Atmospheric transport of persistent organic pollutants (POPs) to Bjørnøya (Bear island).
A first medium term monitoring of atmospheric transport and distribution for persistent organic pollutants (POPs) in Bjørnøya (Bear island) air samples has been performed in the period between week 51/1999 and week 28/2003. A total of 50 single compounds consisting of polychlorinated biphenyls (33 congeners), hexachlorobenzene (HCB), hexachlorocyclohexane isomers (alpha-, beta-, gamma-HCH), alpha-endosulfan, cyclodiene pesticides (chlordanes, nonachlor-isomers, oxy-chlordane, heptachlor and chlordane) as well as dichlorodiphenyltrichloroethane (DDT) derivatives were analysed and quantified. Atmospheric transport of POPs was identified as an important contamination source for the island. PCBs, HCB and HCH isomers were the predominant POP groups, contributing with 70-90% to the overall POP burden quantified in the Bjørnøya air samples. The highest concentration levels for a single compound were found for HCB (25-35 pg m(-3)). However, the sum of 33 PCB congeners was found to be in the same concentration range (annual means between 15 and 30 pg m(-3)). Cyclodiene pesticides, DDT derivatives and alpha-endosulfan were identified as minor contaminants. Several atmospheric long-range transport episodes were identified and characterised. Indications for industrial emissions as well as agricultural sources were found for the respective atmospheric transport episodes. A first simple statistical correlation assessment showed that for long-range transport of pollution, the local meteorological situation is not as important as the air mass properties integrated over the time period of the transport event. The local weather situation, on the other hand, is important when investigating deposition rates and up-take/accumulation properties in the local ecosystem. Based upon chemical data interpretation, valuable information about the influence of primary and secondary sources on the air mass contamination with chlorinated insecticides (e.g., HCHs) was found and discussed. The interdisciplinary interpretation of contaminant data using statistical methods, chemical analysis, meteorological modelling and classical meteorological information for a comprehensive evaluation of atmospheric long range transport into the European Arctic (Bjørnøya) has proven to be a highly versatile tool not only for atmospheric scientists but also with strong potential for regulatory purposes.


Validation and Comparison of Accelerometers Worn on the Hip, Thigh, and Wrists for Measuring Physical Activity and Sedentary Behavior.
Recent evidence suggests that physical activity (PA) and sedentary behavior (SB) exert independent effects on health. Therefore, measurement methods that can accurately assess both constructs are needed. To compare the accuracy of accelerometers placed on the hip, thigh, and wrists, coupled with machine learning models, for measurement of PA intensity category (SB, light-intensity PA [LPA], and moderate- to vigorous-intensity PA [MVPA]) and breaks in SB. Forty young adults (21 female; age 22.0 ± 4.2 years) participated in a 90-minute semi-structured protocol, performing 13 activities (three sedentary, 10 non-sedentary) for 3-10 minutes each. Participants chose activity order, duration, and intensity. Direct observation (DO) was used as a criterion measure of PA intensity category, and transitions from SB to a non-sedentary activity were breaks in SB. Participants wore four accelerometers (right hip, right thigh, and both wrists), and a machine learning model was created for each accelerometer to predict PA intensity category. Sensitivity and specificity for PA intensity category classification were calculated and compared across accelerometers using repeated measures analysis of variance, and the number of breaks in SB was compared using repeated measures analysis of variance. Sensitivity and specificity values for the thigh-worn accelerometer were higher than for wrist- or hip-worn accelerometers, > 99% for all PA intensity categories. Sensitivity and specificity for the hip-worn accelerometer were 87-95% and 93-97%. The left wrist-worn accelerometer had sensitivities and specificities of > 97% for SB and LPA and 91-95% for MVPA, whereas the right wrist-worn accelerometer had sensitivities and specificities of 93-99% for SB and LPA but 67-84% for MVPA. The thigh-worn accelerometer had high accuracy for breaks in SB; all other accelerometers overestimated breaks in SB. Coupled with machine learning modeling, the thigh-worn accelerometer should be considered when objectively assessing PA and SB.


Role of Paraventricular Nucleus Glutamate Signaling in Regulation of HPA Axis Stress Responses.
The hypothalamus-pituitary-adrenal (HPA) axis is the main neuroendocrine arm of the stress response, activation of which leads to the production of glucocorticoid hormones. Glucocorticoids are steroid hormones that are secreted from the adrenal cortex, and have a variety of effects on the body, including modulation of the immune system, suppression of reproductive hormones maintenance of blood glucose levels, and maintenance of blood pressure. Glutamate plays an important role in coordination of HPA axis output. There is strong evidence that glutamate drives HPA axis stress responses through excitatory signaling via ionotropic glutamate receptor signaling. However, glutamate signaling via kainate receptors and group I metabotropic receptors inhibit HPA drive, probably via presynaptic inhibitory mechanisms. Notably, kainate receptors are also localized in the median eminence, and appear to play an excitatory role in control of CRH release at the nerve terminals. Finally, glutamate innervation of the PVN undergoes neuroplastic changes under conditions of chronic stress, and may be involved in sensitization of HPA axis responses. Altogether, the data suggest that glutamate plays a complex role in excitation of CRH neurons, acting at multiple levels to both drive HPA axis responses and limit over-activation.


Changes in burn scar contracture: utilization of a severity scale and predictor of return to duty for service members.
A medical records review of Operation Iraqi Freedom and Operation Enduring Freedom burn injury survivors admitted to the U.S. Army Institute of Surgical Research Burn Center from April 2003 to August 2005 was conducted. The study proposed the use of a newly developed scale, the Burn Scar Contracture Severity Scale, to potentially provide standardization in quantifying burn scar contracture severity. Changes in the active range of motion from in-patient discharge to out-patient follow-up of individuals with upper extremity burn injuries were compared. Changes in the impairment via American Medical Association impairment scores and perceived disability using the disabilities of the arm, shoulder, and hand questionnaire scores from the in-patient discharge to the out-patient follow-up were also compared. A weak, yet positive correlation (r = .417, .451, P ≤ .001) between the proposed scale and the disabilities of the arm, shoulder, and hand questionnaire and the American Medical Association impairment scores was found, respectively. A receiver operating characteristic curve analysis revealed a cut-off score of 6.5 for the burn scar contracture severity scale, indicating that individuals scoring below a 6.5 returned to duty and those scoring above 6.5 did not return to duty. Results suggest that the burn scar contracture severity scale is able to discriminate between the individuals who returned to duty and those who did not return to duty.


Low-Income Childless Adults' Access To Antidiabetic Drugs In Wisconsin Medicaid After Coverage Expansion.
Medicaid coverage was expanded for childless adults in Wisconsin through an amended Section 1115 demonstration waiver on April 1, 2014. Coverage for prescription drugs was expanded via copayment reductions and a drug formulary expansion. We analyzed administrative drug claims data to evaluate changes in the use of and out-of-pocket spending on antidiabetic drugs among childless adults who experienced the drug coverage expansion. Compared to parents or caretakers, who were not affected by the expansion, childless adults experienced a significant increase of 4 percent in the use of antidiabetic drugs-driven mainly by an increase in the population using the drugs, rather than by more intense use. The expanded drug coverage also reduced the burden of out-of-pocket spending for childless adults by 70 percent. Our findings demonstrate that expanding prescription drug benefits led to increased access to antidiabetic drugs for childless adults in Wisconsin Medicaid.


Identification of microRNAs in blood and urine as tumour markers for the detection of urinary bladder cancer.
Since differential expression of microRNAs (miRNAs) has been found to be highly associated with several types of cancer, the goal of the present study was to identify an miRNA fingerprint as a non‑invasive diagnostic tool to detect urinary bladder cancer using the easily accessible samples of whole blood and urine. Blood and urine samples from 4 controls and from patients suffering from superficial and invasive bladder cancer were analyzed using miRNA microarray consisting of 754 human miRNAs from the Sanger database v14. Using RT‑qPCR technique, 6 of the differentially expressed miRNAs were validated in the controls (20 blood, 19 urine samples) and patients with superficial (18 blood, 16 urine samples) or invasive (20 blood and urine samples each) tumours. Three blood miRNAs (miR‑26b‑5p, miR‑144‑5p, miR‑374‑5p) were found to be significantly upregulated in invasive bladder tumour patients (P<0.05) when compared to the control group. The expression of 2 miRNAs (miR‑618, miR‑1255b‑5p) in the urine of patients with invasive tumours was significantly (P<0.05) increased in comparison to the control group. Blood miR‑26b‑5p detected the presence of invasive bladder tumours with 94% specificity and 65% sensitivity. The urine miR‑1255b‑5p reached 68% specificity and 85% sensitivity in the diagnosis of invasive tumours. This pilot study represents the first characterization of an miRNA profile for urinary bladder tumours in whole blood samples. In addition, it was shown that invasive bladder tumours could be identified by differentially expressed urine miRNAs. Further studies are needed to test the clinical usefulness for bladder cancer detection and surveillance.


[Radiocrystallographic study of 46 salivary calculi. Physiopathogenic hypotheses (author's transl)].
The radiocrystallographic study of 46 salivary calculi using the Debye and Scherrer powder methods showed that such stones, whether submaxillary, parotid or "accessory" consist essentially of hydroxyapatite with the frequent presence of tricalcium and octocalcium phosphates, Whitlockite and rarely Brushite and Calcite. In order for a stone to form, the following conditions would seem to be necessary; transient supersaturation of the saliva in Ca++ and PO4--, a pH greater than normal, intracellular precepitation of amorphous tricalcium phosphate which is transformed into crystalline hydroxyapatite and, then, the fixation of crystals on a "matrix" such as desquamated cells, fibrils and collagens.


[Placebo and nocebo : How can they be used or avoided?]
The expectations of patients enhance the probability of their occurrence and are thereby the main triggers for inducing placebo and nocebo responses. Strong placebo effects are not only regularly observed in pharmaceutical and non-pharmaceutical sham treatment in placebo controlled studies but also make a considerable contribution to any real treatment. The accompanying words are essential to ensure maximum impact of drugs and other forms of treatment. They should contain positive expressions instead of negations. Such a strengthening of drug therapy by placebo effects is more important than the widespread use of placebos that remains a problem because of the obligation to provide information and effective therapy and because of inherently induced side effects. Any false comments about symptoms or side effects can aggravate or induce them. Nocebo effects are not imagined but real symptoms that can definitely be harmful. They constitute a considerable proportion of the side effects requiring treatment. Awareness and knowledge is needed to prevent or neutralize them. Nocebo effects are avoidable when risk information is always directly combined with positive aspects, such as the expected benefits of the treatment or the prophylactic measures and therapeutic options for side effects. Existing negative expectations are disrupted by providing more alternative options and by leaving negative experiences in the past where they belong. Placebo and nocebo effects are strongly sensitive to the context. They are dependent on the experiences and conceptions of the individual patient, as well as on the physician-patient relationship. The latter can provide the best protection against harm from risk disclosure. In addition, the expectations of patients and their consequences are strongly affected by the expectations of the treating doctor, by fellow patients, the media and society.


