Predictors of intent to utilize the emergency department among a free clinic's patients.
Primary care use helps reduce utilization of more expensive modes of care, such as the emergency department (ED). Although most studies have investigated this association among patients with insurance, few have done so for patients without insurance. We used data from a free clinic network to assess the association between free clinic use and intent to use the ED. Data were collected from a free clinic network's electronic health records on adult patients from January 2015 to February 2020. Our outcome was whether patients reported themselves as 'very likely' to visit the ED if the free clinics were unavailable. The independent variable was frequency of free clinic use. Using a multivariable logistic regression model, we controlled for other factors, such as patient demographic factors, social determinants of health, health status, and year effect. Our sample included 5008 visits. When controlling for other factors, higher odds of expressing ED interest were observed for patients who are non-Hispanic Black, older, not married, lived with others, had lower education, were homeless, had personal transportation, lived in rural areas, and had a higher comorbidity burden. In sensitivity analyses, higher odds were observed for dental, gastrointestinal, genitourinary, musculoskeletal, or respiratory conditions. In the free clinic space, several patient demographic, social determinants of health and medical conditions were independently associated with greater odds of reporting intent on visiting the ED. Additional interventions that improve access and use of free clinics (e.g., dental) may keep patients without insurance from the ED.


Direct optical characterization of graphene growth and domains on growth substrates.
We detailed a facile detection technique to optically characterize graphene growth and domains directly on growth substrates through a simple thermal annealing process. It was found that thermal annealing transformed the naked Cu to Cu oxides while keeping graphene and graphene-covered Cu intact. This increases the interference color contrast between Cu oxides and Cu, thus making graphene easily visible under an optical microscope. By using this simple method, we studied the factors that affect graphene nucleation and growth and achieved graphene domains with the domain size as large as ~100 μm. The concept of chemically making graphene visible is universal, as demonstrated by the fact that a solution process based on selective H(2)O(2) oxidation has been developed to achieve the similar results in a shorter time. These techniques should be valuable for studies towards elucidating the parameters that control the grains, boundaries, structures and properties of graphene.


Expression of mutant non-cleavable Fas ligand on retrovirus packaging cells causes apoptosis of immunocompetent cells and improves prodrug activation gene therapy in a malignant glioma model.
Recombinant retroviruses (RV) have been widely used as vectors for clinical gene therapy of malignant brain tumors. Because of the very limited stability of these vectors in vivo, RV producing cells (VPC) are routinely used for intratumoral RV release. The host immune system, however, recognizes the intratumorally grafted allogeneic or xenogeneic VPC, and mounts an immune response against them. Humoral and cellular immune responses eventually result in reduction of VPC numbers and in limited success of RV mediated gene therapy approaches. This study presents a non-pharmacological and spatially limited approach for protection of VPC grafted in the CNS against destruction by host immune responses. Murine fibroblast-derived VPC expressing herpes-simplex-virus type I thymidine kinase (HSV-tk) were genetically modified to co-express a human Fas ligand (CD95L) deletion mutant (DeltaFasL) resistant to enzymatic cleavage and shedding. Direct interactions between Fas (CD95) on lymphocytes and DeltaFasL on VPC upon cell-cell contact rapidly caused apoptosis in lymphocytes. In addition, cultured malignant brain tumor cells (U87, LN18, LN229) transduced with DeltaFasL-RV were rendered apoptotic by Fas/DeltaFasL interaction. DeltaFasL-expressing VPC grafted in a 9L rat brain tumor model survived in significantly higher numbers compared with control VPC, and did not cause an increase in neutrophil infiltration of tumors. Gene therapy of tumor bearing animals grafted with the modified DeltaFasL-VPC and given the prodrug Ganciclovir resulted in significantly increased survival rates compared to treatment with control VPC and Ganciclovir. In conclusion, prolonged intratumoral presence of DeltaFasL-VPC seems to be a direct consequence of the expression of the membrane-bound mutant FasL, and may result in increased total RV output and improved tumor transduction with RV.


A new flow injection preconcentration method based on multiwalled carbon nanotubes for the ETA-AAS determination of Cd in urine.
A new flow injection (FIA) procedure for the preconcentration of cadmium in urine using multiwalled carbon nanotubes (MWCNT) as sorbent and posterior electrothermal atomization atomic absorption spectrometry (ETA-AAS) Cd determination has been developed. Cadmium was retained in a column filled with previously oxidized MWCNTs and it was quantitatively eluted with a nitric acid solution. The parameters influencing the adsorption-elution process such as pH of the sample solution, amount of sorbent and flow rates of sample as well as eluent solutions have been studied. Cd concentration in the eluent was measured by ETA-AAS under the optimized conditions obtained. The results indicated the elimination of urine matrix effect as a consequence of the preconcentration process performed. Total recovery of cadmium from urine at pH 7.2 using a column with 45 mg of MWCNTs as sorbent and employing a HNO(3) 0.5 mol L(-1) solution for elution was attained. The detection limit obtained was 0.010 μg L(-1) and the preconcentration factor achieved was 3.4. The method showed adequate precision (RSD: 3.4-9.8%) and accuracy (mean recovery: 97.4-100%). The developed method was applied for the determination of cadmium in real urine samples from healthy people (in the range of 0.14-2.94 μg L(-1)) with satisfactory results.


The contribution of copper efflux transporters ATP7A and ATP7B to chemoresistance and personalized medicine in ovarian cancer.
Ovarian cancer has the highest mortality rate among all gynecologic cancers, with most patients presenting with advanced stage tumors. About a third of patients do not respond to primary platinum-based chemotherapy treatment, and over time up to 80 % of others develop chemoresistance, rendering recurrent disease incurable. Moreover, according to latest EMSO-ESGO (European Society for Medical Oncology - European Society for Gynecological Oncology) consensus conference manuscript on ovarian cancer, there are currently no validated molecular predictive biomarkers for platinum resistance. Recent studies suggest that the copper efflux transporters ATP7A and ATP7B play an important role in platinum resistance. In addition, by exploring their role in mediating resistance, new pathways of platinum resistance emerge, such as lysosomal storage disorders, which might be explored in the future as a new target to circumvent platinum resistance. This review outlines a challenging clinical hurdle in ovarian cancer therapy due to platinum resistance, links between the essential trace element copper and cytotoxic platinum-based medicines, and enigmatic mechanisms of ATP7A and ATP7B mediating platinum resistance. It then presents clinical studies showing a significant association of ATP7A and ATP7B with response to cisplatin/carboplatin and prognosis. Based on the results of in vitro assays, disease-relevant animal models, and clinical studies to date, it may be concluded that APT7A and ATP7B deserve further development as predictive markers of platinum resistance in ovarian cancer. Both transporters could play a particularly important role in early estimation of therapy response to identify platinum-resistant tumors and to adjust the treatment of ovarian cancer patients accordingly.


Phototherapy with the argon laser on human melanoma cells "sensitized" with rhodamine-123: a new method for tumor growth inhibition.
Laser photodynamic therapy of superficial malignancies is a promising new approach that will become clinically useful when fluorochromes with high tumor specificity and low toxicity to normal tissues are identified. We recently reported that the mitochondrial dye, Rhodamine-123 (Rh-123), at nontoxic doses, is an effective sensitizing agent for argon laser treatment of human squamous carcinoma and melanoma cells in vitro. We now report the complete inhibition of in vivo tumor development by human M24 melanoma cells transplanted subcutaneously into nu/nu mice after exposure to 1 microgram/ml of Rh-123 for 1 hour and treatment with an argon laser at nonthermal temperatures of 36 to 40 degrees C. Significant in vivo growth was observed for all control tumors. These results demonstrate that Rh-123 enhances the tumoricidal effects of the argon laser at nonthermal temperatures and provides evidence that effective photodynamic therapy may be possible in vivo with the new fluorochrome Rhodamine-123.


Delayed-onset muscle damage and lipid peroxidation in man after a downhill run.
Lipid peroxidation initiated by free radical reactions is associated with tissue necrosis in a variety of conditions. We have measured serum lipid peroxide concentrations (as total thiobarbituric acid-reactive substances, TBARS) and creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) activities and subjective muscle soreness in 16 men before and after a 45-minute downhill treadmill run. TBARS concentrations and enzyme activities were increased after exercise, with peak values observed at 6 hours (TBARS, LDH) or 24 hours (CK, AST) after exercise. Serum LDH activity returned to preexercise levels by 48 hours after exercise and TBARS by 72 hours after exercise: CK and AST activities remained elevated 72 hours after exercise. Leg muscle soreness also increased, with the greatest degree of soreness seen at 24 or 48 hours after exercise. Subjects with the greatest increase in CK, LDH, and AST also showed the highest serum TBARS concentration. This suggests a possible relationship between free radical generation and exercise-induced muscle damage.


Mapping human long bone compartmentalisation during ontogeny: a new methodological approach.
Throughout ontogeny, human bones undergo differentiation in terms of shape, size and tissue type; this is a complex scenario in which the variations in the tissue compartmentalisation of the cortical bone are still poorly understood. Currently, compartmentalisation is studied using methodologies that oversimplify the bone tissue complexity. Here, we present a new methodological approach that integrates a histological description and a mineral content analysis to study the compartmentalisation of the whole mineralised and non-mineralised tissues (i.e., spatial distribution in long bone sections). This new methodology, based on Geographical Information System (GIS) software, allows us to draw areas of interest (i.e., tracing vectorial shapes which are quantifiable) in raw images that are extracted from microscope and compared them spatially in a semi-automatic and quantitative fashion. As an example of our methodology, we have studied the tibiae from individuals with different age at death (infant, juvenile and adult). The tibia's cortical bone presents a well-formed fibrolamellar bone, in which remodelling is clearly evidenced from early ontogeny, and we discuss the existence of "lines of arrested growth". Concurrent with the histological variation, Raman and FT-IR spectroscopy analyses corroborate that the mineral content in the cortical bone changes differentially. The anterior portion of the tibia remains highly pierced and is less crystalline than the rest of the cortex during growth, which is evidence of more active and continuous remodelling. Finally, while porosity and other "non-mineralised cavities" are largely modified, the mineralised portion and the marrow cavity size persist proportionally during ontogeny.


