Shift work and cancer research: a thought experiment into a potential chronobiological fallacy of past and perspectives for future epidemiological studies.
With their 2007 classification - shift work involving "circadian disruption" is probably carcinogenic to humans (Group 2A) - the International Agency for Research on Cancer [IARC] provided a riddle for scientists and the public alike. Thereafter, eighteen epidemiological investigations into shift work and a host of malignant endpoints (including cancers of the breast, prostate, lung, colon, rectum, pancreas, bladder, skin and non-Hodgkin lymphoma [NHL]) as well as mortality were published. Although IARC experts identified "circadian disruption" as the critical link in the "probable" chains of cancer causation, almost none of the post-IARC studies specifically considered a disturbed temporal organization of biology. This implies that epidemiological research to-date is less focused than it should be. To illustrate a potential chronobiological fallacy of past studies, we offer a thought experiment. In addition, we consider first empirical evidence from recent research which avoided such bias. Methodological perspectives for future chronobiology-driven epidemiological research are outlined.


[The effect of acupuncture on endocrine regulation in hypertensive patients].
Thirty-five stage I-II essential hypertension subjects aged 25-63 were examined after the 1st and 10th acupuncture to clarify the effect of a single procedure and a course of acupuncture treatment on blood ACTH, STH, TTH, beta-endorphine, neurotensin, thyroxine, aldosterone, hydrocortisone and plasma renin activity. The hormonal spectrum was determined by radioimmunoassay using special kits. The blood was obtained before acupuncture, 5 min after introduction of the needles, immediately and 30 min after their removal. It is shown that acupuncture-related decline of arterial pressure occurs in participation of pituitary and adrenal hormones as well as polypeptides beta-endorphine and neurotensin.


Coexistent Superscan and Lincoln Sign on Bone Scintigraphy.
A 70-year-old man underwent Tc-methylene diphosphonate scintigraphy for staging of adenocarcinoma prostate. Scintigraphy revealed diffuse increased tracer uptake in skeletal system along with faint renal visualization, a pattern compatible with metastatic superscan. The scintigraphy also revealed increased radiotracer uptake in the body of the mandible-Lincoln sign or black beard sign. Radiological imaging revealed sclerotic lesions throughout the skeleton including the mandible, confirming widespread skeletal metastases. Lincoln sign is previously described in monostotic Paget disease of the mandible and in contiguous spread of oral malignancy. We describe this pattern in distant metastatic involvement from carcinoma prostate with coexistent superscan pattern.


Characterization of B cells in muscle-specific kinase antibody myasthenia gravis.
To characterize B-cell subsets in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). In accordance with Human Immunology Project Consortium guidelines, we performed polychromatic flow cytometry and ELISA assays in peripheral blood samples from 18 patients with MuSK MG and 9 healthy controls. To complement a B-cell phenotype assay that evaluated maturational subsets, we measured B10 cell percentages, plasma B cell-activating factor (BAFF) levels, and MuSK antibody titers. Immunologic variables were compared with healthy controls and clinical outcome measures. As expected, patients treated with rituximab had high percentages of transitional B cells and plasmablasts and thus were excluded from subsequent analysis. The remaining patients with MuSK MG and controls had similar percentages of total B cells and naïve, memory, isotype-switched, plasmablast, and transitional B-cell subsets. However, patients with MuSK MG had higher BAFF levels and lower percentages of B10 cells. In addition, we observed an increase in MuSK antibody levels with more severe disease. We found prominent B-cell pathology in the distinct form of MG with MuSK autoantibodies. Increased BAFF levels have been described in other autoimmune diseases, including acetylcholine receptor antibody-positive MG. This finding suggests a role for BAFF in the survival of B cells in MuSK MG, which has important therapeutic implications. B10 cells, a recently described rare regulatory B-cell subset that potently blocks Th1 and Th17 responses, were reduced, which suggests a potential mechanism for the breakdown in immune tolerance in patients with MuSK MG.