Anxiety and depression symptoms among gas and oil industry workers.
Oil and gas industry workers appear to suffer from anxiety and depression more frequently than the general population. To establish the prevalence of depression and anxiety symptoms among offshore workers working for an oil and gas company and to identify the main stressors that lead to symptoms of these disorders. One thousand seven hundred and forty-seven workers employed in an offshore oil and gas company in the Middle East completed the Generalized Anxiety Disorder (GAD-7) and Patient Health (PHQ-9) questionnaires. Anxiety and depressive symptoms were estimated from these surveys. Anxiety and depression symptoms were reported by nearly 15% of workers surveyed. Ordered logistic regression analyses showed that age, rotation length, years of service and local origin (versus expatriate) were significant predictors for symptoms of anxiety. With adjustment for age, older local workers had a lower risk of anxiety symptoms than expatriates. Younger workers, workers with longer rotations and those with fewer years of service were more likely to report anxiety symptoms. In addition, older local workers and expatriates had a lower prevalence of anxiety symptoms than younger local workers. Future recommendations should address improvements in psychological health of offshore workers in the gas and oil industries.


Clinical trials in nutrition.
Trials of nutritional intervention in a wide range of health and disease states, preventive and therapeutic, are required. Not only has the emergence of chronic non-communicable disease (CNCD) with acknowledged nutritional pathogenesis created this imperative need, but so also have other conditions which, previously, had not been regarded as nutritionally based. Among the latter are health problems associated with ageing: the menopause, a decline in immune function, and a decline in cognitive function. At the same time, there is a new set of materno-foetal and infant nutrition issues for investigation which relate to new food exposures and the long-term effects of nutritionally mediated gene expression. The emergence of the new food science of phytochemicals with human biological importance also sets the scene for their evaluation in traditional diets and novel foods. Such trials are more complex than comparable pharmacotherapeutic studies because of the complexity of food chemistry, as well as the food behavioural changes which may accompany a nutritional intervention, and the general problem of there not being a 'gold standard' for food intake methodology. Choice of study population is also a key issue in relation to the extrapolation of findings from a particular trial, with population representativeness being an advantage. In order to obtain useful information on manageable sample sizes, either intermediate end-points (short of morbidity and mortality) need to be studied or high-risk groups (such as the aged) need to be recruited. There are some unique ethical issues which must inform clinical nutrition trials. These include certain preventive imperatives like the right to be fed, the risks in disruption of food cultures and the need for food security and sustainability. Rapid changes in the food supply do, however, make such trials more important, while the value of food-health knowledge that cannot be obtained by trial must still be appreciated.


Comparison of peripheral nerve damages according to glucose control timing in experimental diabetes.
In addition to tight glucose control, early intensive therapy has been reported to be more important for the prevention of diabetic micro- and macro-vascular complications. What is not known exactly is the quantitative difference according to timing delay in glucose control and whether early period control is really better than late control in terms of diabetic peripheral neuropathy. In this study, we investigated the effect of timing differences in glucose control on the peripheral nerves in an experimental diabetic model. 5 groups (6-8 rats in each group) were comprised of normal glucose rats (designated control), rats with hyperglycemia (designated DM), rats with glucose control for the entire 28-week study period (designated DM + INS [W0-28]), rats with glucose control for the early 14-week period followed by hyperglycemia for the late 14-week period (designated DM + INS [W0-14]), and rats with hyperglycemia for the early 14-week period followed by glucose control in the late 14-week period (designated DM + INS [W15-28]). We found that the current perception threshold (CPT) was lower in the DM + INS (W0-28) and DM + INS (W15-28) groups than in the DM + INS (W0-14) or DM groups (P<0.05). The mean myelinated fiber area of the sciatic nerve was significantly greater in the DM + INS (W0-28) and DM + INS (W15-28) groups (63.5±2.32 and 60.1±2.14 um, respectively) than in the DM + INS (W0-14) or DM groups (55.5±2.81 or 51.5±2.64 um, respectively) (P<0.05), and the intraepidermal nerve fiber (IENF) density was significantly higher in the DM + INS (W0-28) and DM + INS (W15-28) groups (6.9±0.46 and 6.8±0.11, respectively) than in the DM + INS (W0-14) or DM groups (59.5±0.32 and 5.3±0.39/mm, respectively) (P<0.05). Our results indicate that continuous glucose control is necessary to alleviate peripheral nerve damage and that glycemic control during the later period may be more important than early period management. The importance of continuous glucose control, including the later period of diabetes, should therefore be emphasized in diabetic peripheral neuropathy.


Exposure artifacts in raster scanned equalization radiography.
The image artifacts characteristic of a scanning chest radiographic system are reviewed. The technique employs a pulsed beam of radiation swept in an overlapping raster pattern that can result in severe ripple and scan line artifacts with improper scanning parameters. A one-dimensional treatment of the scanner geometry shows that the artifacts can be eliminated when the beam width is an integral multiple of interpulse spacing. An extension to a two-dimensional analysis indicates that with the collimator geometries employed, artifact-free images are not possible with a fixed x-ray frequency but can be achieved when a variable frequency source is used. A treatment of the sensitivity for artifact formation shows that with proper choice of scanning parameters sizable errors in beam width can be tolerated without significant artifact formation.


Multiple nevoid basal cell carcinoma syndrome and Hodgkin's disease.
A patient with nodular sclerosing Hodgkin's disease and basal cell carcinoma syndrome is reported. Medulloblastoma and ovarian fibromas have already been associated with the syndrome and its coexistence with other malignant neoplasms has been described. The authors report here the first case of Hodgkin's disease with the multiple nevoid basal cell carcinoma syndrome. The fact that the patient's mother also has the syndrome, and the maternal grandfather had Hodgkin's disease seems to indicate more than a chance association of two independent events.


Probing the Aggregation and Immune Response of Human Islet Amyloid Polypeptides with Ligand-Stabilized Gold Nanoparticles.
The use of nanomaterials has recently become an emerging strategy against protein amyloidosis associated with a range of metabolic and brain diseases. To facilitate research in this area, here we first demonstrated the use of hyperspectral imaging (HSI) and COMSOL simulations for reporting the aggregation of human islet amyloid polypeptides (IAPPs), a hallmark of type 2 diabetes, as well as the physical interactions between the peptide and gold nanoparticles (AuNPs) grafted with citrate and poly(ethylene glycol) (PEG400 and PEG3000). We found a distinct anticorrelation between increased IAPP aggregation and decreased spectral red shifts incurred in the AuNP plasmonic resonance. Moreover, Jurkat cells exposed to IAPP and AuNPs were characterized by quantifying their cytokine secretions with a localized surface plasmon resonance (LSPR) immunoassay, where a peak response was registered for the most toxic IAPP oligomers and most suppressed by citrate-coated AuNPs. This study demonstrated the potential of using HSI and LSPR as two new platforms for the facile examination of protein aggregation and their induced immune response associated with amyloid diseases.


Exploiting Exosomes in Cancer Liquid Biopsies and Drug Delivery.
Exosomes are cell-derived nanovesicles that transfer molecular cargo from donor to recipient cells and mediate intercellular communication. Advancement in elucidating the biological capabilities and functionalities of exosomes has revealed the striking roles of exosomes as conveyors of bioactive molecules across the biological barriers. Tumor-derived exosomes hold great promise to serve as a liquid biopsy tool for cancer diagnosis and prognosis, as large quantities of exosomes are excreted by tumor cells continuously into the circulation, carrying the molecular cargo (DNA, RNA, proteins) reflective of the genetic and signaling alterations in tumor cells. Two inherent characteristics of exosomes offer important opportunities for drug delivery: their superb transcellular permeability and biocompatibility. Exosomes are uniquely capable of encapsulating a variety of payloads and deliver them to the target tissues. This review discusses the potential of tumor-derived exosomes in cancer liquid biopsies as well as the underlying mechanisms. Furthermore, the recent progress of developing exosomes as highly versatile and efficient drug carriers is also summarized.


The POTRA domains of Toc75 exhibit chaperone-like function to facilitate import into chloroplasts.
Protein trafficking across membranes is an essential function in cells; however, the exact mechanism for how this occurs is not well understood. In the endosymbionts, mitochondria and chloroplasts, the vast majority of proteins are synthesized in the cytoplasm as preproteins and then imported into the organelles via specialized machineries. In chloroplasts, protein import is accomplished by the TOC (translocon on the outer chloroplast membrane) and TIC (translocon on the inner chloroplast membrane) machineries in the outer and inner envelope membranes, respectively. TOC mediates initial recognition of preproteins at the outer membrane and includes a core membrane channel, Toc75, and two receptor proteins, Toc33/34 and Toc159, each containing GTPase domains that control preprotein binding and translocation. Toc75 is predicted to have a β-barrel fold consisting of an N-terminal intermembrane space (IMS) domain and a C-terminal 16-stranded β-barrel domain. Here we report the crystal structure of the N-terminal IMS domain of Toc75 from Arabidopsis thaliana, revealing three tandem polypeptide transport-associated (POTRA) domains, with POTRA2 containing an additional elongated helix not observed previously in other POTRA domains. Functional studies show an interaction with the preprotein, preSSU, which is mediated through POTRA2-3. POTRA2-3 also was found to have chaperone-like activity in an insulin aggregation assay, which we propose facilitates preprotein import. Our data suggest a model in which the POTRA domains serve as a binding site for the preprotein as it emerges from the Toc75 channel and provide a chaperone-like activity to prevent misfolding or aggregation as the preprotein traverses the intermembrane space.