Association between serotonin transporter gene promoter-region polymorphism and 4- and 12-week treatment response to sertraline in posttraumatic stress disorder.
We examined the association between serotonin transporter (5HTTLPR) genotype (SS vs SL vs LL) and sertraline treatment outcome in posttraumatic stress disorder (PTSD). Outpatients (n=330) with PTSD underwent 5HTTLPR genotyping. All patients received sertraline (100 mg/day) for 12 weeks. Patients were assessed using the Clinician-Administered PTSD Scale (CAPS) and other instruments. Patients and rater were blind to the genotyping results. The primary outcome was completer sample CAPS improvement at 12 weeks. Response was defined as ≥30% improvement in CAPS total score with a CGI-I score of 1 or 2. The discontinuation rate was 31.5%. Adverse events led to drop out in 18.1%, 15.3%, and 5.9% of SS, SL, and LL patients, respectively (P=0.038). Among completers, there were 95, 43, and 88 patients with the SS, SL, and LL genotypes, respectively. At endpoint, CAPS total scores improved by 26% vs 46%, respectively, in SS and SL vs LL patients (P<0.001); much of this improvement (15% vs 31% in SS and SL vs LL patients, respectively; P<0.001) was apparent by week 4. The findings were largely similar for the other outcome measures. The response rate was 0%, 0%, and 47.7% in the SS, SL, and LL groups, respectively (P<0.001). We administered a fixed dose of sertraline. For sociopolitical reasons, we planned a completer analysis only. Relative to the SS and SL 5HTTLPR genotypes, the LL genotype is associated with greater responsiveness of PTSD to sertraline (100mg/day) and with lower drop out due to adverse events. The S allele is associated with a striking specificity for treatment nonresponse, as defined in this study.


Oral malodor reduction by a palatal mucoadhesive tablet containing herbal formulation.
The aim of the present study was to test the effect of a palatal mucoadhesive tablet containing an herbal formulation on oral malodor production and volatile sulfide compound (VSC) levels, and to evaluate its antimicrobial activity. A total of 56 healthy young volunteers participated in experiments 1 and 2. The palatal adhesive tablets were prepared with different active ingredients (herbal formulation, zinc and chlorhexidine), or without an active ingredient as control (placebo). Measurement included odor judge scores (two judges) and VSC readings by a sulfide monitor (Halimeter). In experiment 3, the antimicrobial activity of the herbal formulation ingredients (i.e. sage, Echinacea, Lavender and Mastic gum) were tested against three oral pathogens (Streptoccocus mutans, Porphyromonas gingivalis and Candida albicans) by the agar diffusion test. Application of the palatal adhesive tablets containing herbal formulation resulted in a significant reduction in both oral malodor scores (p<0.001) and VSC levels (p=0.013). Herbal formulation showed higher significance in VSC reduction (p=0.001), as compared to zinc and chlorhexidine (p=0.024 and 0.032, respectively). Sage, Lavender and Mastic gum showed antimicrobial activity against all three oral pathogens. Results of the present study suggest that the palatal adhesive tablets containing herbal formulation may serve as an effective means of treatment for patients complaining of oral malodor.


Effective pretreatment technologies for fresh foods aimed for use in central kitchen processing.
The central kitchen concept is a new trend in the food industry, where centralized preparation and processing of fresh foods and the distribution of finished or semi-finished products to catering chains or related units take place. Fresh foods processed by a central kitchen mainly include fruit and vegetables, meat, aquatic products, and edible fungi; these foods have high water activities and thermal sensitivities and must be processed with care. Appropriate pretreatments are generally required for these food materials; typical pretreatment processes include cleaning, enzyme inactivation, and disinfection, as well as packaging and coating. To improve the working efficiency of a central kitchen, novel efficient pretreatment technologies are needed. This article systematically reviews various high-efficiency pretreatment technologies for fresh foods. These include ultrasonic cleaning technologies, physical-field enzyme inactivation technologies, non-thermal disinfection technologies, and modified-atmosphere packagings and coatings. Mechanisms, applications, influencing factors, and advantages and disadvantages of these technologies, which can be used in a central kitchen, are outlined and discussed. Possible solutions to problems related to central-kitchen food processing are addressed, including low cleaning efficiency and automation feasibility, high nutrition loss, high energy consumption, and short shelf life of products. These should lead us to the next step of fresh food processing for a highly demanding modern society. © 2020 Society of Chemical Industry.


A novel human muscle factor related to but distinct from MyoD1 induces myogenic conversion in 10T1/2 fibroblasts.
We have isolated the cDNA encoding a novel human myogenic factor, Myf-5, by weak cross-hydridization to the mouse MyoD1 probe. Nucleotide sequence analysis and the identification of the corresponding gene indicate that human Myf-5 is a member of a small gene family which also contains the human homologue to MyoD1. Although structurally related to the mouse factor, the human Myf-5 constitutes a different protein which nevertheless is capable of inducing the myogenic phenotype in embryonic C3H mouse 10T1/2 'fibroblasts'. The existence of more than one MyoD1-like protein in human skeletal muscle is further suggested by the detection of several similar but distinct cDNA clones. The phenotypic conversion of 10T1/2 cells by the human factor is recognized by the capacity of the cells to form multinucleated syncytia and synthesize sarcomeric myosin heavy chains. Moreover, transient expression of Myf-5 in 10T1/2 cells leads to the activation of a co-transfected muscle-specific CAT reporter gene which by itself is transcriptionally silent in the non-muscle cell background. The deduced amino acid sequence of clone Myf-5 reveals a region which is highly similar to myc proteins and the developmental factors from Drosophila encoded by the achaete scute locus and the twist gene. The myc homology region and a preceding cluster of basic amino acids are located in a larger sequence domain with strong similarity to the mouse myogenic factor MyoD1. Two additional short segments with high serine and threonine content are conserved between the two proteins.(ABSTRACT TRUNCATED AT 250 WORDS)


Cell specificity of nuclear protein antigens in the development of Xenopus species.
Protein antigens accumulated in the oocyte nucleus of Xenopus spp. are found later in all nuclei of the embryo. During and after organogenesis, the fate of different nuclear antigens diverges: Some are permanently expressed in all nuclei, some are no longer detectable in any nuclei, and some show a high degree of specificity relative to cell type. Of the class of antigens permanently expressed in all cells, a nucleolar antigen has been studied that is relatively enriched in the gonia of both sexes. A possible correlations of its occurrence with ribosomal DNA amplification and transcription is examined. The cell-specific expression of 4 antigens has been analyzed in detail, using indirect immunofluorescent staining methods as well as conventional histology. The tissue-specificity of 2 of these antigens does not change during metamorphosis, whereas the pattern of others is dynamic until after metamorphosis. We conclude that the observed tissue-specificity does not correlate with descendence from one of the 3 primary germ layers: Some antigens appear to accumulate in the nucleus when a cell takes up its specific function.


Long-term outcomes of epilepsy surgery in Sweden: a national prospective and longitudinal study.
To investigate prospective, population-based long-term outcomes concerning seizures and antiepileptic drug (AED) treatment after resective epilepsy surgery in Sweden. Ten- and 5-year follow-ups were performed in 2005 to 2007 for 278/327 patients after resective epilepsy surgery from 1995 to 1997 and 2000 to 2002, respectively. All patients had been prospectively followed in the Swedish National Epilepsy Surgery Register. Ninety-three patients, who were presurgically evaluated but not operated, served as controls. In the long term (mean 7.6 years), 62% of operated adults and 50% of operated children were seizure-free, compared to 14% of nonoperated adults (p < 0.001) and 38% of nonoperated children (not significant). Forty-one percent of operated adults and 44% of operated children had sustained seizure freedom since surgery, compared to none of the controls (p < 0.0005). Multivariate analysis identified ≥30 seizures/month at baseline and long epilepsy duration as negative predictors and positive MRI to be a positive predictor of long-term seizure-free outcome. Ten years after surgery, 86% of seizure-free children and 43% of seizure-free adults had stopped AEDs in the surgery groups compared to none of the controls (p < 0.0005). This population-based, prospective study shows good long-term seizure outcomes after resective epilepsy surgery. The majority of the patients who are seizure-free after 5 and 10 years have sustained seizure freedom since surgery. Many patients who gain seizure freedom can successfully discontinue AEDs, more often children than adults. This study provides Class III evidence that more patients are seizure-free and have stopped AED treatment in the long term after resective epilepsy surgery than nonoperated epilepsy patients.


Energy considerations during exercise.
Maintenance of muscular contraction during exercise requires large amounts of chemical energy. Although various sources of energy are available, adenosine triphosphate (ATP) is the universal intracellular vehicle of chemical energy within skeletal muscle. This article will focus on the various mechanisms of the production and breakdown of ATP.


Pretreatment endocrine symptoms and recurrence-free survival among young premenopausal patients with breast cancer: a prospective cohort study.
Pretreatment endocrine symptoms in premenopausal patients might be considered as a potential marker of poor prognosis. We conducted a cohort study to evaluate the association between endocrine symptoms prior to treatment and recurrence-free survival (RFS) among premenopausal patients with breast cancer aged ⩽40 years. Data were obtained from a prospective cohort study (NCT03131089) conducted at the Samsung Medical Center from 2013 to 2021. We included patients aged ⩽40 years who had been diagnosed with breast cancer. The primary outcome measure was RFS. Endocrine symptoms were measured using the Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES). We also calculated the hazard ratio (HR) for recurrence or all-cause mortality by comparing the tertiles of the FACT-ES score at diagnosis. Among the 977 participants, the mean (standard deviation) age was 35.3 (3.9) years. At diagnosis, 17.2% of the patients had at least one severe endocrine symptom. During 3512 person-years of follow-up, the high symptom group had a worse RFS than the low-symptom group [HR = 2.05; 95% confidence interval (CI) = 1.19-3.54]. In particular, hot flashes (HR = 5.59; 95% CI = 1.96-15.93) and breast sensitivity (HR = 1.82; 95% CI = 1.00-3.32) were associated with reduced RFS. Close monitoring of pretreatment endocrine symptoms may be important in patients diagnosed with breast cancer at a young age.


Magnitude estimation of warmth: intra- and intersubject variability.
Fifty-two subjects, both male and female, 18 to 62 years old, were asked to hold a metal bar maintained at different temperatures (33 degrees to 42 degrees C), and to estimate the magnitude of the resulting thermal sensation. On the average, the estimates were linearly related to the stimulus temperature, although most individual subjects either under- or overestimated middle-range values. Intersubject variability, which was twice as large as intrasubject variability, could not be accounted for by gender, age, or body-temperature differences.