Predictive role of P-wave axis abnormalities in secondary cardiovascular prevention.
Background Abnormal P-wave axis has been correlated with an increased risk of all-cause and cardiovascular mortality in a general population. We aimed to evaluate the prognostic role of abnormal P-wave axis in patients undergoing myocardial revascularisation or cardiac valve surgery. Methods We considered data of 810 patients with available P-wave axis measure from a prospective monocentric registry of patients undergoing cardiovascular rehabilitation. A total of 436 patients (54%) underwent myocardial revascularisation, 253 (31%) valve surgery, 71 (9%) combined valve and coronary artery bypass graft surgery and 50 (6%) cardiac surgery for other cardiovascular disease. Mean follow-up was 47 ± 27 months. Results Over the whole group, P-wave axis was 43.8° ± 27.5° and an abnormal P-wave axis was found in 94 patients (12%). The risk of overall (hazard ratio (HR) 2.5, 95% confidence interval (CI) 1.6-4.0, P < 0.001) and cardiovascular mortality (HR 2.9, 95% CI 1.5-5.8, P = 0.002) was significantly higher in patients with abnormal P-wave axis even after adjustment for age, other electrocardiographic variables (PR, QRS, QTc intervals), left ventricular ejection fraction and left atrial volume index. After dividing the population according to the type of disease, patients with abnormal P-wave axis and ischaemic heart disease had 3.9-fold higher risk of cardiovascular mortality (HR 3.9, 95% CI 1.3-12.1, P = 0.017), while a 2.2-fold higher risk of cardiovascular mortality (HR 3.6, 95% CI 1.3-10.1, P = 0.015) was found in those with cardiac valve disease. Conclusion An abnormal P-wave axis represents an independent predictor of both overall and cardiovascular mortality in patients undergoing myocardial revascularisation or cardiac valve surgery.


Impact of a pre-clinical clinical skills curriculum on student performance in third-year clerkships.
Research on the outcomes of pre-clinical curricula for clinical skills development is needed to assess their influence on medical student performance in clerkships. To better understand the impact of a clinical-skills curriculum in the pre-clinical setting on student performance. We conducted a non-randomized, retrospective, pre-post review of student performance evaluations from 3rd-year clerkships, before and after implementation of a clinical-skills curriculum, the Colleges (2001-2007). Comparisons of clerkship performance data revealed statistically significant differences favoring the post-Colleges group in the Internal Medicine clerkship for 9 of 12 clinical-skills domains, including Technical Communication Skills (p < 0.023, effect size 0.16), Procedural Skills (p < 0.031, effect size 0.17), Communication Skills (p < 0.003, effect size 0.21), Patient Relationships (p < 0.003, effect size 0.21), Professional Relationships (p < 0.021, effect size 0.17), Educational Attitudes (p < 0.001, effect size 0.24), Initiative and Interest (p < 0.032, effect size 0.15), Attendance and Participation (p < 0.007, effect size 0.19), and Dependability (p < 0.008, effect size 0.19). Statistically significant differences were identified favoring the post-Colleges group in technical communication skills for three of six basic clerkships (Internal Medicine, Surgery, and Pediatrics). Implementation of a pre-clinical fundamental skills curriculum appears to be associated with improved clerkship performance in the 3rd year of medical school, particularly in the Internal Medicine clerkship. Similar curricula, focused on teaching clinical skills in small groups at the bedside with personalized mentoring from faculty members, may improve student performance. Continued efforts are needed to understand how to best prepare students for clinical clerkships and how to evaluate outcomes of similar pre-clinical skills programs.


Intergenerational Contacts Influence Health Related Quality of Life (HRQL) and Subjective Well Being among Austrian Elderly.
Over the last century population ageing is a well described phenomenon all over the world. The dramatic absolute and relative increase in the population component of the elderly and the very old has influenced not only population structure but also the relationships within families, in particular between older parents and their adult children. The aim of the present study was to examine the impact of intergenerational contact frequency on health related quality of life among 62 men and 98 women ranging in age between 60 and 94 years. All participants of the study were healthy and lived independently in their private homes. Data concerning subjective well being and health related quality of life were collected by personal interviews based on structured questionnaires. Health related quality of life was tested by means of the WHOQOL-BREF. The main finding of this study is that the frequency of intergenerational contacts has a significant impact on health related quality of life. Contact frequency with grandchildren per month correlated significantly (p<0. 01) with all five domains of the WHOQOL-BREF. Contact frequency with sons and daughters per month correlated significantly (p<0.05) with the social and the global domain. According to Kruskall-Wallis tests and regression analyses with increasing intergenerational contacts health related quality of life increased significantly (p<0.01). According to these results a close and frequent contact to offspring is an important source for quality of life during old age.