Effects of single and combined infusions of human biosynthetic proinsulin and insulin on glucose metabolism and on plasma hormone concentrations in euglycaemic clamp experiments.
Euglycaemic clamp experiments with single or combined infusions of human biosynthetic proinsulin and insulin were performed in 6 healthy, normal weight subjects in order to assess the possibility of antagonistic, additive, or synergistic effects on whole body glucose metabolism. Insulin (i: 2.02 pmol x kg-1 x min-1) or proinsulin (p: 9.26 pmol x kg-1 x min-1) were infused under euglycaemic clamp conditions over 240 min. After 120 min, the infusion rates were doubled (protocols ii and pp), or proinsulin (protocol ip) or insulin (protocol pi) infusions were added. After 240 min of infusing insulin or proinsulin alone, euglycaemia was maintained for an additional 60 min period without hormone infusions to measure the decay of hormone concentrations and of effects on glucose metabolism. Effects on glucose uptake were measured as the glucose infusion rate necessary to maintain euglycaemia. IR-insulin, IR-proinsulin, IR-C-peptide and IR-glucagon were determined by specific radioimmunoassays. After 240 min, similar steady state glucose infusion rates were reached for all protocols (mean +/- SEM, mg x kg-1 x min-1: ii: 10.6 +/- 1.0; ip: 9.1 +/- 0.4; pi: 10.0 +/- 0.9; pp: 8.4 +/- 0.7). The infusion rate with proinsulin alone (pp), however, was significantly smaller than with insulin alone (ii), indicating a somewhat lower effectiveness of the proinsulin dose employed. With all protocols, nonesterified fatty acid and IR-glucagon concentrations were decreased to a similar extent. Steady state hormone concentrations were reached within 30 min of each infusion period.(ABSTRACT TRUNCATED AT 250 WORDS)


Simple access to highly functional bicyclic γ- and δ-lactams: origins of chirality transfer to contiguous tertiary/quaternary stereocenters assessed by DFT.
This paper describes the synthesis of both polysubstituted oxazolo-pyrrolidinones and -piperidinones by a domino process. The methodology is based on the reaction between hydroxyl halogenoamides and Michael acceptors, which leads efficiently to bicyclic lactams. The process is compatible with unsymmetrical electron-withdrawing groups on the Michael acceptor, which allows the formation of two contiguous and fully controlled tertiary and quaternary stereocenters. In the case of tetrasubstituted Michael acceptors, two adjacent quaternary stereocenters are formed in good yield. Starting from (R)-phenylglycinol derived amides results in the formation of enantioenriched bicyclic lactams in low to good yields and with high levels of stereoselectivity, thus greatly increasing the scope and interest of this strategy. The origins of chirality transfer and diastereoselectivity were studied by DFT calculations and have been attributed to a kinetic control in one of the last two steps of the reaction sequence. This selectivity is dependent upon both the substituents on the Michael acceptor and the sodium cation chelation.


Cytotoxicity of cortivazol in childhood acute lymphoblastic leukemia.
Glucocorticoids are the most important group of drugs used in the treatment of childhood acute lymphoblastic leukemia (ALL), however, resistance to this group remains the main obstacle in curing the disease. One of the possibilities to circumvent glucocorticoid resistance is the use of new compounds, such as cortivazol (CVZ), which has two binding sites for the glucocorticoid receptor. Analysis of ex vivo sensitivity to cortivazol and other glucocorticoids in childhood acute lymphoblastic leukemia, as well as the relationship to anticancer therapy outcome. Leukemic samples from 60 children with ALL were tested by the M7T assay for glucocorticoid resistance. Cell cycle before and after ex vivo glucocorticoid treatment was analyzed by flow cytometry. Although all tested glucocorticoids presented significant cross-resistance, CVZ showed high antileukemic activity. The equivalent activity of CVZ was 165-fold higher than prednisolone, 7.ZS5-fold higher than dexamethasone and 2.8-fold higher than betamethasone. CVZ showed relatively better cytotoxicity than other glucocorticoids in prednisolone-poor-responders. CVZ, like other glucocorticoids, caused cell cycle arrest in the GI-phase, and increased the percentage of apoptotic cells to a greater extent than other glucocorticoids. The results of antileukemic therapy were strongly related to the ex vivo resistance to all tested glucocorticoids. Cortivazol has potent antileukemic activity in childhood ALL. Its activity is related to cell cycle arrest and induction of apoptosis.


Interleukin-1β and tumor necrosis factor-α increase stiffness and impair contractile function of articular chondrocytes.
Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are major proinflammatory cytokines involved in osteoarthritis (OA). These cytokines disturb chondrocyte metabolism by suppressing the synthesis of extracellular matrix proteins and stimulating the release of catabolic proteases, but little is known about their role in chondrocyte mechanics. Thus, the aim of this study was to measure the effects of IL-1β and TNF-α on the mechanical properties of the chondrocytes. Chondrocytes from goat knee joints were cultured in 96-well plates. The cellular stiffness and contractile function were probed using optical magnetic twisting cytometry, the cytoskeleton and the expression of extracellular matrix proteins were visualized using immunofluorescent staining, and chondrocyte phenotypical expression was measured by western blot analysis. Results showed that chondrocyte stiffness was dramatically decreased by disruption of F-actin but was unaffected by disruption of the intermediate filament vimentin. Treatment with 10 ng/ml IL-1β or 40 ng/ml TNF-α for 24 h substantially increased the expression level of F-actin and cellular stiffness, and impaired cell stiffening in response to the contractile agonist histamine, but these effects were blocked by the Rho-associated protein kinase inhibitor Y27632. In conclusion, IL-1β and TNF-α substantially change the mechanical properties of the chondrocytes in vitro. While changes of chondrocyte mechanics in vivo during OA progression remain unclear, this finding reveals a prominent role of these cytokines in cellular mechanics and provides insight for anti-cytokine therapies of OA.


Clinical Trials in the Genomic Era.
Personalization of therapy to target specific molecular pathways has been placed in the forefront of cancer research. Initial reports from clinical trials designed to select patients for appropriate treatment on the basis of tumor characteristics not only have generated considerable excitement but also have identified several challenges. These challenges include the overcoming of regulatory and logistic difficulties, identification of the best selection biomarkers and diagnostic platforms that can be applied in the clinical setting, definition of relevant outcomes in small preselected patient populations, and the design of methods that facilitate rapid enrollment and interpretation of clinical trials by aggregating data across histologically diverse malignancies with common genetic alterations. Furthermore, because our knowledge of the functional consequences of many genetic alterations lags, investigators and sponsors struggle with choosing between ideal clinical trial designs and more practical ones. These challenges are amplified when more than one biomarker is used to select patients for a combination of targeted agents. This review summarizes the current status and challenges of clinical trials in the genomic era and proposes ways to address these challenges.


The Impact of Gender Stereotypes on the Self-Concept of Female Students in STEM Subjects with an Under-Representation of Females.
It's possible to assume that women who study STEM topics with a low proportion of females have successfully overcome barriers in school and the family, making them less prone to stereotypic views, and influences. The present study focuses on these kinds of factors and analyzes to which degree family factors, school-related factors, and individual stereotypes may influence a woman's academic self-concept. The following study presents a latent regression model which is based on a survey of 296 women from different German universities, all of whom are part of STEM programs of study that have <30% females. It was investigated to which degree individual stereotypes, support in school, and family support contribute to the self-concept in STEM. Gender stereotypes were negatively related to students' STEM-specific self-concept in the selected sample. This study also reveals negative family-related influences that lower a woman's self-concept. Positive predictors on the other hand included school aspects that are found in the students' favorite subjects at school. The results of the study provide important aspects for STEM education. Even though the students participating in the study presumably had good grades in STEM, stereotypes still corrupted their self-concept. One of the reasons for this might lie in stereotypes that attribute girls' achievements to diligence instead of talent. The results also point out that direct support, particularly by parents, can have a negative impact on female students' self-concept. Activities that are meant to support pupils directly may actually backfire and transport stereotypes instead. This stresses the need for indirect support during socialization, e.g., by providing opportunities for children to have positive experiences or by giving them the chance to meet role models that are enthusiastic about their STEM professions. These kinds of measures have the potential to spur students' interest in STEM subjects-something that in the present study proved to be especially beneficial for women's positive self-concept when studying STEM topics.


The effect of respiratory immunization on cell-mediated immune effector cells of the lung.
In order to understand the mechanisms of cellular immune injury in hypersensitivity pneumonitis, the effect of type of antigen on cell-mediated immunity in guinea-pigs receiving respiratory immunization was studied. Lymphocytes obtained by pulmonary lavage were compared with those from peritoneal exudate following immunization with either a soluble protein, human serum albumin, or a particulate suspension of Thermoactinomyces vulgaris. Assays were obtained without mixing cells from these two sources. Statistically significant increases (13-22%) in the number of alveolar rosette-forming cells (RFC) were found in the animals immunized with either antigen, but only the particulate T. vulgaris was also capable of inducing a systemic increase of such cells. That this increase in RFC could be due to specifically reactive lymphocytes was demonstrated by the production of antigen-stimulated macrophage migration inhibition. Some evidence was obtained that indicated that T. vulgaris could act both as a non-specific B-cell stimulant and a specific T-cell activator. The concept of a hypothetical pulmonary 'barrier' is discussed which must be overcome to induce systemic immune responses following respiratory immunization. T. vulgaris must be added to the list of known agents or means for overcoming this 'barrier'.


[Mathematical model for epidemiologic survey of the cardiorespiratory fitness without effort test].
Develop models to estimate the cardiopulmonary fitness without the effort test accomplishment, focusing an epidemiologic survey in young Brazilians. For that purpose, 243 volunteers were evaluated: 137 men (25 ,4 +/-6,39 years old) and 106 women (23,68+/-5,23 years old). The volunteers were randomized into two groups (Group 1 : control - with 81 men and 58 women; and Group 2 : cross-validation - with 56 men and 48 women), submitted to cardiopulmonary effort tests with direct gas analysis. The models were developed through multiple regression , applying the stepwise method, followed by the ANOVA One-Way analysis as Tukey's Post Hoc test to compare the averages. The average of the maximum oxygen consumption in Group 1 was 48 ,45 +/-11,91 ml/kg.min -1 and in Group 2 was 46,54+/-9,89 ml/kg.min -1 . The multiple regression lines had described two models to estimate the maximum oxygen consumption with the following average values: model 1 =48 ,46 +/-11,41 and model 2=46,83+/-11.11 ml/kg.min -1 . No important difference was observed for the effort value. The average results of the maximum oxygen consumption estimated for Group 2 model 1=48 ,14 +/-10,74 ml/kg.min -1 and model 2 =46,59+/-10,36 ml/kg.min -1 were not significantly different from the values observed in the effort test. the models for estimating the maximum oxygen consumption demonstrated good applicability in the epidemiologic survey for young Brazilians.