Conformationally restrained analogues of sympathomimetic catecholamines. Synthesis and adrenergic activity of 5,6- and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-2',5'-morpholines].
The 5,6- (10a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-)-2',5'-morpholine](11a) and their N-isopropyl derivatives (10b and 11b) (DDSNMs), which can be viewed as the result of the combination of the structure of the 2-(3,4-dihydroxyphenyl)morpholine 5a or 5b (DPMs) with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy- (8a or 8b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydro-1-naphthalen-ol (9a or 9b) (1-AMDTNs) were synthesised. The new compounds DDSNMs 10a,b and 11a,b were assayed for their alpha- and beta-adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described morpholine (5) and tetrahydronaphthalene (8, 9) derivatives. The affinity and activity indices thus obtained indicate in general a low ability of the new compounds 10 and 11 to interact with the alpha- and beta-adrenoceptors, which, in all cases, was lower than that of the corresponding morpholine (5) and tetrahydronaphthalene (8, 9) analogues.


Gait analysis and clinical outcome in patients after pilon fracture surgery.
In this study kinematic parameters, radiographic findings and PROM in pilon fractures after operative treatment were compared with healthy subjects. 16 patients treated with osteosynthesis after pilon fracture underwent kinematic analysis with the OFM. Fractures were evaluated for post-operative step-off and gap on CT-scans and PROM were collected. Results were compared to 10 healthy persons. Range of motion (ROM) crural was lower in the flexion/extension for pilon fractures (10.03 vs. 13.15, p = 0.017). The ROM in the inversion/eversion was low, but ROM in the abduction/adduction was higher. Correlations were found between flexion/extension and AO-classification (r = -0.357 p < 0.05), PROM score of the AOFAS (r = 0.445 p < 0.01), post-operative gap and step-off in the tibia plafond. Pilon fractures showed decreased ROM between the hindfoot and tibia in the sagittal and transverse plane, but increased ROM in the frontal plane during push-off phase as compensatory kinetics. ROM showed significant correlations with PROM and intra-articular step-off and gap in the tibia plafond.


Direct determination of lead in blood by differential pulse stripping voltammetry.
A simple and rapid method for determination of lead in blood by differential pulse stripping voltammetry (DPS) without preliminary mineralization of the sample, is described. Lead determination was performed in native samples of blood in the electrolyte of Britton-Robinson buffer (pH 5-5.5). The proposed method is shown to be reproducible and in good agreement with the reference technique AAS used on mineralized blood samples. Our results indicate that differential pulse stripping voltammetry is a reliable, rapid and highly sensitive method for blood lead analysis.


Short-Term Cessation of Dabigatran Causes a Paradoxical Prothrombotic State.
It is unclear if stopping treatment with dabigatran, a new oral anticoagulant (NOAC), induces a paradoxical rebound prothrombotic state. We investigated if short-term (1-3 days) dabigatran cessation is associated with a higher thrombus volume than expected from a simple reversal of the anticoagulant effect. Ten-week-old C57Bl/6 mice (n = 338) received one of the following oral treatments: phosphate-buffered saline (PBS), dabigatran for 7 days with or without 1 to 4 day cessation, and aspirin in either a single dose or daily for 7 days. Some of the animals that ceased dabigatran for 1 to 3 days received single-dose aspirin. Thereafter, we induced FeCl3 -mediated carotid thrombosis in 130 mice, after which we performed micro computed tomography thrombus imaging. The other 208 mice underwent coagulation assays or platelet function tests. As an explorative pilot study, we reviewed the medical records of 18 consecutive patients with NOAC cessation-related cerebral infarction in a large acute stroke cohort. We observed a ~ 40% higher volume of carotid thrombus after dabigatran cessation at 1 to 3 days than after vehicle treatment and showed that this effect could be prevented by single-dose aspirin pretreatment. Dabigatran cessation unduly increased platelet aggregability for 2 days after drug cessation, an effect mediated through thrombin or arachidonic acid, which effect was significantly attenuated by single-dose aspirin pretreatment. In patients, short-term (≤ 3 days) cessation of NOAC therapy, compared with longer-term (≥ 5 days) cessation, tended to be associated with relatively high stroke severity. We provide the first preclinical evidence that a rebound prothrombotic state follows short-term cessation of dabigatran therapy. ANN NEUROL 2021;89:444-458.


Shear Stress Activates eNOS at the Endothelial Apical Surface Through β1 Containing Integrins and Caveolae.
There is now a large body of evidence demonstrating that fluid mechanical forces generated by blood flowing through the vasculature play a direct role in regulating endothelial cell structure and function. Integrin receptors that localize to the basal surface of the endothelium participate in both outside-in and inside-out signaling events that influence endothelial gene expression and morphology in response to flow. Our analyses of apical plasma membranes derived from cultured bovine aortic endothelial cells revealed that integrins are also expressed on this cell surface. Here, we tested whether these integrins participate in mechanotransduction events that are known to occur on the endothelial cell luminal/apical membrane. We found that apically expressed β1 integrins are rapidly activated in response to acute shear stress. Blockade of β1 integrin activation attenuated a shear-induced signaling cascade involving Src-family kinase, PI3-kinase, Akt and eNOS on this cell surface. In addition, β1 integrin activation and associated signaling events were dependent on the structural integrity of caveolae but not the actin cytoskeleton. Taken together, these data indicate that endothelial responses to shear stress are mediated by spatially distinct pools of integrins.


Spirulina (Arthrospira maxima) mitigates the toxicity induced by a mixture of metal and NSAID in Xenopus laevis.
Cadmium (Cd) is often detected in the environment due to its wide use in industry; also, NSAIDs are one of the most consumed pharmaceuticals, particularly diclofenac (DCF). Several studies have reported the presence of both contaminants in water bodies at concentrations ranging from ng L-1 to μg L-1; in addition, they have shown that they can induce oxidative stress in aquatic species and disturb signal transduction, cell proliferation, and intercellular communication, which could lead to teratogenesis. Spirulina has been consumed as a dietary supplement; its antioxidant, anti-inflammatory, neuroprotective, and nutritional properties are well documented. This work aimed to evaluate if Spirulina reduces the damage induced by Cd and DCF mixture in Xenopus laevis at early life stages. FETAX assay was carried out: 20 fertilized oocytes were exposed to seven different treatments on triplicate, control, Cd (24.5 μg L-1), DCF (149 μg L-1), Cd + DCF, Cd+DCF+Spirulina (2 mg L-1), Cd+DCF+Spirulina (4 mg L-1), Cd+DCF+Spirulina (10 mg L-1), malformations, mortality, and growth were evaluated after 96 h, also lipid peroxidation, superoxide dismutase and catalase activity were determined after 192 h. Cd increased DCF mortality, Cd and DCF mixture increased the incidence of malformations as well as oxidative damage; on the other hand, the results obtained show that Spirulina can be used to reduce the damage caused by the mixture of Cd and DCF since it promotes growth, reduce mortality, malformations, and oxidative stress in X. laevis.


Erratum: Weible et al., Differential Involvement of Three Brain Regions during Mouse Skill Learning.
[This corrects the article DOI: 10.1523/ENEURO.0143-19.2019.].


Is there a link between dizziness and vision? A systematic review.
The aim of this study was to systematically review the literature to investigate the link (if any) between vision and dizziness. Medline, CINAHL, AMED, Web of Science and The Cochrane Library were searched with keywords chosen to find articles which investigated the causes of dizziness and considered vision as a possible trigger. Citation chaining of all included papers was performed in addition to the hand searching of all reference lists. Unpublished literature was identified using www.opengrey.eu. The review considered studies involving adults which link, measure or attempt to improve any aspect of vision in relation to dizziness. Nine thousand six hundred and eighty one possible references were found, and the abstracts were screened independently by two reviewers to determine if they should be included in the study. Thirteen papers were found which investigated whether dizziness was linked to an assessment of vision. Visual impairment measures were crude and typically self-report, or Snellen visual acuity with little or no measurement details. Five studies found an independent link between dizziness and vision, five found a weak association (typically finding a link when univariate analyses were used, but not when multivariate analyses were used), and three found no association. Studies finding a strong link were usually cross-sectional with a large study population whereas those finding a weak association had relatively small numbers of participants. Studies which did not find an association used a broad definition of dizziness that included the term light-headedness, an unreliable Rosenbaum near visual acuity chart or an unusual categorisation of visual acuity. This review suggests that dizziness (although likely not 'light-headedness') is linked with poor vision although further studies using more appropriate measures of vision are recommended.


Characterization of cells cultured from early lactation milks.
Two major types of cells can be cultured from early lactation human milks: a colony-forming epithelial cell and an adherent nondividing cell referred to as a foam cell. The epithelial cells show a positive reaction with a specific antiserum reactive against membrane components of the milk fat globule, whereas the foam cells do not. The nondividing foam cells are phagocytic and can be killed by silica particles; they produce lysozyme, are resistant to trypsinization, and have Fc receptors. These properties, together with the lack of reaction with antiserum to the milk fat globule membrane, suggest that the foam cells are not terminally differentiated epithelial cells, but tissue macrophages.


PIM1 encodes a mitochondrial ATP-dependent protease that is required for mitochondrial function in the yeast Saccharomyces cerevisiae.
The PIM1 nuclear gene in the yeast Saccharomyces cerevisiae encodes a mitochondrial ATP-dependent protease that exhibits over 30% identity with ATP-dependent protease La from Escherichia coli, Lon from Bacillus brevis, and one from Myxococcus xanthus. In addition, Pim1 is 1133 amino acids long and has a putative mitochondrial import signal in the N-terminal region. Enzymatic comparisons of normal PIM1+ and deficient pim1-delta strains revealed that the ATP-dependent protease is located within the mitochondrial matrix. The pim1-delta strains are unable to utilize nonfermentable substrates as the sole carbon source and are unable to maintain functional mitochondrial DNA, indicating that the Pim1 protease is required for mitochondrial function. PIM1 mRNA is constitutively expressed but is increased after thermal stress, suggesting that Pim1 may play a role in the heat shock response.


Cardiovascular disease: the female heart is vulnerable: a call to action from the 10Q report.
February was Heart Month. Clinical Cardiology has embraced the opportunity to share with clinicians and scientists the major adverse impact of cardiovascular disease in women, identifying actionable items derived from recent research studies and highlighting gaps in our knowledge that require investigation.


