT01371838) including 1916 hospitalized patients with CAP randomized 1:1 to empirical ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (1-2 g every 24 h) for 5-7 days were included in the meta-analysis. Primary outcome was clinical response at the test-of-cure visit (8-15 days after end of treatment) in the PORT risk class 3-4 modified ITT (MITT) and clinically evaluable (CE) populations. Data were tested for heterogeneity (χ(2) test) and, if not significant, results were pooled and OR and 95% CI constructed. A logistic regression analysis assessed factors impacting cure rate and treatment interactions. Clinical cure rates in each trial consistently favoured ceftaroline fosamil versus ceftriaxone, with no evidence of heterogeneity. In the meta-analysis, ceftaroline fosamil was superior to ceftriaxone in the MITT (OR: 1.66; 95% CI 1.34, 2.06; P < 0.001) and CE (OR: 1.65; 95% CI 1.26, 2.16; P < 0.001) populations. Results were consistent across various patient- and disease-related factors including patients' age and PORT score. Prior antimicrobial use within 96 h of starting study treatment was associated with diminished differences in cure rates between treatments. Ceftaroline fosamil was superior to ceftriaxone for empirical treatment of adults hospitalized with CAP. Receipt of prior antimicrobial therapy appeared to diminish the observed treatment effect.


Chronic neuropathic pain-like behavior and brain-borne IL-1β.
Neuropathic pain in animals results in increased IL-1β expression in the damaged nerve, the dorsal root ganglia, and the spinal cord. Here, we discuss our results showing that this cytokine is also overexpressed at supraspinal brain regions, in particular in the contralateral side of the hippocampus and prefrontal cortex and in the brainstem, in rats with neuropathic pain-like behavior. We show that neuropathic pain degree and development depend on the specific nerve injury model and rat strain studied, and that there is a correlation between hippocampal IL-1β expression and tactile sensitivity. Furthermore, the correlations between hippocampal IL-1β and IL-1ra or IL-6 observed in control animals, are disrupted in rats with increased pain sensitivity. The lateralization of increased cytokine expression indicates that this alteration may reflect nociception. The potential functional consequences of increased IL-1β expression in the brain during neuropathic pain are discussed.


Analysis of within-individual variation in extrapair paternity in blue tits (Cyanistes caeruleus) shows low repeatability and little effect of changes in neighborhood.
Many studies investigated variation in the frequency of extrapair paternity (EPP) among individuals. However, our understanding of within-individual variation in EPP remains limited. Here, we comprehensively investigate variation in EPP at the within-individual level in a population of blue tits (Cyanistes caeruleus). Our study is based on parentage data comprising >10 000 genotyped offspring across 11 breeding seasons. First, we examined the repeatability of the occurrence of EPP, the number of extrapair offspring, the number of extrapair partners, and the occurrence of paternity loss using data from males and females that bred in multiple years. Second, we tested whether within-individual changes in EPP between breeding seasons relate to between-year changes in the local social environment. Repeatabilities were generally low but significant for the occurrence and number of extrapair young in females and for whether a male sired extrapair young or not. We found no evidence that the presence of the former social partner or changes in the proportion of familiar individuals or in phenotypic traits of the neighbors influenced changes in levels of EPP in females. However, in adult males, a decrease in the average body size of male neighbors was associated with higher extrapair siring success. If confirmed, this result suggests that the competitive ability of a male relative to its neighbors influences his extrapair mating success. We suggest that alternative hypotheses, including the idea that within-individual changes in EPP are due to "chance events" rather than changes in an individual's social breeding environment, deserve more consideration.


Ly-4.2: a cell membrane alloantigen of murine B lymphocytes. II. Functional studies.
The alloantigenic specificity Ly-4.2 can be detected on a proportion of lymphocytes by the antiserum (BALB/c times SWR)F1 anti-B10.D2. In the preceding study it was shown that these lymphocytes were not thymus-derived (T) cells, as they were Thy-1 (theta)(-), and were therefore presumably B (bone marrow-derived) cells. Evidence is now presented for the reaction of the Ly-4.2 antiserum with functional B cells. Thus, the LY-4.2 and Thy-1.2 specificities were detected on antigen-binding rosette-forming cells (RFC) in mice both immune and non-immune to sheep red cells (SRC). RFC formed to endotoxin lipopolysaccharide (LPS) were also Ly-4.2(+). Memory cells to both SRC andLPS could be detected with anti-Ly-4.2 and anti-Thy-1.2 antisera, thereby indicating that both T and B cells are involved in memory to these antigens. Both direct and indirect antibody-forming cells (the PFC) could be inhibited, in vitro, by anti-Ly-4.2 antiserum, although it is likely that not all PFC are Ly-4.2(+). Neither of the specificities Ly-4.2 nor Thy-1.2 were detected on the bone marrow precursor of the splenic colony forming unit (the CFU). In an assay for B cells, the treatment of lymph node or spleen cells with anti-Ly-4.2 before transfer to irradiated recipients could inhibit the ability of these cells to make PFC to SRC, and this capacity could only be restored by bone marrow cells and not by thymus cells. These studies provide clear evidence for the presence of the Ly-4.2 specificity on antibody-forming cells and their precursor (B cells).