Rhinovirus-bacteria coexposure synergistically induces CCL20 production from human bronchial epithelial cells.
Exacerbations of chronic obstructive pulmonary disease are triggered by viral or bacterial pathogens, with human rhinovirus (HRV) and nontypeable Hemophilus influenzae (NTHI) among the most commonly detected pathogens. Patients who suffer from concomitant viral and bacterial infection have more severe exacerbations. The airway epithelial cell is the initial site of viral and bacterial interactions, and CCL20 is an epithelial chemokine that attracts immature dendritic cells to the airways and can act as an antimicrobial. As such, it contributes to innate and adaptive immune responses to infection. We used primary cultures of human bronchial epithelial cells and the BEAS-2B cell line to examine the effects of bacterial-viral coexposure, as well as each stimulus alone, on epithelial expression of CXCL8 and, in particular, CCL20. HRV-bacterial coexposure induced synergistic production of CXCL8 and CCL20 compared with the sum of each stimulus alone. Synergistic induction of CCL20 did not require viral replication and occurred with two different HRV serotypes that use different viral receptors. Synergy was also seen with either NTHI or Pseudomonas aeruginosa Synergistic induction of CCL20 was transcriptionally regulated. Although NF-κB was required for transcription, it did not regulate synergy, but NF-IL-6 did appear to contribute. Among MAPK inhibitors studied, neither SB203580 nor PD98059 had any effect on synergy, whereas U0126 prevented synergistic induction of CCL20 by HRV and bacteria, apparently via "off-target" effects. Thus bacterial-viral coexposure synergistically increases innate immune responses compared with individual infections. We speculate that this increased inflammatory response leads to worse clinical outcomes.


Detection of pentylenetetrazol-induced seizure activity in the 19-21 Hz beta range using a magnetic coil induction method.
A force transducer or automatic scoring system is not sufficient to detect small or fine seizure activity. To improve previous assessments of epileptic behavior, a novel coil method was developed to detect an early behavioral marker for epileptic seizures. The present study used the γ-aminobutyric acid (GABA) receptor antagonist pentylenetetrazol (PTZ) to induce seizure activity and epileptic behavior in mice. A coil method was used to detect motor seizures consisting of small amplitude 19-21 Hz muscle contractions. Seizure activity in the 19-21 Hz range detected by the coil method was positively correlated with generalized clonic seizures with a kangaroo posture after PTZ administration. GABA receptor agonist valproic acid and ethosuximide decreased PTZ-induced 19-21 Hz seizure activity. The pattern of the amplitude ratio (%) of 19-21 Hz seizure activity after administration of the GABAA/C receptor antagonist picrotoxin was similar to the group that was treated with PTZ but different from the group that was treated with the nonselective muscarinic receptor agonist pilocarpine. The coil method detected 19-21 Hz seizure activity after PTZ administration. However, the force transducer method did not detect 19-21 Hz seizure activity. The coil method was more sensitive than the force transducer method for detecting epileptic behaviors. The findings may indicate a novel behavioral marker that can be detected by the coil method to reveal epileptic seizures, thus improving our understanding of the brain mechanisms of action and specific brain waves that are associated with PTZ-induced 19-21 Hz seizure activity.


Exploring parasite heterogeneity using single-cell RNA-seq reveals a gene signature among sexual stage Plasmodium falciparum parasites.
The malaria parasite has a complex lifecycle, including several events of differentiation and stage progression, while actively evading immunity in both its mosquito and human hosts. Important parasite gene expression and regulation during these events remain hidden in rare populations of cells. Here, we combine a capillary-based platform for cell isolation with single-cell RNA-sequencing to transcriptionally profile 165 single infected red blood cells (iRBCs) during the intra-erythrocytic developmental cycle (IDC). Unbiased analyses of single-cell data grouped the cells into eight transcriptional states during IDC. Interestingly, we uncovered a gene signature from the single iRBC analyses that can successfully discriminate between developing asexual and sexual stage parasites at cellular resolution, and we verify five, previously undefined, gametocyte stage specific genes. Moreover, we show the capacity of detecting expressed genes from the variable gene families in single parasites, despite the sparse nature of data. In total, the single parasite transcriptomics holds promise for molecular dissection of rare parasite phenotypes throughout the malaria lifecycle.


Sleep and somatic complaints in university students.
Sleep problems are common among university students. Poor sleep is associated with impaired daily functioning, increased risk of psychiatric symptoms, and somatic complaints such as pain. Previous results suggest that poor sleep exacerbates pain, which in turn negatively affects sleep. The purpose of the present study was to determine prevalence rates, comorbidity, and role of depression as a factor of moderating the relationship between sleep and physical complaints in German university students. In total, 2443 German university students (65% women) completed a web survey. Self-report measures included the Pittsburg Sleep Quality Index, three modules of the Patient Health Questionnaire, and a questionnaire on the functional somatic syndromes (FSSs). More than one-third (36.9%) reported poor sleep as assessed by the Pittsburgh Sleep Quality Index. Somatoform syndrome was identified in 23.5%, and the prevalence of any FSS was 12.8%. Self-reported sleep quality, sleep onset latency, sleep disturbances, use of sleep medications, and daytime dysfunctioning were significant predictors of somatoform syndrome, whereas sleep efficiency and sleep duration influenced somatic complaints indirectly. Moderate correlations were found between stress, anxiety, somatoform syndrome, depression, and overall sleep quality. The effect of somatic complaints on sleep quality was associated with the severity of depression. Anxiety shows direct effects on somatization and depression but only indirect associations with sleep quality.


An ethA mutation in Bacillus subtilis 168 permits induction of sporulation by ethionine and increases DNA modification of bacteriophage phi 105.
In contrast to Escherichia coli and Salmonella typhimurium, Bacillus subtilis could convert ethionine to S-adenosylethionine (SAE), as can Saccharomyces cerevisiae. This conversion was essential for growth inhibition by ethionine because metE mutants which were deficient in S-adenosylmethionine synthetase activity, were resistant to 10 mM ethionine and converted only a small amount of ethionine to SAE. Another mutation (ethA1) produced partial resistance to ethionine (2 mM) and enabled continual sporulation in glucose medium containing 4 mM DL-ethionine. This sporulation induction probably resulted from the effect of SAE, since it was abolished by the addition of a metE1 mutation. The induction of sporulation was not simply controlled by the ratio of SAE to S-adenosylmethionine, but apparently depended on another effect of the ethA1 mutation, which could be demonstrated by comparing the restriction of clear plaque mutants of bacteriophage phi 105 grown in an ethA1 strain with the restriction of those grown in the standard strain. The phages grown in the ethA1 strain showed increased protection against BsuR restriction. We propose that SAE induces sporulation through the inhibition of a key methylation reaction.


Current hypospadias management: Diagnosis, surgical management, and long-term patient-centred outcomes.
In this article, we present the current approach to hypospadias, a review of the classification, preoperative evaluation, and factors that enable decision-making during surgery. We will then discuss patient-reported outcomes, evaluating the patients' and parents' perspectives regarding hypospadias repair.


Nasal polyposis in the laryngectomee.
We report the cases of two laryngectomy patients who were diagnosed with de novo nasal polyposis, more than 15 years after their laryngectomies. This phenomenon has not previously been reported in the literature. We discuss the changes in nasal physiology of the laryngectomy patient, with regards to the aetiology of polyp formation, and highlight the importance of examining the nose in such patients.


Specific isolation of N-terminal fragments from proteins and their high-fidelity de novo sequencing.
A new method to determine N-terminal amino acid sequences of multiple proteins at low pmol level by a parallel processing has been developed. The method contains the following five steps: (1) reduction, S-alkylation and guanidination for targeted proteins; (2) coupling with sulfosucccimidyl-2-(biotinamido)ethyl-1,3-dithiopropionate(sulfo-NHS-SS-biotin) to N(alpha)-amino groups of proteins; (3) digestion of the modified proteins by an appropriate protease; (4) specific isolation of N-terminal fragments of proteins by affinity capture using the biotin-avidin system; (5) de novo sequence analysis of peptides by MALDI-TOF-/MALDI-TOF-PSD mass spectrometry with effective utilization of the CAF (chemically assisted fragmentation) method.1 This method is also effective for N-terminal sequencing of each protein in a mixture of several proteins, and for sequencing components of a multiprotein complex. It is expected to become an essential proteomics tool for identifying proteins, especially when used in combination with a C-terminal sequencing method.


A new method of identifying the site of tyrosyl radicals in proteins.
Protein-bound tyrosyl radicals catalyze many important enzymatic reactions. They can also initiate oxidative damage to cells. Here we report a new method of computer simulation of tyrosyl radical electron paramagnetic resonance spectra. The method enables the determination of the rotational conformation of the phenoxyl ring in a radical with unprecedented accuracy (approximately 2 degrees ). When coupled with a new online database, all tyrosine residues in a protein can be screened for that particular conformation. For the first time we show relationships between the spin density on atom C1 (rho(C1)) and the principal g-factors measured by electron paramagnetic resonance spectroscopy (rho(C1) on g(x) is shown to be linear). The new method enables the accurate determination of rho(C1) in all known tyrosyl radicals, evaluates the likelihood of a hydrogen bond, and determines the possibility of a rho(C1) distribution in the radicals. This information, together with the accurately determined rotational conformation, is frequently sufficient to allow for an unambiguous identification of the site of radical formation. The possibility of a similar relationship between rho(C) and g(x) in other radicals, e.g., tryptophanyl, is discussed.