Surface Modification of Glass Slides with Aminosilanes for Microarray Use.
Glass serves as the solid support for a variety of array types; however, the chemical nature of glass makes it unsuitable for high-affinity binding to most biomolecules. In this chapter, we describe the activation and surface coating of glass with silane, a wide-ranging group of molecules that can covalently attach to the surface of glass and modify it with a variety of functional groups.


Medication Errors: New EU Good Practice Guide on Risk Minimisation and Error Prevention.
A medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient. Reducing the risk of medication errors is a shared responsibility between patients, healthcare professionals, regulators and the pharmaceutical industry at all levels of healthcare delivery. In 2015, the EU regulatory network released a two-part good practice guide on medication errors to support both the pharmaceutical industry and regulators in the implementation of the changes introduced with the EU pharmacovigilance legislation. These changes included a modification of the 'adverse reaction' definition to include events associated with medication errors, and the requirement for national competent authorities responsible for pharmacovigilance in EU Member States to collaborate and exchange information on medication errors resulting in harm with national patient safety organisations. To facilitate reporting and learning from medication errors, a clear distinction has been made in the guidance between medication errors resulting in adverse reactions, medication errors without harm, intercepted medication errors and potential errors. This distinction is supported by an enhanced MedDRA(®) terminology that allows for coding all stages of the medication use process where the error occurred in addition to any clinical consequences. To better understand the causes and contributing factors, individual case safety reports involving an error should be followed-up with the primary reporter to gather information relevant for the conduct of root cause analysis where this may be appropriate. Such reports should also be summarised in periodic safety update reports and addressed in risk management plans. Any risk minimisation and prevention strategy for medication errors should consider all stages of a medicinal product's life-cycle, particularly the main sources and types of medication errors during product development. This article describes the key concepts of the EU good practice guidance for defining, classifying, coding, reporting, evaluating and preventing medication errors. This guidance should contribute to the safe and effective use of medicines for the benefit of patients and public health.


Degradation of Extracellular DNA by DNase1 Significantly Reduces Testicular Damage After Testicular Torsion in Rats.
To examine the effects of DNase1 treatment on testicular damage after testicular torsion (TT). It has been demonstrated that TT induces thrombus formation and that anticoagulation significantly reduces testicular damage after TT. It was hypothesized that these thrombi are dependent on neutrophil extracellular traps (NETs) and thus NETs disintegration would reduce testicular cell damage. A sham operation was performed in 10 rats. Thirty-four rats underwent induction of iatrogenic TT for 3 hours. After de-torsion and randomization, 24 rats received DNase1 or inactivated DNase1. The following parameters were assessed: testicular damage via Cosentino grading; spermatogenesis via Johnsen score; stem cell factor and c-Kit, apoptosis via Bax, Bcl2, Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling assay, and cleaved caspase3 staining; oxidative stress via superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde; neutrophil recruitment via myeloperoxidase and neutrophil elastase staining; and NET formation via cell-free DNA. Forty-three rats were included in the study. Subjects treated with DNase1 showed significantly less cellular damage, oxidative stress, and apoptosis. Further, DNase1-treated rats demonstrated a significant improvement of spermatogenesis, compared with the controls. The results of the study indicate that thrombus formation during TT is quite likely NET associated, and that dissolution of cell-free DNA (including NETs) significantly improves testicular damage in rats. As treatment with DNase1 reduced apoptosis, oxidative stress, and inflammation, without adversely affecting coagulation, it might be a suitable treatment for (neonatal) TT and ought to be evaluated in humans.


Plasmacytoid dendritic cells and their Toll-like receptor 9 expression selectively decrease with age.
Dendritic cells (DCs) play a crucial role in the initiation of immune responses against infectious particles and tumor cells; however, the impact of age, anthropometric parameters, and gender on the number and the expression of function-associated molecules of human DCs is poorly understood. In this study, blood DCs of 50 volunteers (19-84 years old) with no acute or chronic inflammatory diseases were examined using 4-color flow cytometry. Increasing age was associated with a decrease in blood plasmacytoid, but not myeloid DCs and a selective decrease in Toll-like receptor 9 (TLR9) expression by plasmacytoid DCs. In contrast, gender and body mass index did not impact the number of DC subsets or the expression of function-associated DC molecules. Thus, we demonstrate that age has a selective impact on plasmacytoid DCs and their TLR9 expression. This may contribute to an increased susceptibility to infections and tumors with increasing age.


Morning or evening dosage of omeprazole for gastro-oesophageal reflux disease?
When routinely checking patients receiving omeprazole treatment for gastro-oesophageal reflux, we have been finding patients with surprisingly low nocturnal gastric pH. The aim of this study was to evaluate the impact of timing of the 40 mg omeprazole once daily regimen. We evaluated the difference in effect of 40 mg omeprazole, given as a morning or evening dose, in 17 patients with gastro-oesophageal reflux disease. Gastric and oesophageal pH was recorded by portable 24-h two-channel pH-metry in a cross-over design of 14 days of morning and 14 days of evening administration. In five patients pathological reflux was abolished by both regimens, four only during morning dosage, and three only during evening dosage. In the remaining five patients abolition of pathological reflux was not achieved. The therapeutic outcome and patient preference for morning or evening administration were closely related to the individual oesophageal pH curves. Patients with reflux induced by physical activity had a clear preference for morning dosage, patients with nocturnal reflux showed a clear preference for evening dosage. Gastric pH profiles showed a high inter-individual variation; paired statistics, however, revealed a significant impact of dosage timing on the gastric pH profile. After morning dosage the work-day part (the first 7 h) of the gastric pH profile is 0.72 +/- 0.91 (mean difference of pairs +/- s.d.) higher than after evening dosage (P < 0.01). After evening dosage the gastric pH during the supine period is 0.64 +/- 0.83 (mean difference of pairs +/- s.d.) higher than after morning dosage (P = 0.02). The timing of a 40 mg omeprazole dosage regimen has a clinically significant impact on the 24-h pH profile, and that--by relating to the patient 24-hour oesophageal pH-metry in combination with the patient symptomatology--the timing of this dosage is highly important for therapeutic efficacy.


Life satisfaction and adverse effects in renal transplant recipients: a longitudinal analysis.
Previous cross-sectional analyses have identified significant associations between quality of life (QOL), comorbidities and adverse effects in renal transplant recipients. This report examines the longitudinal relationship between adverse effects and QOL, with particular attention to the relative impact of adverse effects associated with immunosuppression. The Transplant Learning Center (TLC) is a program designed to improve QOL and preserve graft function in transplant recipients. Self-selected enrollees filled out questionnaires at roughly 3-month intervals. Each questionnaire included QOL scales developed for the program. Repeated measures multiple regression analysis was used to examine the relationship between the QOL scales, comorbidities, adverse effects, adjusting for other factors. A total of 4247 TLC enrollees were included in the analysis, with a mean time since transplant of 5.1 yr. Comorbidities and adverse effects were common, with high blood pressure reported by 87% of respondents and unusual hair growth reported by 69.6%. In bivariate analysis, emotional/psychological problems and headaches had the largest impact on QOL. In multivariate analysis, emotional/psychological problems decreased sexual interest or ability, and headache had the largest adverse QOL effect. We have identified QOL issues that have been previously underemphasized in transplant recipients. These findings open new areas of research to further explore and define these issues. They provide new opportunities for interventions to address factors adversely impacting QOL and to develop strategies to improve QOL in these patients. Clinicians should actively solicit information about adverse effects of medications, particularly information about sexual and relationship issues, when evaluating renal recipients. These issues should be taken into account when making therapeutic decisions.


Xenotransplantation of stem/progenitor cells from human fetal brain to adult rats with spinal trauma.
In vitro grown neural stem cells from human fetal brain were transplanted to adult rats with spinal trauma. The spinal cord was examined morphologically using histological and immunohistochemical methods on days 5, 15, 30, and 110. Human neural stem/progenitor cells were viable, migrated, and differentiated into neurons and glia in the traumatized spinal cord in adult rats.


Sequential changes in growth kinetics and cellular phenotype during hepatocarcinogenesis.
Sequential changes in cell proliferation and cellular phenotype during hepatocarcinogenesis induced in rats with N-nitrosomorpholine were investigated by autoradiographic determination of the [3H]thymidine-labelling index in morphologically defined focal lesions and extrafocal hepatic tissue at different times between 4 and 48 weeks after withdrawal of the carcinogen (stop model). The labelling index was found to be significantly increased in all types of preneoplastic and neoplastic hepatic lesions as compared to both the liver tissue of untreated controls and the extrafocal parenchyma of N-nitrosomorpholine-treated rats. However, the extent of the increase in labelling index differed in the phenotypically diverse types of preneoplastic and neoplastic lesions. There was a significant but relatively small increase in the labelling index in clear and acidophilic cell foci. A much stronger elevation of cell proliferation was characteristic of mixed and basophilic cell foci. The development of hepatocellular adenomas and carcinomas from preneoplastic hepatic foci was further characterized by an additional increase in cell proliferation. Each specific cellular phenotype was associated with a rather uniform proliferation rate, which remained elevated at all time points studied, suggesting that the rate of cell proliferation in the phenotypically diverse preneoplastic hepatic foci mainly reflects the intrinsic growth potential of the respective cellular phenotypes. The results support the concept that the predominant sequence of cellular changes in hepatocarcinogenesis induced by the stop model leads from the clear and acidophilic cell foci, storing glycogen in excess, through mixed and basophilic cell foci to hepatocellular adenomas and carcinomas. The fact that the labelling index of the extrafocal liver tissue of N-nitrosomorpholine-treated rats was also significantly higher than that of the normal parenchyma of untreated controls might indicate an involvement of extrafocal hepatocytes, in addition to that of foci of altered hepatocytes, in hepatocarcinogenesis.


Linc00662 plays an oncogenic role in bladder cancer by sponging miR-199a-5p.
To investigate the specific roles of linc00662 and miR-199a-5p in bladder cancer (BC). A total of 104 cases of BC tissues and 52 cases of normal para-cancerous tissues were included to detect the expression of linc00662 and miR-199-5p by real-time quantitative PCR. The expression of linc00662 and miR-199a-5p in BC cells T24 was regulated to observe the changes in apoptosis, proliferation, adhesion, invasion, and migration. The nude mice bearing a BC cell transplanted xenograft was constructed, and the expression of linc00662 in rats was regulated. Tumor size and quality were observed within 24 days. The relationship between linc00662 and patients' survival was observed. The targeting relationship between linc00662 and miR-199a-5p was verified by dual luciferase reporter gene assay. Linc00662 was enhanced and miR-199a-5p was decreased in BC patients. Linc00662 targeted and negatively regulated the expression of miR-199a-5p. Down-regulation of linc00662 could reduce proliferation, migration, invasion, and adhesion activities of BC cells, but enhance the apoptosis. Down-regulation of miR-199a-5p counteracted the cell biological changes caused by linc00662. Down-regulating linc00662 cinduced the expression of miR-199a-5p in BC and suppressed tumor growth. Linc00662 plays an oncogenic role in BC by sponging miR-199a-5p.