Spatial Angular Compounding of Photoacoustic Images.
Photoacoustic (PA) images utilize pulsed lasers and ultrasound transducers to visualize targets with higher optical absorption than the surrounding medium. However, they are susceptible to acoustic clutter and background noise artifacts that obfuscate biomedical structures of interest. We investigated three spatial-angular compounding methods to improve PA image quality for biomedical applications, implemented by combining multiple images acquired as an ultrasound probe was rotated about the elevational axis with the laser beam and target fixed. Compounding with conventional averaging was based on the pose information of each PA image, while compounding with weighted and selective averaging utilized both the pose and image content information. Weighted-average compounding enhanced PA images with the least distortion of signal size, particularly when there were large (i.e., 2.5 mm and 7 (°)) perturbations from the initial probe position. Selective-average compounding offered the best improvement in image quality with up 181, 1665, and 1568 times higher contrast, CNR, and SNR, respectively, compared to the mean values of individual PA images. The three presented spatial compounding methods have promising potential to enhance image quality in multiple photoacoustic applications.


Treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma: a national perspective.
Surgery remains the only potentially curative option for patients with hepatocellular carcinoma (HCC) and fibrolamellar carcinoma (FLC). We sought to investigate the differences over time in surgically managed FLC compared with conventional HCC using population-based data. Using SEER data, we identified 7,225 patients with surgically managed FLC or HCC from 1986 to 2008. We examined differences in clinicopathologic and surgical factors associated with long-term survival. Of the 7,225 patients, the majority had HCC (n = 7,135; 99%) vs FLC (n = 90; 1%). Patients with FLC were younger (25 years vs 59 years) and more often were women (44% vs 27%) than patients with HCC (both p < 0.001). Regional disease was more common among patients with FLC (42.2%) vs patients with HCC (22.1%) (p < 0.001). More than one-third of patients with FLC (36.9%) were operatively managed with a hemihepatectomy compared with patients with HCC, who were more often managed with a liver transplant (p < 0.001). On univariable analysis, there was a marked difference in overall survival, with patients with FLC surviving a median of 75 months vs 43 months for HCC (hazard ratio [HR]: 0.59; p = 0.001). There was a marked difference in survival when patients were stratified by localized (FLC, 78 months vs HCC, 49 months; p = 0.012) vs regional disease (FLC, 46 months vs HCC, 23 months; p = 0.002. Patients with FLC have many clinicopathologic features that are different from those of patients with HCC, including younger age and female sex. Despite a higher likelihood of advanced disease at the time of diagnosis, surgically treated FLC patients had better long-term outcomes than patients with conventional HCC.


MiR-455-3p acts as a prognostic marker and inhibits the proliferation and invasion of esophageal squamous cell carcinoma by targeting FAM83F.
The aim of the current study was to elucidate the role of miR-455-3p in the pathogenesis of esophageal squamous cell carcinoma (ESCC) and its prognostic value in patients with ESCC. Expression levels of miR-455-3p and FAM83F mRNA in ESCC tissues and adjacent normal tissues were detected by quantitative RT-PCR. The X2-test was used to assess miR-455-3p expression on clinicopathological parameters. The association with overall survival of patients was analyzed by Kaplan-Meier survival analysis. Cox's multivariate regression model was performed to identify independent prognostic factors of overall survival. The effect of miR-455-3p on proliferation was evaluated by kit-8 (CCK-8), and cell invasion was evaluated by transwell assays. The molecular target of miR-455-3p was identified using a computer algorithm and confirmed experimentally. Furthermore, the effect of miR-455-3p up-regulation on FAM83F expression was examined by Western blot. miRNA-455-3p was significantly increased in ESCC tissues and cell lines. Also, miR-455-3p expression was significantly associated with histological grade, lymph nodes metastasis and clinical stage (all p < 0.05). The patients with low miR-455-3p expression had shorter survival time than those with high miR-455-3p expression. Furthermore, univariate and multivariate analysis identified low miR-455-3p expression as an unfavorable prognostic factor for overall survival. Moreover, transfection with the miR-455-3p mimic enhanced the cell proliferation and invasion in ESCC cells. Luciferase reporter assays confirmed that miR-455-3p binding to the 3'-UTR regions of FAM83F inhibited the expression of FAM83F in ESCC cells. Western blot confirmed that overexpression of miR-455-3p resulted in down-regulation of FAM83F in ESCC cells. Our findings indicate that miR-455-3p plays an anti-oncogenic role in the development of ESCC by downregulation of FAM83F and could be an independent marker for predicting the clinical outcome of ESCC patients.