Metabolic processes of Methanococcus maripaludis and potential applications.
Methanococcus maripaludis is a rapidly growing, fully sequenced, genetically tractable model organism among hydrogenotrophic methanogens. It has the ability to convert CO2 and H2 into a useful cleaner energy fuel (CH4). In fact, this conversion enhances in the presence of free nitrogen as the sole nitrogen source due to prolonged cell growth. Given the global importance of GHG emissions and climate change, diazotrophy can be attractive for carbon capture and utilization applications from appropriately treated flue gases, where surplus hydrogen is available from renewable electricity sources. In addition, M. maripaludis can be engineered to produce other useful products such as terpenoids, hydrogen, methanol, etc. M. maripaludis with its unique abilities has the potential to be a workhorse like Escherichia coli and S. cerevisiae for fundamental and experimental biotechnology studies. More than 100 experimental studies have explored different specific aspects of the biochemistry and genetics of CO2 and N2 fixation by M. maripaludis. Its genome-scale metabolic model (iMM518) also exists to study genetic perturbations and complex biological interactions. However, a comprehensive review describing its cell structure, metabolic processes, and methanogenesis is still lacking in the literature. This review fills this crucial gap. Specifically, it integrates distributed information from the literature to provide a complete and detailed view for metabolic processes such as acetyl-CoA synthesis, pyruvate synthesis, glycolysis/gluconeogenesis, reductive tricarboxylic acid (RTCA) cycle, non-oxidative pentose phosphate pathway (NOPPP), nitrogen metabolism, amino acid metabolism, and nucleotide biosynthesis. It discusses energy production via methanogenesis and its relation to metabolism. Furthermore, it reviews taxonomy, cell structure, culture/storage conditions, molecular biology tools, genome-scale models, and potential industrial and environmental applications. Through the discussion, it develops new insights and hypotheses from experimental and modeling observations, and identifies opportunities for further research and applications.


PCSK9 Promotes oxLDL-Induced PC12 Cell Apoptosis Through the Bcl-2/Bax-Caspase 9/3 Signaling Pathway.
Hyperlipidemia is a risk factor for neurodegenerative diseases. Proprotein convertase subtilisin / Kexin type 9 (PCSK9) degrades hepatic low-density lipoprotein receptor (LDLR) to regulate lipid metabolism. It is unclear if PCSK9 plays a role in neurodegenerative diseases. This study was designed to determine whether PCSK9 is crucial between hyperlipidemia and Alzheimer's disease. The interrelationship between PCSK9 and neuronal apoptosis was explored in PC12 cells in response to treatment with oxidized low-density lipoprotein (oxLDL). Cultured PC12 cells were serum-starved and incubated with different concentrations of oxLDL for 24 h. Intracytoplasmic lipid droplets were observed by oil red O staining. Morphological assessment of apoptotic cells was performed using Hoechst 33258 staining and flow cytometry analysis. The expression of mRNA and protein was detected by reverse-transcription polymerase chain reaction (RT-PCR) and western blot analyses, respectively. Transfection of small interfering RNA (siRNA) into PC12 cells was conducted using HiperFect Transfection Reagent. Concentrations of Aβ40 and Aβ42 were detected by enzyme-linked immunosorbent assay (ELISA) kit. Intracellular lipid content, the number of apoptotic cells, and PCSK9 expression were increased in PC12 cells after oxLDL treatment. Transfection with PCSK9 siRNA reduced the oxLDL-induced apoptosis of PC12 cells. We further confirmed the involvement of Bcl-2/Bax-Caspase (9, 3) signaling pathway in the regulation of PC12 cells apoptosis.β-Secretase 1, another target gene of PCSK9, was downregulated in PC12 cells in response to oxLDL treatment. Aβ40 and Aβ42 contents were also decreased. PCSK9 promotes oxLDL-induced PC12 cell apoptosis through the Bcl-2/Bax-Caspase 9/3 signaling pathway.


Prognosis and management strategies of lymphatic neoplasias in the elderly. I. Aggressive non-Hodgkin's lymphomas.
Lymphomas belong to the class of malignant diseases with the fastest increasing incidence. High-grade non-Hodgkin's lymphomas (NHL) display a peak of incidence in the age group above 65. In the last few years, age has been recognized as a major risk factor for overall survival of high-grade NHL patients, and numerous attempts have been made to analyze the contribution of factors to the age-related worsening of prognosis in this disease, e.g. the biology of the disease on the one hand, and age-specific comorbidity or degree of cytotoxicity, reluctance in diagnosis and treatment and socioeconomic factors on the other. Furthermore, age-adapted treatment protocols have been designed and tested for their practicability and efficacy in the elderly. Very recently, large randomized prospective clinical trials have been carried out which support the idea that treatment with a curative intent is warranted even in the very elderly and that a successful attempt to cure requires the use of full-dose anthracycline-containing regimens closely similar to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). In addition, progress has been made in systematically defining maximally tolerated doses of the cytotoxic drugs and in specifically testing anthracyclines with reduced cardiotoxicity with an efficacy similar to that of doxorubicin, and further in investigating the advantage of applying hematopoietic growth factors and/or cardioprotective drugs in this older population. In limited stages of disease, three cycles of CHOP chemotherapy followed by involved field irradiation may be superior to radiotherapy and prolonged chemotherapy and may produce highly satisfying cure rates.


[Labor analgesia by one anesthesiologist in a small obstetric clinic].
In Japan, about 40% of all the parturients give birth in small obstetrician's clinics. There is no anesthesiologist in most clinics. The labor analgesia is not performed or is performed by the obstetrician in many facilities. In this paper the author reports labor analgesia by one anesthetist in a small obstetric clinic in Japan. The management of labor analgesia of this hospital is as follows; 1) The anesthesiologist explains the method and risks of labor analgesia to the patient in the outpatient clinic. The induced labor is recommended to the parturients who request labor analgesia. 2) The combined spinal-epidural analgesia (CSEA) is provided for labor analgesia with a local anesthetic of low concentration and fentanyl. 3) CSEA is usually administered upon the request of a parturient and continued till the end of the delivery. Adequate pain relief and high satisfaction were ascertained by the questionnaire to the parturients who had received labor analgesia in this hospital. The number of parturients who request labor analgesia is increasing. However, it is difficult or almost impossible to provide labor analgesia by one anesthetist for 24 hours and 365 days.


Technical note: a physical phantom for assessment of accuracy of deformable alignment algorithms.
The purpose of this study was to investigate the feasibility of a simple deformable phantom as a QA tool for testing and validation of deformable image registration algorithms. A diagnostic thoracic imaging phantom with a deformable foam insert was used in this study. Small plastic markers were distributed through the foam to create a lattice with a measurable deformation as the ground truth data for all comparisons. The foam was compressed in the superior-inferior direction using a one-dimensional drive stage pushing a flat "diaphragm" to create deformations similar to those from inhale and exhale states. Images were acquired at different compressions of the foam and the location of every marker was manually identified on each image volume to establish a known deformation field with a known accuracy. The markers were removed digitally from corresponding images prior to registration. Different image registration algorithms were tested using this method. Repeat measurement of marker positions showed an accuracy of better than 1 mm in identification of the reference marks. Testing the method on several image registration algorithms showed that the system is capable of evaluating errors quantitatively. This phantom is able to quantitatively assess the accuracy of deformable image registration, using a measure of accuracy that is independent of the signals that drive the deformation parameters.


Functional Connectivity and Complexity Analyses of Resting-State fMRI in Pre-Adolescents with ADHD.
Attention deficit hyperactivity disorder (ADHD) has been characterized by impairments among distributed functional brain networks, e.g., the frontoparietal network (FPN), default mode network (DMN), and reward and motivation-related circuits (RMN). In the current study, we evaluated the complexity and functional connectivity (FC) of resting state fMRI (rsfMRI) in pre-adolescents with ADHD for pathology-relevant networks. We leveraged data from the Adolescent Brain and Cognitive Development (ABCD) Study. The final study sample included 63 children with ADHD and 92 healthy control children matched on age, sex, and pubertal development status. For selected regions in relevant networks, ANCOVA compared multiscale entropy (MSE) and FC between the groups. Finally, differences in the association between MSE and FC were evaluated. We found significantly reduced MSE along with increased FC within the FPN of pre-adolescents with ADHD compared to matched healthy controls. Significant partial correlations between MSE and FC emerged in fewer regions in the participants with ADHD than in the controls. The observation of reduced entropy is consistent with existing literature using rsfMRI and other neuroimaging modalities. The current findings of complexity and FC in ADHD support hypotheses of altered function of inhibitory control networks in ADHD.


Preliminary validation of a new variable pattern for daily quality assurance of medical image display devices.
This paper reports on a comparative study between the well-established test patterns for daily quality assurance (QA) of monitors of the American Association of Medical Physicists, Task Group 18 (AAPMtg18) and the Deutsches Institut für Normung e.V (DIN), and a newly proposed variable test pattern. A characteristic of the test patterns currently used for the QA of monitors is their static nature: The same test pattern is always used. This enables a learning effect that may bias the results over time. To address this problem we have developed a variable pattern for the quality assurance of monitors (MoniQA) that allows an evaluation of contrast visibility, geometric distortion, resolution, global image quality including uniformity, and artifacts. The test pattern includes randomly generated elements intended to prevent the observer from learning the test. Examples are random characters that have to be discriminated from the background to evaluate the threshold luminance difference and variable positions of different features in the test pattern. The newly proposed test patterns were generated and visualized on different viewing stations with a software tool developed in JAVA. In this study, we validated these patterns against the well-known AAPMtg18 and DIN test patterns on 22 monitors. The results showed that the MoniQA test can indicate the same monitor problems as the other well-known patterns and is significantly quicker to evaluate than the AAPMtg18 test patterns. The MoniQA pattern is a promising alternative for daily quality control of medical viewing stations.


Distribution Assessments of Coumarins from Angelicae Pubescentis Radix in Rat Cerebrospinal Fluid and Brain by Liquid Chromatography Tandem Mass Spectrometry Analysis.
Angelicae Pubescentis Radix (APR) is a widely-used traditional Chinese medicine. Pharmacological studies have begun to probe its biological activities on neurological disorders recently. To assess the brain penetration and distribution of APR, a validated ultra-performance liquid chromatography tandem mass spectrometry method was applied to the simultaneous determinations of the main coumarins from APR in the rat cerebrospinal fluid (CSF) and brain after oral administration of APR extract, including psoralen, xanthotoxin, bergapten, isoimperatorin, columbianetin, columbianetin acetate, columbianadin, oxypeucedanin hydrate, angelol B, osthole, meranzin hydrate and nodakenetin. Most of the tested coumarins entered the rat CSF and brain quickly, and double-peak phenomena in concentration-time curves were similar to those of their plasma pharmacokinetics. Columbianetin had the highest concentration in the CSF and brain, while psoralen and columbianetin acetate had the largest percent of CSF/plasma and brain/plasma, indicating that these three coumarins may be worthy of further research on the possible nervous effects. Correlations between the in vivo brain distributions and plasma pharmacokinetics of these coumarins were well verified. These results provided valuable information for the overall in vivo brain distribution characteristics of APR and also for its further studies on the active substances for the central nervous system.