Getting rid of 'rain' and 'stars': Mitigating inhibition effects on ddPCR data analysis, the case study of the invasive crayfish Pacifastacus leniusculus in the streams of Luxembourg.
ddPCR is becoming one of the most widely used tool in the field of eDNA-based aquatic monitoring. Although emulsion PCR used in ddPCR confers a partial mitigation to inhibition due to the high number of reactions for a single sample (between 10K and 20K), it is not impervious to it. Our results showed that inhibition impacts the amplitude of fluorescence in positive droplets with a different intensity among rivers. This signal fluctuation could jeopardize the use of a shared threshold among samples from different origin, and thus the accurate assignment of the positive droplets which is particularly important for low concentration samples such as eDNA ones: amplification events are scarce, thus their objective discrimination as positive is crucial. Another issue, related to target low concentration, is the artifactual generation of high fluorescence droplets ('stars'). Indeed, these could be counted as positive with a single threshold solution, which in turn could produce false positive and incorrect target concentration assessments. Approximating the positive and negative droplets distribution as normal, we proposed here a double threshold method accounting for both high fluorescence droplets ('stars') and PCR inhibition impact in delineating positive droplets clouds. In the context of low concentration template recovered from environmental samples, the application of this method of double threshold establishment could allow for a consistent sorting of the positive and negative droplets throughout ddPCR data generated from samples with varying levels of inhibitor contents. Due to low concentrations template and inhibition effects, Quantasoft software produced an important number of false negatives and positive comparatively to the double threshold method developed here. This case study allowed the detection of the invasive crayfish P. leniusculus in 32 out of 34 sampled sites from two main rivers (Alzette and Sûre) and five of their tributaries (Eisch, Attert, Mamer, Wiltz and Clerve).


Deep insight on mechanism and contribution of arsenic removal and heavy metals remediation by mechanical activation phosphogypsum.
Arsenic-containing wastewater and arsenic-contaminated soil can cause serious environmental pollution. In this study, phosphogypsum with partial mechanical activation of calcium oxide was used to prepare a new phosphogypsum-based passivate (Ca-mPG), and its remediation performance on arsenic-contaminated soil was evaluated in terms of both effectiveness and microbial response. The results showed that the optimum conditions for the preparation of the passivate were optimized in terms of single factor and response surface with a ball milling speed of 200 r/min, a material ratio of 6:4 and a ball milling time of 4 h. Under these conditions, the adsorption capacity was 37.75 mg/g. The leaching concentration of arsenic (As) in the contaminated soil after Ca-mPG modification decreased from 25.75 μg/L to 5.88 μg/L, which was lower than the Chinese national standard (GB/T 5085.3-2007); Ca-mPG also showed excellent passivation effect on other heavy Metals (copper, nickel, cadmium, zinc). In addition, As-resistant bacteria and passivators work together to promote the stabilization effect of contaminants during the remediation of As-contaminated soil. The mechanisms of Cu, As(III)/As(V), Zn, Cd, and Ni removal were related to ion exchange, electrostatic adsorption of substances on heavy metals, calcium binding to other substances to produce precipitation; and microbially induced stabilization of HMs, oxidized. Overall, this study demonstrates an eco-friendly "waste-soil remediation" strategy to solve problems associated with solid waste reuse and remediation of HM-contaminated soils.


Position Statement by Experts of the Polish Menopause and Andropause Society on menopausal hormone therapy with an oral combination drug containing oestradiol 1 mg and progesterone 100 mg.
At a meeting held on 20 May 2021, reviewed the available literature on the use of the medicinal product Bijuva® for the relief of menopausal symptoms.


A novel open source tool for ELISA result analysis.
ELISA has become a standard analytical tool in the numerous branches of science and industry. Processing of the ELISA results may be a multistep process, often requiring a prior adaptation, using proprietary software, or exporting the results into external internet platforms. It may be problematic in the light of good documentation practices and maintaining good data integrity. In this paper, we present the development and application of the ELISA Tool software. The program is based on a Python scripting programming language and is available under an open-source license. The ELISA Tool allows users to fully control and validate the calculation procedure through a user-friendly graphical user interface. The modular architecture of the software allows its application in other information technology (IT) projects used for data processing in research laboratories. We successfully applied the ELISA Tool for the analysis of real-life samples. The ELISA Tool allowed import of the measurement data, an approximation of the calibration curves with two different algorithms, exploration and diagnostics of the model fit, and generation of the final report with the calculations while maintaining the raw data file unchanged. We report here for the first time the implementation of the idea of full control over data processing, from measured raw data to the final report. We obtained a transparent, open, registered system of data processing control, independent of third parties. The modular and flexible architecture of the created software encourages its further development following the individual demands of the users.


Intraocular pressure after bilateral cataract surgery using Healon, Healon5, and Healon GV.
To determine whether there is a difference in frequency or severity of postoperative intraocular pressure (IOP) spikes after bilateral phacoemulsification with complete ophthalmic viscosurgical device (OVD) removal when Healon5 (sodium hyaluronate 2.3%), Healon (sodium hyaluronate 1%), or Healon GV (sodium hyaluronate 1.4%) is used. York Finch Eye Associates and Humber River Regional Hospital, Toronto, Ontario, Canada. Bilateral cataract surgery was performed in 99 patients; 50 were randomly assigned to receive Healon5 in 1 eye and Healon GV in the fellow eye and 49, Healon in 1 eye and Healon GV in the fellow eye. The IOP was measured preoperatively as well as 5 and 24 hours and 7 days postoperatively. The mean IOP and standard deviation at each time interval were calculated for each OVD. The results were compared among the OVDs using Student t tests for each time at which IOP was assessed. There were no significant differences in postoperative IOP spikes among the Healon5, Healon, and Healon GV groups; however, patients receiving lower viscosity OVDs had a lower mean IOP at 24 hours. All groups had increased IOP at 5 and 24 hours and reduced IOP at 7 days. Within a family of molecularly similar OVDs, lower viscosity OVDs appear to cause slightly lower mean elevations in IOP in normal patients at 24 hours. However, if the OVD is removed, postoperative IOP spikes above 21 mm Hg appear related more to patient factors (eg, predisposition in glaucoma patients) and surgically induced trauma than to the specific long-chain non-cross-linked hyaluronan OVD used.


Pharmacist interventions to improve blood pressure control in primary care: a cluster randomised trial.
High blood pressure (BP) is the single largest contributor to mortality world-wide. To investigate the effectiveness of a pharmacists-led intervention to improve BP control using automated office blood pressure (AOBP). In this prospective parallel group, unblinded, cluster-randomised trial, 54 pharmacies enrolled pre-treated patients with uncontrolled AOBP above 135/85 mmHg. In the interventional group, pharmacists referred patients to the treating physician for therapy intensification in a structured fashion. In the control group, AOBP was recorded until the end of the trial. The primary endpoint was the proportion of patients achieving BP control at the threshold of 135/85 mmHg after 10 weeks. Key secondary endpoints were systolic AOBP reductions after 10 and 20 weeks. A total of 497 patients were included between 2017 and 2019. In the interventional and control group, 61.5% and 19.8% of patients underwent a therapy modification within 20 weeks. The primary endpoint was achieved in 38.8% in the interventional group and 31.2% in the control group (mean difference 7.6%, 95% CI -8.1; 23.3, p = 0.336). Mean systolic AOBP reductions were greater in the interventional vs. control group at 10 and 20 weeks (14.3 ± 7.4 vs. 6.9 ± 7.0 mmHg, mean difference 7.3 mmHg, 95% CI 3.2;11.5, p < 0.001, and 15.5 ± 9.0 vs. 9.8 ± 7.5 mmHg, mean difference 5.8 mmHg, 95% CI 0.8;10.7, p = 0.023). Atrial fibrillation was newly detected in 7.8% of patients. Through a pragmatic pharmacist-led disease management program, BP control was improved over time, without significant differences between groups. Greater systolic AOBP reductions were observed in the interventional vs. control group. (Pharmacists Intervention to Improve Hypertension Management in Primary Care:APOTHECARE; ClinicalTrials.gov registration NCT03274531).


Estimating wildlife vaccination coverage using genetic methods.
Vaccination is a useful approach for the control of disease in wildlife populations. However, its effectiveness is dependent in part on delivery to a sufficient proportion of the target population. Measuring the proportions of wild animal populations that have been vaccinated is challenging and so there is a need to develop robust approaches that can contribute to our understanding of the likely efficacy of wildlife vaccination campaigns. We used a modified capture mark recapture technique to estimate vaccine coverage in a wild population of European badgers (Meles meles) vaccinated by live-trapping and injecting with Bacillus Calmette-Guérin as part of a bovine tuberculosis control initiative in Wales, United Kingdom. Our approach used genetic matching of vaccinated animals to a sample of the wider population to estimate the percentage of badgers that had been vaccinated. Individual-specific genetic profiles were obtained using microsatellite genotyping of hair samples, which were collected directly from trapped and vaccinated badgers and non-invasively from the wider population using hair traps deployed at badger burrows (setts). With two nights of trapping at each sett in an annual campaign, an estimated 50 % (95 % confidence interval 40-60 %) of the badger population received at least one dose of vaccine in a single year. Using a simple population model this suggested that the proportion of the population that would have received at least one dose of vaccine over the course of the four year vaccination campaign was between 67 % and 83 %. This is the first attempt, outside of field trials, to quantify the level of vaccine coverage achieved by trapping and injecting badgers, which is currently the only option for delivering BCG vaccine to this species. The results therefore have specific application to bTB control policy and the novel approach may have wider value in wildlife management and research.