Vesicovaginal fistula in Uganda.
Kitovu Hospital in Masaka, Uganda, is a leading obstetric fistula repair centre in the country with the highest rates of fistula in the world. In this retrospective case review, the regional incidence and causative factors were studied in patients with vesicovaginal fistula (VVF) who were admitted at Kitovu Hospital. Fistula history included severity (ICIQ score), causes and outcomes of VVF were measured. Women suffered with symptoms of VVF for an average of 4.97 years with an average ICIQ severity score of 7.21. Patients travelled an average distance of 153 km and the majority travelled by public transport. Rates of prolonged labour were high. 69% of fistula-causing delivery resulted in stillbirth and 12% resulted in early neonatal death. Following surgery, 94% of patients were dry on discharge. Impact statement What is already known on this subject? Vesicovaginal fistula (VVF) is a severe, life-changing injury. Although largely eradicated from the Western world thanks to modern obstetric practice, VVF is still highly prevalent in developing countries where factors such as young childbearing age and poor access to emergency obstetric care increase the incidence (Wall et al. 2005 ). At the current rate of fistula repair, it is estimated that it would take 400 years to treat those already suffering with fistula, providing that no new cases emerged (Browning and Patel 2004 ). What do the results of this study add? The Ugandan women in this study reiterate tales of foetal loss, social isolation and epic journeys in search of fistula repair, as previously described in the literature. The study offers some hope for prompt help-seeking during labour and after fistulas are developed. It demonstrates the success of fistula repairs at Kitovu Hospital but highlights the paucity of service provision across Uganda. What are the implications of these findings for clinical practice and/or further research? Further epidemiological research is required to quantify the true burden of the disease. Only by raising the profile of VVF in both developing and developed countries, can there be a collaborative effort to make universal change. To embark upon the prevention and cure of the disease it is necessary to continue tackling issues of poverty and gender inequality.


Inappropriate use of D-values for determining biocidal activity of various antimicrobials.
The objective of this study was to investigate the application of established D-value calculations to survival curves for various bacteria using the following antimicrobials: acidified sodium chlorite, triclosan, octanoic acid, and sodium hydroxide. D-values can be calculated in 3 ways, a linear regression, an endpoint calculation, or an average of multiple endpoint calculations. The assumption made in calculating a D-value is that the rate of kill follows 1st-order kinetics under specified treatment conditions. Each antimicrobial solution was challenged with approximately 108 CFU/mL of Staphylococcus aureus, Listeria monocytogenes, Salmonella enterica subsp. enterica, and Escherichia coli independently and in triplicate. Test systems were sampled at each of the 10 time points over a period of 7 min, neutralized, pour plated then incubated at 35 °C for 48 h (AOAC official method 960.09). Survival curves using the log-transformed data were calculated using regression analysis. Correlations coefficients for all linear regression analyses ranged between 0.291 and 0.982, with 6 of the 16 different treatment systems having an R2 value below 0.7. Methods used for calculating D-values should lead to the same result if the survival curve in a given condition is linear. The calculated D-values were different using endpoint analysis (Stumbo method), linear regression, and average of multiple endpoints. This study demonstrates the nonlinearity of inactivation curves of antimicrobials. D-value estimations cannot be reliably used to illustrate biocidal activity in antimicrobial test systems.