Informed consent: a crucial step in cancer patient education.
Informed consent is an issue of major importance for cancer patients and for the practitioners who treat them. Recently, the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research emphasized the educational goals of the consent process. Nevertheless, past research confirms that these goals are difficult to attain. In this paper, we present an overview of informed consent and describe a study of informed consent to cancer treatment conducted at the Fox Chase Cancer Center in which the consultation between the patient and physician (and/or other health professional) was observed and patients were interviewed. On the average, patients recalled less than 40% of what they were told. Patients who were told more items recalled more; however, they recalled a smaller proportion of what they were told. Several implications for health education are drawn from the study results.


Cost-effectiveness of point-of-care digital chest-x-ray in HIV patients with pulmonary mycobacterial infections in Nigeria.
Chest-x-ray is routinely used in the diagnosis of smear negative tuberculosis (TB). This study assesses the incremental cost per true positive test of a point-of-care digital chest-x-ray, in the diagnosis of pulmonary mycobacterial infections among HIV patients with presumed tuberculosis undetected by smear microscopy. Consecutive patients with clinical suspicion of pulmonary tuberculosis were serially tested for Human immunodeficiency virus (HIV), their sputum examined for Acid Fast Bacilli then cultured in broth and solid media. Cultures characterized as tuberculous (M.tb) and non-tuberculous (NTM) mycobacteria by Hain assays were used as gold standards. A chest-x-ray was classified as: (1) consistent for TB, (2) not consistent for TB and (3) no pathology. Of the 1391 suspected cases enrolled, complete data were available for 952 (68%): 753/952 (79%) had negative smear tests while 150/753 (20%) had cultures positive for TB. Of those, 82/150 (55%) had chest-x-ray signs consistent with TB and 29/82 (35%) were positive for HIV. Within the co-infected, 9/29 (31%) had NTM infections. Among all suspects, the cost per positive case detected using smear microscopy test was $52.84; the overall incremental cost per positive case using chest-x-ray in smear negatives was $23.42, and in smear negative, HIV positive patients the cost was $15.77. Point-of-care chest-x-ray is a cost-effective diagnostic tool for smear negative HIV positive patients with pulmonary mycobacterial infection.


Sexual dysfunction after radical prostatectomy.
Sexual dysfunction associated with radical retropubic prostatectomy (RRP) may start before the surgery. Men undergoing RRP frequently have some degree of sexual dysfunction. In addition to the psychological stress of the diagnosis, the biopsy may itself have a detrimental effect. After surgery, all men will experience loss of ejaculate, because the organ responsible for ejaculate has been removed. Orgasm quality is adversely affected in many men. Erectile dysfunction is immediate and recovery from it is slow. Initially, phosphodiesterase (PDE)-5 inhibitors do not work, and they take up to 18 months for their effect to be maximized. Younger men who have had bilateral nerve-sparing procedures respond the best. Combination treatment with prostaglandin E1 or high-dose PDE-5 inhibitors may provide salvage therapy when initial PDE-5 inhibitor therapy has failed.


Refusal of autonomy: the use of words by a young adult in analysis.
Analytic work with a depressed twenty-three-year-old woman is presented showing how she used ruminative thoughts to maintain a fixed internal dyadic relationship in which neither self not object had autonomy. The resulting omnipotent/impotent impasse meant that she was unable to move forward in her development. In the analysis this relationship was externalized through her use of words, which were employed as actions designed to have a concrete effect on both her self and her analyst. For a long period in the analysis it was essential to understand and interpret the function of her words, rather than to look for symbolic meaning, and it was this which gradually enabled her to take a third, observing, position from which she had greater freedom to operate as a adult.


[EFFICACY OF SURGICAL TREATMENT OF VARICOSE DISEASE, DEPENDING ON ADSORPTION-RHEOLOGIC PROPERTIES OF BLOOD].
Physico-chemical adsorption-rheological properties of venous blood in patients, suffering varicose disease of the lower extremities, and their impact on efficacy of various methods of surgical treatment were studied. Conduction of endovasal laser coagulation in combination with crossectomy have promoted enhancement of operative treatment efficacy in patients in initial terms of observation (in 1 week), in 1 month a complete occlusion of the vein was noted more rarely. Efficacy of a small--power laser ablation with irradiation power of 10 W and less in 4 weeks postoperatively is higher, than of surgical treatment with a laser irradiation power 15 W. In a varicose disease of the lower extremities there were observed the raising of the blood volume toughness, superficial relaxation and superficial stress on background of reduction of the toughness--elasticity module, superficial toughness and superficial elasticity. Crossectomy conduction did not influence the integral dynamics of adsorption--rheological properties of venous blood, but in 1 month after endovasal laser coagulation a normalization of physicchemical parameters of blood was noted. Application of laser irradiation of the 10 W power and less promotes inhibition of the relaxation properties of venous blood; a prognostic meaning owes initial value of the blood volume toughness.


D-α-tocopheryl polyethylene glycol 1000 succinate: a view from FTICR MS and tandem MS.
D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is an important polymeric excipient frequently used in drug formulation. However, differing compositions of the TPGS samples between batches are believed to result in variable performance of the formulated product. Herein, a high performance method using Fourier-transform ion cyclotron resonance (FTICR) mass spectrometry (MS) and tandem mass spectrometry (MS/MS) to analyze the composition of TPGS samples and the structure of TPGS was established. Aided by high mass accuracy and high resolution, the full MS overview of TPGS is able to provide composition information, and diagnostic fragments from collisionally activated dissociation (CAD) and electron capture dissociation (ECD) MS/MS can be used for the identification of the TPGS structure. ECD and CAD show different preferences in bond cleavage, and an interesting cross-ring cleavage was generated by CAD. Fragmentation information from ECD/ECD MS(3) is useful for providing confidence in the results. The influence of different ionization agents (Na(+), Li(+), and Ag(+)) on fragmentation of TPGS was investigated with the silver adduct providing different fragments. In addition to the methodology study, the MS and MS/MS results from four batches of TPGS samples from two manufacturers were compared. This method can be utilized for the composition and structure study of many other polymeric compounds. FTICR MS/MS demonstrated its promising role as a structural characterization tool complementary to traditional spectroscopy techniques.


Evidence-based recommendations for the use of sealants.
In traditional research, the "level of significance" refers to the probability value used to reject the null hypothesis. In evidence-based research, a similar term, "the level of evidence" refers to the quality of the published report that is analyzed critically in the context of a systematic review. A systematic review, the principal research tool of evidence-based dentistry, is distinct from a classical narrative literature review in that it is focused to examine the strengths and weaknesses of the research methodology, design and data analysis of each report included in the review. A systematic review is very clearly defined, and sets out to find what evidence there is for prescribing a particular intervention for a given patient. Evidence-based recommendations are grounded on systematic reviews, and the evaluation of systematic reviews in a given domain of dentistry is critical for the successful implementation of evidence-based dental practice. In the context of sealants, the evidence indicates that the intervention is effective in preventing dental decay on the molars and premolars of susceptible children and adolescents (Level of evidence: II-1). The preventive effect for second-generation sealants ranges from 33 percent to 71 percent. The median preventive effect is higher when sealants are reapplied, compared to a single application, because sealant effectiveness decreases over time. The majority of studies have focused on molars, and fewer studies have examined the preventive effect of sealants on premolars. In this paper, the authors have developed evidence-based recommendations for the use of sealants by discussing the level of evidence and, when applicable, the number needed to treat (NNT) and the prevented fraction (PF), two fundamental criteria in evidence-based dental practice.


Technology transfer across industries.
Many of the technical challenges faced by next generation medical applications can be solved using established design and manufacturing solutions that originated in other industries. Although these are typically outside the core competence of most medical product developers, partnering with a specialist manufacturer can offer rapid access.


Surface-induced assembly of sophorolipids.
The surface self-assembly properties of acidic sophorolipids, a bolaform microbial glycolipids with pH-responsive properties in solution, were studied based on the chemical nature of the support and pH of the solution. Sophorolipids generally form micelles in water but formation of morphologies like platelets and twisted fibers depending on pH have also been reported. The surface self-assembly was achieved using dip-coating on three different substrates namely gold, silicon(111) and TiO2 anatase. Deposition conditions (dip-coating withdrawal speed, relative humidity, temperature) were tested, and it was found that optimum self-assembly occurs at a withdrawal speed of 1 mm s-1, T of 25 °C and relative humidity of 25%. The local structure of the sophorolipid films was characterized by atomic force microscopy, while scanning electron microscopy was used to characterize the spatial homogeneity. We also attempted to correlate dispersive, electron donor and electron attractor surface energy components, using Good-van Oss's approach, and the behavior of sophorolipids. We found that when the surface energy is dominated by dispersive components, sophorolipids spontaneously assemble into entangled needles at all pH values (4, 6 and 11). However, when the surface energy is dominated by electronic components, pH has a strong influence on the surface self-assembly. We could discriminate three major organizations: homogeneous layer, isolated aggregates and a two-dimensional fibrillar network.


Synergistic Impact of the Symptom Cluster on Health-Related Quality of Life in Patients With Chronic Obstructive Pulmonary Disease: A Secondary Data Analysis.
This study aimed to quantify the synergistic impact of symptom clusters on health-related quality of life (HRQoL) among patients with chronic obstructive pulmonary disease (COPD). We conducted a secondary analysis of a cross-sectional data collected via convenience sampling from patients with COPD. Multiple linear regressions were used to quantify the relationships between symptom clusters and HRQoL. The sample included 106 COPD patients from whom three symptom clusters were identified comprising of dyspnea depression, anxiety-sleep, and depression-anxiety. Depression-anxiety (psychological symptom cluster) was significantly associated with poorer HRQoL (β = 13.88, 95% CI [7.94, 19.82]), while no significant associations were detected with HRQoL for either depression or anxiety alone (β = 6.66, 95% CI [-2.99, 16.31]; β = 7.29, 95% CI [-0.78, 15.35]). Assessment and early intervention led by nurses targeting the psychological symptom cluster may represent an initial approach to improve HRQoL. Understanding the phenomenon of symptom clusters that are present in patients with COPD provides a breakthrough insight to devise strategies for their management.