Depression of reserpine-induced muscular rigidity in rats after administration of lisuride into the spinal subarachnoid space.
Muscular rigidity was induced by reserpine (10 mg/kg) in rats and the tonic activity of the gastrocnemius muscle was recorded in the electromyogram. Systemic administration of lisuride, an ergoline, resulted in a dose-dependent depression of rigidity. To examine the spinal cord as a site of action for lisuride to depress reserpine-induced rigidity, a method for the chronic catheterization of the lumbar spinal subarachnoid space was used, which allowed the administration of drugs to reserpinized, intact rats without anaesthesia. Lisuride injected into the lumbar spinal subarachnoid space resulted in a longlasting depression of rigidity. These results suggest that the spinal cord is an important site of action of lisuride.


Raman spectroscopic analysis of the Maya wall paintings in Ek'Balam, Mexico.
Raman spectroscopy has been applied to the examination of wall painting fragments from the archaeological site of Ek'Balam (Yucatán, Mexico). Thirty-three samples have been studied, all originating from room 23 of the Acropolis, and being representative of the painting technique at Ek'Balam during the late Classic Maya period. Several pigments such as haematite, calcite, carbon, cinnabar and indigo were identified in these samples. The latter pigment was presumed to be present as 'Maya blue', which is an intercalation product of indigo and palygorskite clay. The observed Raman spectra are reported and some band assignments have been made. This survey is the first Raman spectroscopic examination of a whole set of pigments in archaeological Maya wall painting fragments.


Comparative microvascular exchange kinetics of [(77)Br]bromide and (99m)Tc-DTPA in humans.
The plasma clearance curves of small hydrophilic solutes comprise three exponentials, consistent with a three-compartmental distribution model. A previous comparison between inulin and diethylene triamine penta-acetic acid (DTPA) suggested that these three compartments are in series, the first being plasma and the second and third representing compartments within the extravascular space. Moreover, whilst the total distribution volumes of these two indicators were similar, the volume of the second compartment was higher for DTPA. The purpose of the current study was to investigate whether a solute smaller than DTPA, namely bromide, fits the hypothesis that the second space volume is an inverse function of the size of the solute. Two groups of subjects were studied: group A comprised eight patients undergoing routine diagnostic arteriography and group B, eight patients referred for routine measurement of glomerular filtration rate plus two normal volunteers. (99m)Tc-DTPA and sodium [(77)Br]bromide were intravenously administered simultaneously. In group A, frequent arterial samples were obtained up to 40 min after injection, and antecubital venous samples 30 s after each arterial sample. In group B, frequent venous samples were obtained up to 280 min after injection. Volume measurements based on bromide were corrected for erythrocyte bromide accumulation. In both subject groups, the normalised venous concentration ratio of bromide to DTPA, corrected for red cell bromide uptake, was significantly less than unity in the earliest blood samples, being 0.56 (SD 0.08) at 1 min, consistent with faster diffusion of bromide from plasma to interstitial fluid. Furthermore, the extraction fraction of bromide from plasma to interstitial fluid in the forearm was about 0.6, higher than that of DTPA (about 0.5) in spite of red cell bromide accumulation which equilibrated with plasma bromide within 20 s and resulted in a red cell to plasma concentration ratio of 0.51 (0.09). Nevertheless, the net extraction fractions of the two solutes approached asymptotic values with identical time courses over 20-25 min. The total volume of distribution of bromide in group B was 22.5 (3.8) litres, which was higher than that of DTPA, 18.0 (2.8) litres ( P<0.001). It was assumed that this difference was the result of intracellular bromide accumulation. After correction for this, the combined volume of the first and second spaces was significantly higher for bromide, at 13.9 (2.9) litres, than for DTPA, 12.3 (2.0) litres ( P<0.05), but the volume of the third space, 4.1 (2.8) litres, was less compared with DTPA, for which it was 5.8 (2.2) litres ( P<0.05). The proportion of the total space occupied by the first and second spaces was also higher for bromide, 0.78 (0.14), than for DTPA, for which it was 0.69 (0.09; P<0.05). These data are consistent with a three-in series-compartmental model of solute distribution in which the volume of the second space is an inverse function of solute molecular size while the volume of the third is a positive function of solute size.


Comparison of central line-associated bloodstream infection rates when changing to a zero fluid displacement intravenous needleless connector in acute care settings.
This was a multicenter, quasiexperimental, 140-month, acute care study comparing central line-associated bloodstream infection rates associated with positive or negative intravenous connectors to a zero fluid displacement connector. A decrease in central line-associated bloodstream infections was found after changing from either negative or positive intravenous connectors to the zero fluid displacement connector (P = .004) with total cost savings of over $3 million.


Evaluation of tumor morphologies and association with biochemical recurrence after radical prostatectomy in grade group 5 prostate cancer.
We assessed Gleason pattern 5 (GP5) and other prostatic adenocarcinoma (PCa) morphologies to determine their association with biochemical recurrence (BCR). A search for grade group 5 PCa with radical prostatectomy (RP) yielded 49 patients. RPs were reviewed for %GP5 and morphologies (sheets, single cells, cords, small solid cylinders, solid medium to large nests with rosette-like spaces [SMLNRS], comedonecrosis, cribriform glands, glomerulations, intraductal carcinoma of the prostate [IDC-P], and prostatic ductal adenocarcinoma [PDCa]). Prevalence of morphologies was as follows: single cells 100%, cribriform glands 98.7%, cords 85.7%, IDC-P 77.6%, comedonecrosis 53.1%, sheets 49.0%, small solid cylinders 49.0%, PDCa 44.9%, glomerulations 34.7%, and SMLNRS 14.3%. From 28 patients who were treated with RP as monotherapy, 64.3% (18/28) had BCR. Comedonecrosis, sheets, small solid cylinders, IDC-P, and PDCa were significantly associated with BCR. Number of morphologies on RP and %GP5 were higher in patients with BCR (6.8 ± 2.1 versus 3.7 ± 2.9%; P < 0.001 and 26.9 ± 16.8 versus 11.4 ± 14.1%; P = 0.02) with area under ROC curve of 0.89 (confidence intervals [CI] 0.77-1.00). Sensitivity/specificity was 77.8/80.0% for predicting BCR when ≥ 5 morphologies were present and 0.79 (CI 0.60-0.99) with sensitivity/specificity of 66.7/80.0% for predicting BCR when ≥ 15% GP5 was present. Hazard ratio for BCR was higher with increasing number of morphologies (1.23, CI 1.02-1.49; P = 0.034) but not %GP5 (0.99, CI 0.97-1.02, P = 0.622). Our results indicate that GP5 morphologies may represent a biologically heterogeneous group and that an increasing number of PCa morphologies on RP is strongly associated with an increased risk of BCR.


miR-378a: a new emerging microRNA in metabolism.
Metabolic diseases, such as type 2 diabetes or obesity, are the consequence of the disruption of the organism's metabolic pathways. The discovery of small non-coding RNAs-microRNAs (miRNAs)-as post-transcriptional gene regulators opened new doors for the development of novel strategies to combat said diseases. The two strands of miR-378a, miR-378a-3p, and miR-378a-5p are encoded in the Ppargc1b gene and have an active role in the regulation of several metabolic pathways such as mitochondrial metabolism and autophagy. Recent studies recognized miR-378a as an important regulator of energy and glucose homeostasis, highlighting it as a potential target for the improvement of metabolic dysregulation. In the present review, the current knowledge on miR-378a will be discussed with a particular emphasis on its biological functions and mechanisms of action in metabolism, mitochondria, and autophagy.


Changes in Retinol Binding Protein 4 Level in Undernourished Children After a Nutrition Intervention Are Positively Associated With Mother's Weight but Negatively With Mother's Height, Intake of Whole Milk, and Markers of Systemic Inflammation: Results From a Community-Based Intervention Study.
The changes of plasma retinol binding protein 4 (RBP4) level after a nutrition intervention can indicate the metabolic changes associated with the delivered intervention. We investigated the changes in plasma RBP4 level among 12- to 18-month-old children after a nutrition intervention and measured its association with subcutaneous adiposity, maternal characteristics, and inflammation. Data of 520 undernourished children (250 of them had length-for-age Z score [LAZ] <-1 to -2 and 270 had LAZ score <-2) were collected from the Bangladesh Environmental Enteric Dysfunction study conducted in Dhaka, Bangladesh. Multivariable linear regression and generalized estimation equations (GEE) modeling techniques were used to measure the association. At baseline, median RBP4 level was 19.9 mg/L (interquartile range [IQR]: 7.96), and at the end of the intervention, it was 20.6 mg/L (IQR: 9.06). Percentage changes in plasma RBP4 level were not significantly associated (P > .05) with the percentage changes in child's height, weight, and subcutaneous adiposity. But maternal height (regression coefficient, β = -1.62, P = .002) and milk intake (β = -0.05, P = .01) were negatively and maternal weight was positively associated (β = 0.56, P = .03) with the changes in RBP4 levels. The GEE models revealed negative association of RBP4 levels with C-reactive protein (CRP; β = -0.14, P < .05) and α-1-acid glycoprotein (AGP; β = -0.03, P < .05). Children whose mothers were taller experienced less increase in plasma RBP4 level, and children whose mothers had a higher weight experienced more increase in the RBP4 level from baseline. We have also found that CRP and AGP levels and intake of whole milk were negatively associated with the plasma RBP4 level.


[Effect of estrogens on the concentration of carcinoembryonal antigen in the serum of rats with intestinal neoplasms and in the presence of non-specific injuries to its mucous membrane].
Carcinoembryonal antigen (CEA) was shown to be present in 70% of rats with tumours of the large intestine induced with 1,2-dimethyl-hydrazine and in rats with posttraumatic mucosa regeneration of the same organ. After treatment with estrogen--diethyl stilbestrol propionate (0.57 microgram/day for 6 days) the incidence of CEA finding in the serum of these rats was increased. In rats with an injured mucosa of the large intestine estrogen treatment prevented the natural decrease of CEA during the decline of regeneration.


A retrospective analysis of endometrial carcinoma cases surgically treated with or without para-aortic lymph node dissection followed by adjuvant chemotherapy.
To analyze the efficacies of para-aortic node (PAN) dissection for patients undergoing surgery and adjuvant chemotherapy for endometrial carcinomas. At the Osaka University Hospital and the Kaizuka City Hospital in Osaka, Japan, either pelvic lymph nodes (PLN) plus para-aortic lymph nodes (PAN) or PLN-only dissections were performed for endometrial carcinomas. An adjuvant chemotherapy using paclitaxel, epirubicin, and carboplatin was conducted for all such patients. A retrospective comparison of the efficacy of PAN dissection was conducted. Disease-free and overall survivals and frequency of PAN involvement at the first recurrence did not exhibit a statistically significant difference between the PLN-only group and the PLN + PAN group. Operation time was significantly longer in the PLN + PAN group than the PLN-only group, and the total blood loss was also significantly greater in the PLN+PAN group. PAN dissection may be omitted, without adverse effect on prognosis, for endometrial carcinoma patients with recurrence risks who undergo adjuvant chemotherapy using platinum, anthracycline and taxane derivatives.