Array-CGH is an effective first-tier diagnostic test for EFTUD2-associated congenital mandibulofacial dysostosis with microcephaly.
Mandibulofacial dysostosis with microcephaly (MFDM) is a sporadic malformation syndrome with severe craniofacial abnormalities, microcephaly, developmental delay, and dysmorphic features. Most cases of clinically diagnosed MFDM remain genetically unexplained, and to the best of our knowledge a total of 35 patients, 31 different mutations, 4 deletions, and 6 reports have been published. Our proband was born at 36 weeks gestation with microcephaly, microcrania, cleft palate, severe retrognathia, oral and pharyngeal dysphagia, bilateral proximal radioulnar synostosis, 11 thoracic ribs, abnormal magnetic resonance imaging (MRI) findings including simplified gyral pattern and mild dilatation of the posterior bodies of the lateral ventricles secondary to thinning of the white matter, high-pitched cry due to unilateral vocal cord paralysis, and dysmorphic features. Array comparative genomic hybridization (aCGH) + single nucleotide polymorphism (SNP) analysis identified a likely de novo pathogenic deletion on chromosome 17q21.31, encompassing the EFTUD2 gene. Our case represents the fifth reported proband to have MFDM caused by small deletions involving EFTUD2. All known mutations involving EFTUD2 result in genetic haploinsufficiency, consistent with our proband's case as well. Her phenotypic features both overlap and expand on the clinical features of previously reported cases, and her genetic diagnosis also supports the use of aCGH as a first-tier testing option for this disorder.


Genotypic diversity, antimicrobial resistance and screening of Vibrio cholerae molecular virulence markers in Vibrio alginolyticus strains recovered from a Tunisian Ruditapes decussatus hatchery.
In this study, a total of 54 Vibrio alginolyticus strains were analyzed. The isolates were recovered from different compartments of the Ruditapes decussatus hatchery in the National Institute of Marine Sciences and Technologies, Monastir, Tunisia. All isolates were biochemically identified (API 20E and API ZYM strips), characterized by amplification of the Hsp-40 gene polymerase chain reaction (PCR) and analyzed by enterobacterial repetitive intergenic consensus (ERIC)-based genotyping to evaluate genetic relationship between the isolated strains. We also looked for the presence of ten V cholera virulence genes (toxRS, toxR, toxT toxS, tcpP, tcpA, ace, vpi, zot and ctxA) in the genomes of Vibrio isolates. The antibiotics susceptibility, exoenzymes production and in vitro cytotoxic activitiy against HeLa cell line were also carried out for all tested bacteria. Most of V alginolyticus isolates showed significant antimicrobial resistance rates to at least ten antibacterial agents. For most isolates, the minimum inhibitory concentration (MIC) data showed that tetracydclin and streptomycin were the most effective antibiotics. Construction of the phylogenetic dendogram showed that studied isolates were in general genetically heterogeneous; however some Vibrio strains were present in different structures of the R. decussatus hatchery. The V cholerae virulence genes investigation showed a wild distribution of toxS (49/54), toxaR (45/54) and toxT (22/54) genes among V alginolyticus strains isolated from the R. decussatus rearing system. Cytotoxic effects of several Vibrio extracellular products (28154) were also observed on HeLa cells.