Complex network-driven view of genomic mechanisms underlying Parkinson's disease: analyses in dorsal motor vagal nucleus, locus coeruleus, and substantia nigra.
Parkinson's disease (PD)—classically characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta—has a caudal-rostral progression, beginning in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the midbrain and eventually to the basal forebrain and the neocortex. About 90% of the cases are idiopathic. To study the molecular mechanisms involved in idiopathic PD we conducted a comparative study of transcriptional interaction networks in the dorsal motor vagal nucleus (VA), locus coeruleus (LC), and substantia nigra (SN) of idiopathic PD in Braak stages 4-5 (PD) and disease-free controls (CT) using postmortem samples. Gene coexpression networks (GCNs) for each brain region (patients and controls) were obtained to identify highly connected relevant genes (hubs) and densely interconnected gene sets (modules). GCN analyses showed differences in topology and module composition between CT and PD networks for each anatomic region. In CT networks, VA, LC, and SN hub modules are predominantly associated with neuroprotection and homeostasis in the ageing brain, whereas in the patient's group, for the three brain regions, hub modules are mostly related to stress response and neuron survival/degeneration mechanisms.


Nitrogen dioxide production in a nitric oxide inhalation system using the Servo Ventilator 900C.
During nitric oxide (NO) inhalation therapy, toxicity may be produced by the reactive metabolite nitrogen dioxide (NO2). The purpose of the present study was to determine the NO2 concentration in a NO inhalation system used for respiratory failure in children at relatively low concentrations of NO (< 20 ppm). The production of NO2 in the NO inhalation system using the Servo Ventilator 900C connected to the test lung under each of 30 combinations of NO concentrations (0, 4, 8, 12, 16, and 19 ppm) and inspired oxygen (O2) concentrations (21, 40, 60, 80, and 100%). Pressure controlled ventilation was used with a respiratory rate of 20 breaths/min. NO and NO2 measurements were obtained on the inspiratory side of the Y-piece connected to the test lung. At a given NO level, increases in the concentration of inspired O2 resulted in increases in the concentration of NO2 produced, as did increases in the amount of NO at a given concentration of O2. The mean NO concentration at the inspiratory site of the Y-piece did not exceed 0.05 ppm (the limit of NO2 as an outdoor air pollutant in the United States) when the NO concentration did not exceed 8 ppm, regardless of the O2 concentration. NO inhalation therapy for children with severe respiratory failure using the Servo Ventilator 900C can be performed safely when the concentration of NO does not exceed 8 ppm.


Metabolic syndrome in heart transplantation: impact on survival and renal function.
The aim of our study was to analyze the early presence of metabolic syndrome (MS) in heart transplant (HTx) patients, and to assess its long-term impact on survival and renal function. From January 2000 to October 2011, 253 consecutive HTx patients who survived more than 90 days were included. MS was diagnosed if patients met revised NCEP-ATP III criteria at HTx or within 3 months post-HTx. The prevalence of MS was 41.9%. Patients with MS had greater overall mortality after a mean follow-up of 1700 ± 979 days (log-rank test, P = 0.020). In the multivariate analysis, and subject to a minimum survival of 90 days, the only independent predictor variables of long-term mortality were the presence of MS (OR, odds ratio 2.087, P = 0.032), and rejection episodes (OR 1.833, P = 0.001). Patients with MS had worse renal function at baseline both in plasma creatinine (1.19 ± 0.44 vs. 1.03 ± 0.29 mg/dl, P = 0.002) and glomerular filtration rate estimated by modified diet in renal disease (73.60 ± 26.76 vs. 87.30 ± 43.55 ml/min/1.73 m(2) , P = 0.005), whereas progressive impairment of renal function was of equal magnitude in both groups. The presence of MS prior to transplant or its development within the first 3 months identified a subgroup at greater risk of mortality and long-term renal dysfunction.


The determination of sulfonamides in honey by high performance liquid chromatography--mass spectrometry method (LC/MS).
The sulfonamides (SAs) are stable chemotherapeutics used against the bacterial disease affecting bees, known as American foulbrood (Bacillus larvae), so their residues could appear in the honey of treated bees. Their presence at a concentration above the limit value could be a potential danger to human health. Therefore, a simple, rapid, and reliable method for determination of 11 available SAs in honey was optimized. The samples were homogenized and cleaned with extraction on solid phase by means of Chromabond C18 end-capped cartridge followed by LC/MS analyses. A detection limit of 25 microg/kg was achieved for all analytes. The repeatability of the method was proven and the optimal parameters for temperature and pH of the mobile phase and acetic buffer, respectively, were determined. In this study, 20 samples of domestic honey were included. Six of the analyzed samples were positive, but all results were below the Croatian permissible limit value (100 microg/kg).


Profiling of cell-free DNA methylation and histone signatures in pediatric NAFLD: A pilot study.
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children and adolescents, increasing the risk of its progression toward nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. There is an urgent need for noninvasive early diagnostic and prognostic tools such as epigenetic marks (epimarks), which would replace liver biopsy in the future. We used plasma samples from 67 children with biopsy-proven NAFLD, and as controls we used samples from 20 children negative for steatosis by ultrasound. All patients were genotyped for patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOAT7), and klotho-β (KLB) gene variants, and data on anthropometric and biochemical parameters were collected. Furthermore, plasma cell-free DNA (cfDNA) methylation was quantified using a commercially available kit, and ImageStream(X) was used for the detection of free circulating histone complexes and variants. We found a significant enrichment of the levels of histone macroH2A1.2 in the plasma of children with NAFLD compared to controls, and a strong correlation between cfDNA methylation levels and NASH. Receiver operating characteristic curve analysis demonstrated that combination of cfDNA methylation, PNPLA3 rs738409 variant, coupled with either high-density lipoprotein cholesterol or alanine aminotransferase levels can strongly predict the progression of pediatric NAFLD to NASH with area under the curve >0.87. Conclusion: Our pilot study combined epimarks and genetic and metabolic markers for a robust risk assessment of NAFLD development and progression in children, offering a promising noninvasive tool for the consistent diagnosis and prognosis of pediatric NAFLD. Further studies are necessary to identify their pathogenic origin and function.


Utility of diffusion MRI characteristics of cervical lymph nodes as disease classifier between patients with head and neck squamous cell carcinoma and healthy volunteers.
Diffusion MRI characteristics assessed by apparent diffusion coefficient (ADC) histogram analysis in head and neck squamous cell carcinoma (HNSCC) have been reported as helpful in classifying tumours based on diffusion characteristics. There is little reported on HNSCC lymph nodes classification by diffusion characteristics. The aim of this study was to determine whether pretreatment nodal microstructural diffusion MRI characteristics can classify diseased nodes of patients with HNSCC from normal nodes of healthy volunteers. Seventy-nine patients with histologically confirmed HNSCC prior to chemoradiotherapy, and eight healthy volunteers, underwent diffusion-weighted (DW) MRI at a 1.5-T MR scanner. Two radiologists contoured lymph nodes on DW (b = 300 s/m2 ) images. ADC, distributed diffusion coefficient (DDC) and alpha (α) values were calculated by monoexponential and stretched exponential models. Histogram analysis metrics of drawn volume were compared between patients and volunteers using a Mann-Whitney test. The classification performance of each metric between the normal and diseased nodes was determined by receiver operating characteristic (ROC) analysis. Intraclass correlation coefficients determined interobserver reproducibility of each metric based on differently drawn ROIs by two radiologists. Sixty cancerous and 40 normal nodes were analysed. ADC histogram analysis revealed significant differences between patients and volunteers (p ≤0.0001 to 0.0046), presenting ADC distributions that were more skewed (1.49 for patients, 1.03 for volunteers; p = 0.0114) and 'peaked' (6.82 for patients, 4.20 for volunteers; p = 0.0021) in patients. Maximum ADC values exhibited the highest area under the curve ([AUC] 0.892). Significant differences were revealed between patients and volunteers for DDC and α value histogram metrics (p ≤0.0001 to 0.0044); the highest AUC were exhibited by maximum DDC (0.772) and the 25th percentile α value (0.761). Interobserver repeatability was excellent for mean ADC (ICC = 0.88) and the 25th percentile α value (ICC = 0.78), but poor for all other metrics. These results suggest that pretreatment microstructural diffusion MRI characteristics in lymph nodes, assessed by ADC and α value histogram analysis, can identify nodal disease.


A comprehensive lipidomic screen of pancreatic β-cells using mass spectroscopy defines novel features of glucose-stimulated turnover of neutral lipids, sphingolipids and plasmalogens.
Glucose promotes lipid remodelling in pancreatic β-cells, and this is thought to contribute to the regulation of insulin secretion, but the metabolic pathways and potential signalling intermediates have not been fully elaborated. Using mass spectrometry (MS) we quantified changes in approximately 300 lipid metabolites in MIN6 β-cells and isolated mouse islets following 1 h stimulation with glucose. Flux through sphingolipid pathways was also assessed in (3)H-sphinganine-labelled cells using TLC. Glucose specifically activates the conversion of triacylglycerol (TAG) to diacylglycerol (DAG). This leads indirectly to the formation of 18:1 monoacylglycerol (MAG), via degradation of saturated/monounsaturated DAG species, such as 16:0_18:1 DAG, which are the most abundant, immediate products of glucose-stimulated TAG hydrolysis. However, 16:0-containing, di-saturated DAG species are a better direct marker of TAG hydrolysis since, unlike the 18:1-containing DAGs, they are predominately formed via this route. Using multiple reaction monitoring, we confirmed that in islets under basal conditions, 18:1 MAG is the most abundant species. We further demonstrated a novel site of glucose to enhance the conversion of ceramide to sphingomyelin (SM) and galactosylceramide (GalCer). Flux and product:precursor analyses suggest regulation of the enzyme SM synthase, which would constitute a separate mechanism for localized generation of DAG in response to glucose. Phosphatidylcholine (PC) plasmalogen (P) species, specifically those containing 20:4, 22:5 and 22:6 side chains, were also diminished in the presence of glucose, whereas the more abundant phosphatidylethanolamine plasmalogens were unchanged. Our results highlight 18:1 MAG, GalCer, PC(P) and DAG/SM as potential contributors to metabolic stimulus-secretion coupling.


The fundamental T cell proliferative repertoire in a nonresponder strain and its qualitative alteration by suppression.
B10 mice, although genetically nonresponsive to hen egg-white lysozyme (HEL) after i.p. immunization due to suppressor T cells, make a vigorous helper and proliferative T cell response in the draining popliteal lymph nodes (P-LN) soon after footpad immunization with HEL. The fundamental specificity repertoire in B10 P-LN analyzed with cross-reactive lysozymes, was then compared with that found after the delayed appearance of suppression, in the PETLES. In contrast with B10.A mice, whose T cell specificity pattern was unchanged with time, or anatomical site, the onset of HEL-induced suppression in B10 mice led to a marked heteroreactive shift in specificity pattern. This shift did not occur after immunization with REL (ring-necked pheasant lysozyme), which fails to induce suppression.