Evidence-based tick acaricide resistance intervention strategy in Uganda: Concept and feedback of farmers and stakeholders.
The emergence of multi-acaricide resistant ticks has led to unprecedented level of acaricide failure in central and western Uganda. In the absence of a national acaricide resistance management strategy, the country's dairy sector is threatened by upsurge of ticks and tick-borne diseases. In this study, we developed a short-to-medium-term intervention approach called Evidence-Based Acaricide Tick Control (EBATIC): Identify, Test, Intervene and Eradicate (IT-IE). Furthermore, the perception of 199 farmers and extension workers, 12 key informants in four districts and 47 stakeholders in the animal industry in Uganda were assessed using semi-structured questionnaires. We report that the establishment of a specialized laboratory is pivotal in identifying and testing (IT) acaricide resistant ticks for prompt intervention and eradication (IE). The laboratory test results and the farm tick control gaps identified are very important in guiding acaricide resistance management strategies such as evidence-based acaricide rotation, development and dissemination of extension materials, training of farmers and extension workers, and stakeholders' engagement towards finding sustainable solutions. All the 47 stakeholders and 91.0% (181/199) of the farmers and extension workers reported that the EBATIC approach will help in solving the tick acaricide resistance crisis in Uganda. Similarly, all the 12 key informants and 92.5% (184/199) of the farmers and extension workers suggested that the EBATIC approach should be sustained and rolled out to other districts. The EBATIC stakeholders' dialogue generated both short-to-medium and long-term strategies for sustainable management of tick acaricide resistance in the country. Overall, the positive feedback from farmers, district veterinarians and stakeholders in the animal industry suggest that the EBATIC approach is a useful proof-of-concept on scalable intervention pathway against tick acaricide resistance in Uganda with possibility of adoption in other African countries.


Enhancement of activation-induced cell death by fibronectin in murine CD4+ CD8+ thymocytes.
Development of T cells in the thymus is achieved through the interactions of thymocytes with their microenvironments. This study focused on the function of fibronectin (FN), a major extracellular matrix molecule in the thymus, in the cell death induced by activation via the T-cell antigen receptor. FN alone did not increase cell death in murine thymocytes above the baseline level, but it significantly enhanced the cell death induced by fixed anti-CD3 monoclonal antibody (mAb), especially when a high concentration of anti-CD3 mAb was used. DNA fragmentation increased in parallel with cell death, indicating that cell death was a result of the apoptosis. Fluorescence-activated cell sorter (FACS) analysis revealed that the activation-induced cell death (AICD) caused by anti-CD3 mAb alone, or by a combination of anti-CD3 mAb and FN, occurred selectively in CD4+ CD8+ thymocytes. Very late activation antigen (VLA)-4 and VLA-5 are two major ligands to FN on thymocytes. The expression of both ligands was investigated at different stages of thymocyte development. VLA-4 was predominantly expressed at the CD4- CD8- stage, and thereafter the expression was reduced, whereas VLA-5 was constantly expressed during maturation. Furthermore, the enhancing effect by FN was inhibited in the presence of the Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) peptide but not in the presence of the connecting segment-1 (CS-1) peptide, suggesting that enhancement of AICD observed in CD4+ CD8+ thymocytes is mediated through VLA-5.


Treatment success with a mandibular advancement device is related to supine-dependent sleep apnea.
To evaluate the effect of a mandibular advancement device in patients with supine-dependent sleep apnea and patients with non-supine-dependent sleep apnea. Prospective study. Department of Respiratory Medicine, University Hospital, Umeå, Sweden. Twenty-six patients with obstructive sleep apnea. Individually fabricated and adjusted mandibular advancement devices. Overnight polysomnographic sleep recordings with and without the device. Supine-dependent sleep apnea was defined when the supine apnea-hypopnea index was > or = 10, together with a lateral apnea-hypopnea index of < 10. Non-supine-dependent sleep apnea was considered when the lateral apnea-hypopnea index was > or = 10. In 12 patients with supine-dependent sleep apnea, the device reduced the supine apnea-hypopnea index from a median of 41 (range, 16 to 70) to 5.9 (range, 0.0 to 15) (p < 0.01). In 14 patients with non-supine-dependent sleep apnea, the treatment reduced the supine apnea-hypopnea index from 44 (range, 1.8 to 73) to 21 (range, 6.3 to 60) (p < 0.05) and the lateral apnea-hypopnea index from 21 (range, 12 to 70) to 4.5 (range, 0.0 to 31) (p < 0.01). The odds ratio for a successful apnea reduction to an apnea-hypopnea index of < 10 in both the supine and the lateral positions was 30 for supine-dependent sleep apnea adjusted for age, obesity, mandibular advancement, and mandibular opening (p < 0.01). Successful apnea reduction with a mandibular advancement device is highly related to supine-dependent sleep apnea.


Oral Carcinoma Cuniculatum: A Variant of Squamous cell Carcinoma with Unique Histological Characteristics and a Diagnostic Challenge.
Oral carcinoma cuniculatum (OCC) is a rare squamous cell carcinoma (SCC) variant with low incidence often due to misdiagnosis. This report aims to highlight this unique variant of SCC which is suggested to have a better prognosis with a focus on its histopathological features in comparison with similar clinical entities.


Impact of atherosclerosis on the relationship of glycemic control and mortality in diabetic patients on hemodialysis.
The impact of preexisting cardiovascular disease (CVD) on glycemic control-improved survival in hemodialysis patients with diabetes mellitus (DM) was investigated. Glycoalbumin (GA) was used as a glycemic marker. A single-center 4-year follow-up study was performed in an observational cohort of 178 DM hemodialysis patients to analyze the relationship between GA and all-cause mortality in patients with (n = 70) and without (n = 108) CVD. The subjects were divided into three categories based on GA value at the start of study. Baseline characteristics did not differ between the two groups of patients. During the 4-year follow-up, 24 of 108 (23.3%) CVD(-) patients and 30 of 70 (42.8%) CVD(+) patients died. The mortality was significantly higher in the CVD(+) group. Multivariate Cox analyses including GA, logCRP, age, gender, hemodialysis duration, albumin, hemoglobin, BMI, SBP, DBP, smoking habit, and SUN as independent variables showed that GA, in addition to logCRP and age, was independently associated with mortality in all patients. Kaplan-Meier analysis showed lower GA levels to be a significant predictor of lower mortality in the CVD(-) group, but not in the CVD(+) group. Multivariable-adjusted Cox proportional hazards models demonstrated a significant association between GA with allcause mortality risk in the CVD(-) group (p = 0.004), in contrast with the CVD(+) group in the same model (p = 0.842). These results demonstrate a beneficial effect of improved glycemic control on survival in DM hemodialysis patients, which might be attenuated by the presence of CVD.


Nutritional profile of the land snail Cyclophorus saturnus, a rich-in-nutrients food item from Thailand.
Cyclophorus saturnus is an edible land snail traditionally harvested for human food, yet little is known about its nutritional value, especially in Thailand. This study aimed to investigate its nutritional potential as an alternative food resource. In the present study, proximate composition, essential mineral content, amino acid, and lipid profiles of the meat were evaluated. Proximate analysis showed that C. saturnus contained 80.04% moisture, 11.88% protein, 6.04% carbohydrate, and 0.93% fat, with 80.01 kcal/100 g fresh matter. For minerals, calcium was the most abundant element in the meat. Its protein contained glutamic and aspartic as the major amino acids, while it was not a good source of tryptophan and methionine but was considered a very rich source of other essential amino acids (amino acid scores greater than 100). Its lipid fraction showed a higher proportion of mono and polyunsaturated fatty acids (MUFA and PUFA, 67.69%) and a lower proportion of saturated fatty acids (SFA) (32.31%). The PUFA/SFA ratio (1.56), hypocholesterolemic/hypercholesterolemic ratio (HH; 5.58), atherogenicity index (AI; 0.48), and thrombogenicity index (TI; 0.20) are considered nutritionally healthy for humans. Overall, this study demonstrates the nutritional potential of C. saturnus to serve as a nutritious part of the human diet and as an alternative ingredient in food systems; therefore, its production and consumption should be more extensively promoted.


Producing knowledge by admitting ignorance: Enhancing data quality through an "I don't know" option in citizen science.
The "noisy labeler problem" in crowdsourced data has attracted great attention in recent years, with important ramifications in citizen science, where non-experts must produce high-quality data. Particularly relevant to citizen science is dynamic task allocation, in which the level of agreement among labelers can be progressively updated through the information-theoretic notion of entropy. Under dynamic task allocation, we hypothesized that providing volunteers with an "I don't know" option would contribute to enhancing data quality, by introducing further, useful information about the level of agreement among volunteers. We investigated the influence of an "I don't know" option on the data quality in a citizen science project that entailed classifying the image of a highly polluted canal into "threat" or "no threat" to the environment. Our results show that an "I don't know" option can enhance accuracy, compared to the case without the option; such an improvement mostly affects the true negative rather than the true positive rate. In an information-theoretic sense, these seemingly meaningless blank votes constitute a meaningful piece of information to help enhance accuracy of data in citizen science.


Female-perpetrated intimate partner violence and romantic attachment style in a college student sample.
The frequency, severity, and reciprocity of female-perpetrated intimate partner violence and its consequences (i.e., injuries) were investigated in a college sample of women (N = 457). Participants were classified into one of the following four groups on the basis of self-reported physical assault perpetration and victimization against their relationship partners: nonviolent, perpetrator-only, victim-only, and bidirectionally violent. Results showed that females in the bidirectionally violent group had a reportedly higher occurrence (although not always statistically significant) of perpetration and victimization than those in the perpetrator-only and victim-only groups. Additionally, a similar degree of reciprocity was indicated by females in bidirectionally violent relationships in terms of violence severity and the occurrence of injury. Adult romantic attachment style was also examined among a subset of females (N = 328), and bidirectionally violent females were found to have the highest reported levels of attachment anxiety. Further, females high in attachment anxiety and low in attachment avoidance were more likely to report perpetrating violence than females high in both styles. Implications for prevention are discussed.