Anti-tumor necrosis factor treatment increases both the Th17 and Th22 T helper subsets in spondyloarthritis.
The aim was to examine anti-tumor necrosis factor α (anti-TNFα) therapy influence changes on Th17 and Th22 cells in patients with spondyloarthritis (SpA), and its correlation with changes in clinical and magnetic resonance imaging (MRI) activity and chronicity scores. The Th17 and Th22 cells were assessed at baseline, after 12 and 52 weeks of anti-TNFα therapy by flow cytometry (ClinicalTrials.gov NCT4682724). The percentages of both Th17 and Th22 cells were increased by 70% at baseline compared with healthy controls (both p < 0.01). During treatment, these two subsets increased further to be 170% (Th17) and 123% (Th22) above levels in healthy controls (both p < 0.01). The same subsets decrease their expression of IL-23R significantly during the observation period (p < 0.05). High levels of Th17 and Th22 cells at baseline were associated with the degree of chronic changes in the sacroiliac joints on MRI and a good clinical response to anti-TNFα treatment after one year. Plasma levels were not associated with clinical changes. Th17 cells, and Th22 subsets, increased during one year of anti-TNF-α therapy in SpA, regardless of their clinical improvement. This supports that both the Th17 and Th22 subsets could be involved in the progression in SpA.


Acoustic waveform inversion with application to seasonal snow covers.
The amplitude and waveform shape of atmospheric acoustic pulses propagating horizontally over a seasonal snow cover are profoundly changed by the air forced into the snow pores as the pulses move over the surface. This interaction greatly reduces the pulse amplitude and elongates the waveform compared to propagation above other ground surfaces. To investigate variations in snow-cover effects, acoustic pulses were recorded while propagating horizontally over 11 different naturally occurring snow covers during two winters. Two inversion procedures were developed to automatically match the observed waveforms by varying the snow-cover parameters in theoretical calculations. A simple frequency-domain technique to match the dominant frequency of the measured waveform suffered from multiple solutions and poor waveform matching, while a time-domain minimization method gave unique solutions and excellent waveform agreement. Results show that the effective flow resistivity and depth of the snow are the parameters controlling waveform shape, with the pore shape factor ratio of secondary importance. Inversion estimates gave flow resistivities ranging from 11 to 29 kN s m(-4), except for two late-season cases where values of 60 and 140 were determined (compared to 345 for the vegetation-covered site in the summer). Acoustically determined snow depths agreed with the measured values in all but one case, when the depth to a snow layer interface instead of the total snow depth was determined. Except for newly fallen snow, the pore shape factor ratio values clustered near two values that appear to correspond to wet (1.0) or dry (0.8) snow.


[Two variants of ornithine decarboxylase activity in the mouse liver. The nature of enzyme induction].
Ornithine decarboxylase activity in mouse liver is predominantly located in the cell nuclei. After injection of some inducing agents (thioacetamide, diethylnitrosamine, hydrocortisone) the enzyme leaves the nucleus for cytosol. A circadian rhythm of ornithine decarboxylase activity has been observed in nucleus and cytosol, the decrease of enzyme activity in the nucleus being accompanied by its increase in cytosol. The enzyme obtained from intact mice with a minimal level of ornithine decarboxylase activity in the cytosol differs in ion-exchange properties, pH-optimum and Km for ornithine from the thioacetamide stimulated (nucleus enzyme).


Conformational changes induced by polyanions in haemoglobin from Camelus dromedarius. Circular-dichroism study on the oxy derivative.
The c.d. spectrum of oxyhaemoglobin from Camelus dromedarius is significantly affected by the presence of inositol hexakisphosphate. Correlation with O2-binding measurements shows that these dichroic changes parallel the functional properties of the protein. The optical modifications suggest that, in contrast with human haemoglobin, the conformational changes induced by inositol hexakisphosphate on dromedary oxyhaemoglobin are mainly attributable to a local change of the tertiary structure reminiscent of that of the deoxy derivative, the quaternary conformation seeming to be almost unaffected. The results provide direct evidence of the existence on the protein of two distinct sites for polyanions.