SATB2 Cytoplasmic Expression is Characteristic of a Subset of Ovarian Stromal Cells and Sex Cord Stromal Tumors.
Special AT-rich sequence-binding protein 2 (SATB2) is a nuclear transcription factor that shows consistent nuclear staining in colorectal adenocarcinoma and osteosarcoma. Following the observation of cytoplasmic staining with this marker in luteinized ovarian stromal cells, we studied the expression of SATB2 in ovarian stromal cells, various types of follicular cysts, and sex cord-stromal tumors. Eighty-five cases were stained for SATB2. Ovarian hilar Leydig cells (n = 12), luteinized stromal cells (n = 10), corpora lutea (n = 4), luteinized follicular cysts (n = 4), and stromal hyperthecosis (n = 6) exhibited consistent, usually diffuse, granular cytoplasmic staining. In addition, Leydig cell tumors (n = 1) and steroid cell tumors (n = 4) showed diffuse cytoplasmic staining. SATB2 also exhibited cytoplasmic staining in most Sertoli-Leydig cell tumors (n = 16) and gynandroblastomas (n = 3) confined to the Leydig cell component. Adult granulosa cell tumors (n = 14), juvenile granulosa cell tumors (n = 3), sex cord tumors with annular tubules (n = 3), cellular fibromas (n = 3), sclerosing stromal tumors (n = 1), and thecomas (n = 1) were negative apart from cytoplasmic staining in associated luteinized stromal cells. SATB2 cytoplasmic staining has not been previously described in these lesions but is characteristic of a variety of ovarian stromal cells and sex cord-stromal tumors, in particular, those exhibiting luteinization or a Leydig or steroid cell component. SATB2 staining may be of value in identifying luteinized or Leydig cells when these are morphologically inconspicuous.


Double-blind comparison of doxepin versus bupropion in outpatients with a major depressive disorder.
A double-blind controlled study comparing the effects of bupropion to doxepin in outpatients with primary depression was conducted to evaluate efficacy and safety differences between the two drugs. Following a 7-day placebo washout period, patients could be treated for up to 13 weeks on either treatment. Antidepressant response was assessed by the Hamilton Depression and Anxiety Scales, Clinical Global Severity and Improvement Ratings, and the Zung Self-Rating Depression Scale. Comparable efficacy between the compounds was found across the 13-week study. Doxepin differed from bupropion mainly on the sleep factor of the Hamilton Depression Scale, with doxepin improving sleep to a greater extent than bupropion. Doxepin produced a greater incidence of anticholinergic side effects, including dry mouth, constipation, sleepiness, and tiredness, in comparison to bupropion. Also, increased appetite and weight gain were consistent side effects of doxepin relative to bupropion.


Reflection and scattering characteristics of reflectors in SAW tags.
As a foundation of an optimal design for SAW tags,the reflection, scattering, and transmission of the reflector composed of a few electrodes are discussed. A source regeneration method based on Green's function and the finite element method/boundary element method is used to obtain the reflection coefficient and the scattering coefficient for the short-circuited and open circuit reflectors. Examples are presented to show how one can use structure variance to satisfy the requirements for SAW tag design according to the reflection and scattering characteristics.


Isolation and culture of primary adult skin fibroblasts from the Asian elephant (Elephas maximus).
Primary cultures from Asian elephants (Elephas maximus) allow scientists to obtain representative cells that have conserved most of their original characteristics, function, physiology and biochemistry. This technique has thus gained significant importance as a foundation for further cellular, cell biology and molecular research. Therefore, the aim of this study was to describe conditions for the successful establishment of primary adult fibroblasts from Asian elephant carcasses. Ear tissue sample collection from Asian elephant carcasses and our recommendations are given. We describe here a simple modified protocol for successful isolation and maintenance of primary adult fibroblasts from elephant ear skin. Ear samples from each individual (five 3 × 3 cm2 pieces) were brought to the laboratory within 3 h after collection, kept in transportation medium at 0-4 °C. The ear tissues were prepared by a combination of 10% collagenase type II digestion procedure together with a simple explant procedure. Primary fibroblasts were cultured at 37 °C in Dulbecco's modified Eagle's medium (DMEM) with 20% fetal calf serum (FCS) in a humidified atmosphere containing 5% CO2. After the third passage, fibroblasts were routinely trypsinized with 0.25% trypsin/EDTA and cultured in DMEM with 10% FCS at 37 °C and 5% CO2. Traditional cell counting method was used to measure cell viability and growth curve. Long-term storage of cells used freezing medium consisting of 40% FCS (v/v). We explored the most suitable conditions during sample collection (post-mortem storage time and sample storage temperature), which is the most important step in determining primary outgrowth. Our study successfully established and cultured primary adult skin fibroblasts obtained from post-mortem E. maximus ear skin tissues from six carcasses, with a success rate of around 83.3%. Outgrowth could be seen 4-12 days after explantation, and epithelial-like cells were found after 4-7 days of culture, while fibroblasts appeared at around day 7-10. The fibroblasts had viability and post-freezing recovery rates of around 97.3 ± 4.3% and 95.5 ± 7.3%, respectively, and doubling time was about 25 h (passage 6). To our knowledge, this report is the first to describe primary cell cultures derived from adult Asian elephant skin. Future studies should benefit from the information and useful suggestions herein, which may be used as a standard method for establishing primary skin fibroblast cultures in future experiments.


Fertility of postpartum dairy cows after administration of gonadotropin-releasing hormone and prostaglandin F2 alpha: a field trial.
Our objective was to examine further the potential profertility effects of gonadotropin-releasing hormone and prostaglandin F2 alpha in postpartum Holstein cows. Reproductive performance was monitored in 843 cows milked thrice daily. One group of cows (n = 218) was untreated, while three groups received either 100 micrograms gonadotropin-releasing hormone administered once between d 11 and 25 (n = 211); 25 mg prostaglandin F2 alpha given once between d 11 and 25 (n = 215); or 25 mg prostaglandin F2 alpha given once between d 25 and 40 postpartum (n = 190). No profertility effects were detected in cows, regardless of their health status during the periparturient period, except cows given gonadotropin-releasing hormone between d 11 and 18 had shorter intervals to first estrus and to first service than controls. Cows with reproductive disorders (abnormal health status) in the concurrent lactation had longer intervals from calving to conception after receiving gonadotropin-releasing hormone between d 18 and 25 or prostaglandin F2 alpha between d 33 and 40. Abnormal health status adversely affected every reproductive trait measured. Early postpartum treatments with either hormone failed to improve reproductive performance of dairy cows, in contrast to several reports of profertility effects for gonadotropin-releasing hormone, and a few reports for prostaglandin F2 alpha.


Probiotics: functional food ingredients with the potential to reduce hypertension.
Hypertension is an increasingly pressing public health concern across the globe. It can be triggered by a variety of factors such as age and diet, as well as the stress of modern life. The traditional treatment of hypertension includes calcium ion blockers, angiotensin II receptor inhibitors and β-receptor blockers, but these drugs have at least some side effects. Recent studies have revealed that intestinal flora plays a vital role in maintaining and promoting human health. This is due to the type and amount of probiotics present in the flora. Probiotics can reduce hypertension symptoms through four mechanisms: regulating vascular oxidative stress, producing short-chain fatty acids, restoring endothelial cell function, and reducing inflammation. It has been reported that certain functional foods, using probiotics as their raw material, can modify the composition of intestinal flora, thus regulating hypertension symptoms. Consequently, utilizing the probiotic function of probiotics in conjunction with the properties of functional foods to treat hypertension is a novel, side-effect-free treatment method. This study seeks to summarize the various factors that contribute to hypertension, the mechanism of probiotics in mitigating hypertension, and the fermented functional foods with probiotic strains, in order to provide a basis for the development of functional foods which utilize probiotics as their raw material and may have the potential to reduce hypertension.


Phytoremediation: green technology for the removal of mixed contaminants of a water supply reservoir.
The Iraí Reservoir, a water supply in Brazil, is constantly impacted by anthropogenic activities such as waste inputs from agriculture, hospitals and urbanization, resulting toxic cyanobacterial blooms causing economic, social and environmental problems. This study assessed the concentration of some common contaminants of the Iraí Reservoir, namely paracetamol, diclofenac and microcystin-LR and tested whether a laboratory scale Green Liver System® would serve as a suitable technology to remove these contaminants. Further, the study investigated whether the pollutants caused adverse effects to the macrophytes using catalase as a biomarker for oxidative stress and investigated whether biotransformation (glutathione S-transferase) was a main route for detoxification. Egeria densa, Ceratophyllum demersum and Myriophyllum aquaticum were exposed to a mixture of the three contaminants for 14 days in a concentration range similar to those detected in the reservoir. The plants removed 93% of diclofenac and 100% of MC-LR after 14 days. Paracetamol could not be detected. Catalase and glutathione S-transferase enzyme activities remained unaltered after the 14-day exposure, indicating that the mixture did not cause oxidative stress. The study showed that the aquatic macrophytes used are suitable tools to apply in a Green Liver System® for the remediation of mixed pollutants.


Evaluation of Field Map and Nonlinear Registration Methods for Correction of Susceptibility Artifacts in Diffusion MRI.
Correction of echo planar imaging (EPI)-induced distortions (called "unwarping") improves anatomical fidelity for diffusion magnetic resonance imaging (MRI) and functional imaging investigations. Commonly used unwarping methods require the acquisition of supplementary images during the scanning session. Alternatively, distortions can be corrected by nonlinear registration to a non-EPI acquired structural image. In this study, we compared reliability using two methods of unwarping: (1) nonlinear registration to a structural image using symmetric normalization (SyN) implemented in Advanced Normalization Tools (ANTs); and (2) unwarping using an acquired field map. We performed this comparison in two different test-retest data sets acquired at differing sites (N = 39 and N = 32). In both data sets, nonlinear registration provided higher test-retest reliability of the output fractional anisotropy (FA) maps than field map-based unwarping, even when accounting for the effect of interpolation on the smoothness of the images. In general, field map-based unwarping was preferable if and only if the field maps were acquired optimally.