[Linear localized scleroderma. Successful treatment with prednisolone pulse therapy and methotrexate].
Linear localized scleroderma is a variant of localized scleroderma characterized by linear bands and sclerotic plaques of the skin, which can result in contractures, muscle atrophy and debilitating deformities. The etiology remains unknown and no specific therapy is available. Regimens combining pulsed high-dose corticosteroids with methotrexate therapy seem promising. Our patient responded well to intravenous prednisolone (500 mg/d) for 3 consecutive days monthly combined with an oral dose of methotrexate of (15 mg/wk).


Selecting and screening recombinant antibody libraries.
During the past decade several display methods and other library screening techniques have been developed for isolating monoclonal antibodies (mAbs) from large collections of recombinant antibody fragments. These technologies are now widely exploited to build human antibodies with high affinity and specificity. Clever antibody library designs and selection concepts are now able to identify mAb leads with virtually any specificity. Innovative strategies enable directed evolution of binding sites with ultra-high affinity, high stability and increased potency, sometimes to a level that cannot be achieved by immunization. Automation of the technology is making it possible to identify hundreds of different antibody leads to a single therapeutic target. With the first antibody of this new generation, adalimumab (Humira, a human IgG1 specific for human tumor necrosis factor (TNF)), already approved for therapy and with many more in clinical trials, these recombinant antibody technologies will provide a solid basis for the discovery of antibody-based biopharmaceuticals, diagnostics and research reagents for decades to come.


An immobilization-free electrochemical impedance biosensor based on duplex-specific nuclease assisted target recycling for amplified detection of microRNA.
An immobilization-free electrochemical impedance biosensor for microRNA detection was developed in this work, which was based on both the duplex-specific nuclease assisted target recycling (DSNATR) and capture probes (Cps) enriched from the solution to electrode surface via magnetic beads (MBs). In the absence of miR-21, Cps cannot be hydrolyzed due to the low activity of duplex-specific nuclease (DSN) against ssDNA. Therefore, the intact Cps could be attached to the surface of magnetic glass carbon electrode (MGCE), resulting in a compact negatively charged layer as well as a large charge-transfer resistance. While in the presence of miR-21, it hybridized with Cp to form a DNA-RNA heteroduplex. Due to the considerable cleavage preference for DNA in DNA-RNA hybrids, DSN hydrolyzed the target-binding part of the Cp while liberating the intact miR-21 to hybridize with a new Cp and initiate the second cycle of hydrolysis. In this way, a single miR-21 was able to trigger the permanent hydrolysis of multiple Cps. Finally, all Cps were digested. Thus, the negatively charged layer could not be formed, resulting in a small charge-transfer resistance. By employing the above strategy, the proposed biosensor achieved ultrahigh sensitivity toward miR-21 with a detection limit of 60aM. Meanwhile, the method showed little cross-hybridization among the closely related miRNA family members even at the single-base-mismatched level. Successful attempts were made in applying the approach to detect miR-21 in human serum samples of breast cancer patients.


Diagnostic work-up and treatment in patients with pyoderma gangrenosum: retrospective analysis of US insurance claims-based data.
Pyoderma gangrenosum (PG) is a rare, and often challenging to diagnose, inflammatory disorder with relatively high rates of morbidity and mortality. Central to the diagnosis of PG is histologic evaluation and exclusion of other entities. Large-scale studies investigating the proportion of patients receiving a thorough diagnostic work-up, as well as prevalence studies regarding comorbidities and systemic treatment in PG using claims-based data, are sparse. Our objective was to identify patients diagnosed with PG and describe the diagnostic work-up and prevalence of common comorbidities and therapies in this population using claims-based data in a retrospective cohort study. In order to better understand practices of diagnostic work-up, we captured rates of skin biopsy, tissue culture, and/or surgical debridement prior to initial diagnosis. We also identified the prevalence of PG-associated comorbidities and initial immunosuppressive therapy given for PG. Of the 565 patients diagnosed with PG, 9.4% underwent skin biopsy, 8% tissue culture, and 1.4% both skin biopsy AND tissue culture prior to diagnosis. Inflammatory bowel disease was the most prevalent comorbidity (16.3%). The most common treatment administered was systemic corticosteroids (17%). Although practice guidelines explicitly delineate histology and exclusion of infection as important diagnostic criteria, only a minority of patients in this study underwent skin biopsy and/or tissue culture prior to receiving a diagnosis of PG, suggesting that patients may receive a diagnosis of PG without having tissue evaluation. Such discordance between practice guidelines and "real-world" practice inevitably increases the risk for misdiagnosis of PG and misdirected treatment with immunosuppressants for presumptive PG in cases of PG mimickers. Moreover, comorbidities associated with PG may occur, or be identified in, a lower proportion of patients as compared with what is reported in the existing literature. Study limitations include a population restricted to < 65 years with commercial insurance and the reliance upon ICD diagnostic coding to capture the population.


[Results of rehabilitation on quality of walking and outcome in elderly patients following femoral neck fracture. Development after one year].
To examine effects of coordinated multidisciplinary inpatient rehabilitation for older patients with hip fractures. 187 (42 men and 147 women: mean age 80.9 +/- 8.4 years) admitted with a diagnosis of fracture neck of femur. Before fracture 183 patients were living in their own house. We examine medical state before fracture, type of fracture, type of surgery, walking performance at hospital discharge and at one year, destination at this discharge, living location and quality of life at one year. The length stay after intracapsular fracture and prosthesis is significatively lower (p<0.01). At discharge 28% were walking alone, 38% with stick, 17% with technical aid, 8% with human aid, 2% were bedridden and 7% were dead. After hospitalisation 7% were dead, 70% were living in their own homes, 18% were in old people's homes and 6% in another hospital. One year after fracture, 19% were dead, 65% were living in their own homes, 16% were in old people's homes. Older age, medical state before fracture and male gender was found to increase mortality risk following hip fracture (p<0.01). Hip fracture is a major cause of morbidity in older people and its impact, both on the individual and to society is substantial. Many people do not return to their pre-fracture life style. Coordinated multidisciplinary care of patients with fractured neck of femur seems essential.


Relevance of aromatic and polar amino acids in the specificity of Inulinase ISO3 from Kluyveromyces marxianus: A molecular dynamics approach with an experimental verification.
The Inulinase from Kluyveromyces marxianus ISO3 (Inu-ISO3) is an enzyme able to hydrolyze linear fructans such as chicory inulin as well as branched fructans like agavin. This enzyme was cloned and expressed in Komagataella pastoris to study the role of selected aromatic and polar residues in the catalytic pocket by Alanine scanning. Molecular dynamics (MD) simulations and enzyme kinetics analysis were performed to study the functional consequences of these amino acid substitutions. Site-directed mutagenesis was used to construct the mutants of the enzyme after carrying out the MD simulations between Inu-ISO3 and its substrates. Mutation Trp79:Ala resulted in the total loss of activity when fructans were used as substrates, while with sucrose, the activity decreased by 98 %. In contrast, the mutations Phe113:Ala and Gln236:Ala increased the invertase activity when sucrose was used as a substrate. Although these amino acids are not part of the conserved motifs where the catalytic triad is located, they are essential for the enzyme's activity. In silico and experimental approaches corroborate the relevance of these residues for substrate binding and their influence on enzymatic activity.


Impact of ambient air pollution on birth weight in Sydney, Australia.
Studies in Asia, Europe, and the Americas have provided evidence that ambient air pollution may have an adverse effect on birth weight, although results are not consistent. Average exposure during pregnancy to five common air pollutants was estimated for births in metropolitan Sydney between 1998 and 2000. The effects of pollutant exposure in the first, second, and third trimesters of pregnancy on risk of "small for gestational age" (SGA), and of pollutant exposure during pregnancy on birth weight were examined. There were 138,056 singleton births in Sydney between 1998 and 2000; 9.7% of babies (13,402) were classified as SGA. Air pollution levels in Sydney were found to be quite low. In linear regression models carbon monoxide and nitrogen dioxide concentrations in the second and third trimesters had a statistically significant adverse effect on birth weight. For a 1 part per million increase in mean carbon monoxide levels a reduction of 7 (95% CI -5 to 19) to 29 (95% CI 7 to 51) grams in birth weight was estimated. For a 1 part per billion increase in mean nitrogen dioxide levels a reduction of 1 (95% CI 0 to 2) to 34 (95% CI 24 to 43) grams in birth weight was estimated. Particulate matter (diameter less than ten microns) in the second trimester had a small statistically significant adverse effect on birth weight. For a 1 microgram per cubic metre increase in mean particulate matter levels a reduction of 4 grams (95% CI 3 to 6) in birth weight was estimated. These findings of an association between carbon monoxide, nitrogen dioxide, and particulate matter, and reduction in birth weight should be corroborated by further study.


[Endometriosis of the lung diagnosed with videothoracoscopy].
A case of non symptomatic pulmonary endometriosis appearing as multiple nodules on chest X ray and chest CT scan is reported. 43 year old woman was admitted to surgical department because of suspicion of neoplastic dissemination of unknown origin. Non invasive diagnostic procedures were not effective. Diagnosis of pulmonary endometriosis was established with thoracoscopy with lung sampling, confirmed with histopathologic evidence.


The Lepidoptera associated with forestry crop species in Brazil: a historical approach.
Despite the long history of forestry activity in Brazil and its importance to the national economy, there is still much disorder in the information regarding pests of forestry species. Considering the importance of the entomological knowledge for the viability of silvicultural management, this work aimed to gather information on the species of Lepidoptera associated with forestry crops within Brazil using a historical approach. Through a literature review, all registered species of Lepidoptera related to forestry crops in Brazil from 1896 to 2010 were identified. The historical evaluation was based on the comparison of the number of published articles, species richness, and community similarities of the Lepidoptera and their associated forest crops, grouped in 10-year samples. A total of 417 occurrences of Lepidoptera associated with forestry species were recorded, from which 84 species are related with 40 different forestry crops. The nocturnal Lepidoptera were dominant on the records, with Eacles imperialis magnifica Walker as the most frequent pest species cited. Myrtaceae was the most frequent plant family, with Cedrela fissilis as the most cited forestry crop species. A successional change in both Lepidoptera species and their host plants was observed over the decades. The richness of lepidopteran pest species increased over the years, unlike the richness of forestry crop species. This increase could be related to the inefficient enforcement of sanitary barriers, to the increase of monoculture areas, and to the adaptability of native pests to exotic forestry species used in monoculture stands.