Cancer genetics service provision: a comparison of seven European centres.
To conduct a survey in seven European cancer genetics centres to compare service provision, organisation and practices for familial breast and colon cancer consultations and testing. Information was obtained on aspects of services both nationally and locally. A detailed survey questionnaire was adapted collaboratively to obtain the required information. Initial survey data were collected within each centre and interim results were discussed at two European Workshops. Where differences in practice existed, details were clarified to ensure accuracy and adequacy of information. Participating centres were Haifa (Israel), Hannover (Germany), Leiden (The Netherlands), Leuven (Belgium), Manchester (UK), Marseille (France) and Milan (Italy), representing countries with populations ranging from 6.5 to 80 million. The European countries diverged in regard to the number of cancer genetics centres nationally (from 8 in Belgium to 37 in France), and the average population served by each centre (from 0.59 million in Israel to 3.32 million in Italy). All centres offered free care at the point of access, but referral to specialist care varied according to national health care provision. At a centre level, staff roles varied due to differences in training and health care provision. The annual number of counsellees seen in each participating centre ranged from 200 to over 1,700. Access to breast surveillance or bowel screening varied between countries, again reflecting differences in medical care pathways. These countries converged in regard to the wide availability of professional bodies and published guidelines promoting aspects of service provision. Similarities between centres included provision of a multidisciplinary team, with access to psychological support, albeit with varying degrees of integration. All services were dominated (70-90%) by referrals from families with an increased risk of breast cancer despite wide variation in referral patterns. Collection of pedigree data and risk assessment strategies were broadly similar, and centres used comparable genetic testing protocols. Average consultation times ranged between 45 and 90 min. All centres had access to a laboratory offering DNA testing for breast and bowel cancer-predisposing genes, although testing rates varied, reflecting the stage of service development and the type of population. Israel offered the highest number of genetic tests for breast cancer susceptibility because of the existence of specific founder mutations, in part explaining why the cancer genetics service in Haifa differed most from the other six. Despite considerable differences in service organisation, there were broad similarities in the provision of cancer genetic services in the centres surveyed.


Zrf1 is required to establish and maintain neural progenitor identity.
The molecular mechanisms underlying specification from embryonic stem cells (ESCs) and maintenance of neural progenitor cells (NPCs) are largely unknown. Recently, we reported that the Zuotin-related factor 1 (Zrf1) is necessary for chromatin displacement of the Polycomb-repressive complex 1 (PRC1). We found that Zrf1 is required for NPC specification from ESCs and that it promotes the expression of NPC markers, including the key regulator Pax6. Moreover, Zrf1 is essential to establish and maintain Wnt ligand expression levels, which are necessary for NPC self-renewal. Reactivation of proper Wnt signaling in Zrf1-depleted NPCs restores Pax6 expression and the self-renewal capacity. ESC-derived NPCs in vitro resemble most of the characteristics of the self-renewing NPCs located in the developing embryonic cortex, which are termed radial glial cells (RGCs). Depletion of Zrf1 in vivo impairs the expression of key self-renewal regulators and Wnt ligand genes in RGCs. Thus, we demonstrate that Zrf1 plays an essential role in NPC generation and maintenance.


The effect of extrinsic Wnt/β-catenin signaling in Muller glia on retinal ganglion cell neurite growth.
Muller glia are the predominant glial cell type in the retina, and they structurally and metabolically support retinal neurons. Wnt/β-catenin signaling pathways play essential roles in the central nervous system, including glial and neuronal differentiation, axonal growth, and neuronal regeneration. We previously demonstrated that Wnt signaling activation in retinal ganglion cells (RGC) induces axonal regeneration after injury. However, whether Wnt signaling within the adjacent Muller glia plays an axongenic role is not known. In this study, we characterized the effect of Wnt signaling in Muller glia on RGC neurite growth. Primary Muller glia and RGC cells were grown in transwell co-cultures and adenoviral constructs driving Wnt regulatory genes were used to activate and inhibit Wnt signaling specifically in primary Muller glia. Our results demonstrated that activation of Wnt signaling in Muller glia significantly increased RGC average neurite length and branch site number. In addition, the secretome of Muller glia after induction or inhibition of Wnt signaling was characterized using protein profiling of conditioned media by Q Exactive mass spectrometry. The Muller glia secretome after activation of Wnt signaling had distinct and more numerous proteins involved in regulation of axon extension, axon projection and cell adhesion. Furthermore, we showed highly redundant expression of Wnt signaling ligands in Muller glia and Frizzled receptors in RGCs and Muller glia. Therefore, this study provides new information about potential neurite growth promoting molecules in the Muller glia secretome, and identified Wnt-dependent target proteins that may mediate the axonal growth.


Incident diabetes following acute pancreatitis in a multicenter prospective observational cohort.
Diabetes mellitus following an episode of acute pancreatitis (AP) is an increasingly discussed complication, but there are sparse prospective data on the incidence and risk factors. We evaluated data from a prospective, multicenter observational cohort study that enrolled adults hospitalized with AP between 2017 and 2021 and followed them for one year. Ninety-eight participants who completed 12-month follow-up were included in this analysis. Diabetes status was assessed using a combination of measured glycated hemoglobin (HbA1c) at predetermined time intervals or physician diagnosis. In 68 participants without diabetes at enrollment, the cumulative incidence of new-onset diabetes was 4.4 % (n = 3) at 3 months and 10.3 % (n = 7) at 12 months. No differences were observed in demographic or pancreatitis-related characteristics between those who did versus did not develop diabetes, in part due to small sample size. In summary, new-onset diabetes was identified in approximately 10 % within one year after an episode of AP. Larger prospective studies are needed to further define the incidence, risk factors, and mechanisms of diabetes and pre-diabetes following AP. NCT03063398.