Matrix Metalloproteinase-9 inhibitors as therapeutic drugs for traumatic brain injury.
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality among young adults and the elderly. In the United States, TBI is responsible for around 30 percent of all injuries brought on by injuries in general. Vasogenic cerebral edema due to blood-brain barrier (BBB) dysfunction and the associated elevation of intracranial pressure (ICP) are some of the major causes of secondary injuries following traumatic brain injury. Matrix metalloproteinase-9 (MMP-9) is a therapeutic target for being an enzyme that degrades the proteins that make up a part of the microvascular basal lamina as well as inter-endothelial tight junctions of the blood-brain barrier. MMP-9-mediated BBB dysfunctions and the compromise of the BBB is a major pathway that leads the development of vasogenic cerebral edema, elevation of ICP, poor cerebral perfusion and brain herniation following traumatic brain injury. That makes MMP-9 an effective therapeutic target and endogenous or exogenous MMP-9 inhibitors as therapeutic drugs for preventing secondary brain damage after traumatic brain injury. Although our understanding of the mechanisms that underlie the primary and secondary stages of damage following a TBI has significantly improved in recent years, such information has not yet resulted in the successful development of novel pharmacological treatment options for traumatic brain injury. Recent pre-clinical and/or clinical studies have demonstrated that there are several compounds with specific or non-specific MMP-9 inhibitory properties either directly binding and inhibiting MMP-9 or by indirectly inhibiting MMP-9, with potential as therapeutic agents for traumatic brain injury. This article reviews the efficacy of several such medications and potential agents that include endogenous and exogeneous compounds that are at various levels of research and development. MMP-9-based therapeutic drug development has enormous potential in the pharmacological treatment of cerebral edema and/or neuronal injury resulting from traumatic brain injury.


[Hemorrhoidal desarterialization guided by Doppler. A surgical alternative in hemorrhoidal disease management].
Hemorrhoidal disease is a common condition that includes 30% of patients seen for the first time at the Colon and Rectal Unit of the Gastroenterology Service, Hospital General in Mexico City. This study shows experience with hemorrhoidal desarterialization guided by Doppler in patients with internal hemorrhoidal disease stages II or III in the Coloproctology Units of the Hospital General in Mexico City and at the North Medical Unit in Monterrey, Nuevo Leon, Mexico. A prospective, longitudinal, and descriptive study was performed in 56 patients with diagnosis of internal hemorrhoids stages II or III, not complicated, and treated by hemorrhoidal artery ligation guided by Doppler between July 1, 2002 and April 31, 2003. 49 patients were included, 32 male (66%) and 17 female (34%), aged between 21 and 75 years with mean age of 43.5 years; 40 patients had internal hemorrhoids stage II (82%) and nine, stage III (18%). With a follow-up of 4 months or longer, all patients were symptomless: bleeding and hemorrhoidal prolapse disappeared. Doppler-Guided hemorrhoidal desarterialization is indicated in patients with internal hemorrhoids stages II or III; it is a simple technique that requires a short learning curve, minimal anesthetic and surgical materials, and pain after the procedure is mild and short-lived in the majority of patients.


Bone Marrow Homing Enriches Stem Cells Responsible for Neogenesis of Insulin-Producing Cells, While Radiation Decreases Homing Efficiency.
Small-sized adult bone marrow cells isolated by counterflow centrifugal elutriation and depleted of lineage markers (Fr25lin(-)) have the capacity to differentiate into insulin-producing cells and stabilize glycemic control. This study assessed competitive migration of syngeneic stem cells to the bone marrow and islets in a murine model of chemical diabetes. VLA-4 is expressed in ∼ 25% of these cells, whereas CXCR4 is not detected, however, it is transcriptionally upregulated (6-fold). The possibility to enrich stem cells by a bone marrow homing (BM-H) functional assay was assessed in sequential transplants. Fr25lin(-) cells labeled with PKH26 were grafted into primary myeloablated recipients, and mitotically quiescent Fr25lin(-)PKH(bright) cells were sorted from the bone marrow after 2 days. The contribution of bone marrow-homed stem cells was remarkably higher in secondary recipients compared to freshly elutriated cells. The therapeutic efficacy was further increased by omission of irradiation in the secondary recipients, showing a 25-fold enrichment of islet-reconstituting cells by the bone marrow homing assay. Donor cells identified by the green fluorescent protein (GFP) and a genomic marker in sex-mismatched transplants upregulated PDX-1 and produced proinsulin, affirming the capacity of BM-H cells to convert in the injured islets. There was no evidence of transcriptional priming of freshly elutriated subsets to express PDX-1, insulin, and other markers of endocrine progenitors, indicating that the bone marrow harbors stem cells with versatile differentiation capacity. Affinity to the bone marrow can be used to enrich stem cells for pancreatic regeneration, and reciprocally, conditioning reduces the competitive incorporation in the injured islets.