Malvidin and cyanidin derivatives from açai fruit (Euterpe oleracea Mart.) counteract UV-A-induced oxidative stress in immortalized fibroblasts.
UV-A radiations are known to induce cellular oxidative stress, leading to premature skin aging. Consumption of açai fruit (Euterpe oleracea Martius) is known to have many health benefits due to its high level of antioxidants. Herein, we analyzed the ability of phenolic compounds extracted from this fruit to attenuate UV-A-induced oxidative stress in immortalized fibroblast. A methanol/water açai extract was fractionated by HPLC and each fraction tested for anti-oxidant stress activity. Immortalized fibroblasts were pre-incubated with açai fractions and then exposed to UV-A radiations. Açai extract was found to be able to strongly protect cells from oxidative stress. In particular, reactive oxygen species (ROS) production, GSH depletion, lipid peroxidation and no increase in the phosphorylation levels of proteins involved in the oxidative stress pathway was observed in cells pre-incubated with the extract and then irradiated by UV-A. Mass spectrometry analyses of HPLC fractionated extract led us to the identification of malvidin and cyanidin derivatives as the most active molecules able to counteract the negative effects induced by UV-A irradiation. Our results indicate, for the first time, that açai fruit is a valuable natural source for malvidin and cyanidin to be used as anti-stress molecules and represent good candidates for dietary intervention in the prevention of age related skin damage.


Functional and molecular ultrasound imaging: concepts and contrast agents.
Contrast-enhanced ultrasound has shown convincing results for monitoring vessel morphology, surrogate markers of vascularization and changes in molecular marker expression in oncological and cardiovascular diseases. Ultrasound contrast agents have the ability to increase the backscattering signal intensity of an ultrasound pulse. An interesting class of ultrasound contrast agents are gas filled microbubbles, which can be synthesized by external bubble encapsulation using sugar matrices or microspheres consisting of lipids or polymers with or without surfactant and by selecting gases with low blood solubility and diffusion coefficient such as perfluorocarbons or sulphur hexafluoride. Ultrasound contrast agents can be classified according to the rigidity of their shell. Soft-shell microbubbles are coated with a thin monolayer of surfactant molecules such as palmitic acid or phospholipids and are very sensitive to pressure changes. Hard-shell microbubbles have a rigid shell made of polymers such as polycyanoacrylate, which dramatically increases their stability. Depending on the acoustic properties of the microbubbles and on the purpose of the examination either destructive or non destructive methods are preferred for their detection. Microbubbles can be detected by destructive and non-destructive methods. Both soft- and hard-shell microbubbles coated with target-specific molecules can also be used for molecular imaging. Using target-specific approaches, the expression of several angiogenic markers such as VEGFR2, alphavbeta3 Integrins, ICAM, and E-selectin has been investigated in neoplastic and vascular diseases. This article summarizes the synthesis and properties of contrast agents as well as the indications, limitations and future potential of contrast-enhanced functional and molecular ultrasound.


Cellulose thin films: degree of cellulose ordering and its influence on adhesion.
Adhesion measurements have been performed with thin cellulose films using continuum contact mechanics with application of the JKR theory. Three different cellulose surfaces were prepared, one crystalline and two surfaces with a lower degree of crystalline order. Adhesion between two cross-linked poly(dimethylsiloxane) (PDMS) caps, as well as the adhesion between PDMS and the various cellulose surfaces, was measured. The work of adhesion (from loading) was found to be similar for all three surfaces, and from contact angle measurement with methylene iodide it was concluded that dispersive interactions dominate. However, the adhesion hysteresis differed significantly, being larger for a less ordered cellulose surface and decreasing with increasing degree of crystalline order. This is suggested to be due to the surface groups' ability to orient themselves and participate in specific or nonspecific interactions, where a surface with a lower degree of crystalline order has a higher possibility for reorientation of the surface groups. The mobility of cellulose chains increases with water uptake, resulting in stronger adhesive joints. These films will hence allow for determination of the contributions of hydrogen bonding and inter-diffusion on the adhesion, determined from the unloading data, as the thermodynamic work of adhesion was found to be independent of the cellulose surface used.


Treatment of hemorrhagic gastritis by Ankaferd blood stopper versus Omeprazole: experimental randomized rat models.
Ankaferd blood stopper (ABS) is a herbal extract that enhances mucosal healing. It has therapeutic potential in the management of external hemorrhage and controlling gastrointestinal bleeding associated with various benign lesions refractory to conventional antihemorrhagic measures. The aim of this experimental study was to assess the effects of ABS on hemorrhagic lesions and compare them with omeprazole. The study was conducted on 30 rats. Rats were divided into five groups: group A (only indomethacin), group B (ABS administration 60 min before indomethacin-induced injury), group C (ABS administration 30 min after indomethacin-induced injury), group D (omeprazole administration 60 min before indomethacin-induced injury), group E (omeprazole administration 30 min after indomethacin-induced injury). Gastric mucosal lesions were produced by indomethacin in all three groups. The effect was studied morphologically 6 h after oral administration of the drug. Subsequently, affected tissue was examined histologically. Based on the number and the total size of hemorrhagic lesions, the hemorrhagic lesion scores were significantly better in Group C compared to other groups (p < 0.05). The hemorrhagic lesion score of Group B was significantly better than Group D and Group A (p < 0.05). Omeprazole groups (Group D, Group E) did not show significant improvement as indicated by macroscopic scores. There was no significant difference between the groups with respect to microscopic scores. These results indicate that ABS has a potent inhibitory action on indomethacin-induced gastric bleeding and mucosal lesions and it is useful in the treatment of acute gastric mucosal lesions.


Clinical Safety Incident Taxonomy Performance on C4.5 Decision Tree and Random Forest.
The paper applies an artificial intelligence centered method to classify 12 clinical safety incident (CSI) classes. The paper aims to establish a taxonomy that classifies the CSI reports into their correct classes automatically and with high accuracy. The study investigates feasibility of applying the C4.5 decision tree (DT) classifier and the random forest (RF) classifier for this purpose. The classifiers were trained using randomly selected 3600 CSIs from an Incident Information Management System (IIMS) used by seven hospitals. The taxonomies investigated were the Generic Reference Model (GRM) and the World Health Organization (WHO) patient safety classification. The classifiers trained 13 GRM CSI classes and 9 WHO CSI classes using a bag-of-words approach. The overall taxonomies performance on the RF classifier was better than on the DT classifier. The performance achieved by the classifier applying the WHO taxonomy was better than the GRM taxonomy. Four of the five poorly performing classes in the GRM taxonomy significantly improved their performance on changing the taxonomy. To improve the WHO taxonomy performance the improved WHO (WHO-I) taxonomy was built by adding a new class that did not exist in WHO but existed in GRM. The performance of the RF classifier applied to the WHO-I taxonomy further improved.


Calcium and initial surface binding phase of pinocytosis in Amoeba proteus.
The uptake of membrane-bound solute and external medium by bulk-phase pinocytosis in Amoeba proteus is influenced by the level of Ca2+ in the external medium. Increasing external Ca2+ to approximately 10(-4) M increases pinocytotic intensity, while increases in Ca2+ above this level decrease the intensity of pinocytosis. The initial interaction of pinocytotic inducers and Ca2+ at the surface of Amoeba proteus was therefore examined. Alcian blue and Na+, both inducers of pinocytosis, differ in the manner with which they associate with the amoeba surface, suggesting the possibility of different pinocytosis-inducing sites on the amoeba surface. Low levels of external Ca2+ in the range of 3 X 10(-5) to 1.5 X 10(-4) M increase the amount of cationic inducer associated with the cell surface while, at the same time, decreasing anion association with the cell surface. It is suggested that Ca2+ influences ion association with the cell surface by controlling the availability of negative surface sites, which in turn influences pinocytotic intensity.


An explanatory model of older persons' use of dental services. Implications for health policy.
With increasing numbers of people keeping their teeth into their later years, regular dental care should be a health behavior practiced by all older persons. National surveys show, however, that older people use dental services at a much lower rate than other age groups. Even when low-cost dental services are provided, a significant number of eligible elderly do not seek dental care. A survey was conducted among 116 elderly utilizers of low-cost dental services and 142 comparable elderly who had not sought care in 3 or more years. Andersen and Newman's (1973) model was expanded in include attitudes as predisposing factors. The revised model explained 32% of variance in dental utilization; perceived need and two components of attitudes were among the eight significant variables. A follow-up of nonutilizers 6 months later revealed that 27.4% had subsequently sought dental care. The best predictors of the decision to seek care were attitudinal variables, accounting for 21% of the variance. Implications for planning dental services for low-income elderly, developing health education programs, and policies are discussed.