Charged colloids in an aqueous mixture with a salt.
We calculate the ion and composition distributions around colloid particles in an aqueous mixture, accounting for preferential adsorption, electrostatic interaction, selective solvation among ions and polar molecules, and composition-dependent ionization. On the colloid surface, we predict a precipitation transition induced by a strong preference of hydrophilic ions to water and a prewetting transition between weak and strong adsorption and ionization. These transition lines extend far from the solvent coexistence curve in the plane of the interaction parameter χ (or the temperature) and the average solvent composition. The colloid interaction is drastically altered by these phase transitions on the surface. In particular, the interaction is much amplified on bridging of wetting layers formed above the precipitation line. Such wetting layers can either completely or partially cover the colloid surface depending on the average solvent composition.


The use of solid-supported reagents for the multi-step synthesis of analytically pure alpha,beta-unsaturated compounds in miniaturized flow reactors.
Micro reaction technology offers a safe, controllable and information rich technique suitable for the long-term production of pharmaceutical agents and fine chemicals. To date however, few of the syntheses performed using this technology have addressed the problems associated with product purification. With this in mind, we report herein the incorporation of multiple supported reagents into EOF-based miniaturized flow reactors for the two-step synthesis of analytically pure compounds. Using this approach, the successful synthesis of 20 alpha,beta-unsaturated compounds in excellent yields (>99.1%) and purities (>99.9%) has been achieved, illustrating significant improvements compared to traditional batch techniques.


Ultraviolet microbeam irradiations of mitotic diatoms: investigation of spindle elongation.
Our simple instrumentation for generating a UV-microbeam is described UV microbeam irradiations of the central spindle in the pennate diatom Hantzschia amphioxys have been examined through correlated birefringence light microscopy and TEM. A precise correlation between the region of reduced birefringence and the UV-induced lesion in the microtubules (MTs) of the central spindle is demonstrated. The UV beam appears to dissociate MTs, as MT fragments were rarely encountered. The forces associated with metaphase and anaphase spindles have been studied via localized UV-microbeam irradiation of the central spindle. These spindles were found to be subjected to compressional forces, presumably exerted by stretched or contracting chromosomes. Comparisons are made with the results of other writers. These compressional forces caused the poles of a severed anaphase spindle to move toward each other and the center of the cell. As these poles moved centrally, the larger of the two postirradiational central spindle remnants elongated with a concomitant decrease in the length of the overlap. Metaphase spindles, in contrast, did not elongate nor lose their overlap region. Our interpretation is that the force for anaphase spindle elongation in Hantzschia is generated between half-spindles in the region of MT overlap.


Implementing clinical guidelines: how can informatics help?
Clinical guidelines are heralded as a positive contribution to improving quality of care and ensuring the effectiveness of care. From the perspective of the health services researcher, the authors propose a model of how informatics can support the implementation of clinical guidelines and their integration into systems for decision support and clinical audit. Each element of the model is discussed in turn.


Macrophage HIV-1 Gene Expression and Delay Resolution of Inflammation in HIV-Tg Mice.
While antiretroviral therapy increases the longevity of people living with HIV (PLWH), about 30% of this population suffers from three or more concurrent comorbidities, whose mechanisms are not well understood. Chronic activation and dysfunction of the immune system could be one potential cause of these comorbidities. We recently demonstrated reduced macrophage infiltration and delayed resolution of inflammation in the lungs of HIV-transgenic mice. Additionally, trans-endothelial migration of HIV-positive macrophages was reduced in vitro. Here, we analyze macrophages' response to LPS challenge in the kidney and peritoneum of HIV-Tg mice. In contrast to the lung infiltration, renal and peritoneal macrophage infiltrations were similar in WT and HIV-Tg mice. Higher levels of HIV-1 gene expression were detected in lung macrophages compared to peritoneal macrophages. In peritoneal macrophages, HIV-1 gene expression was increased when they were cultured at 21% O2 compared to 5% O2, inversely correlating with reduced trans-endothelial migration at higher oxygen levels in vitro. The resolution of macrophage infiltration was reduced in both the lung and the peritoneal cavity of HIV-Tg mice. Taken together, our study described the organ-specific alteration of macrophage dynamics in HIV-Tg mice. The delayed resolution of macrophage infiltration might constitute a risk factor for the development of multiple comorbidities in PLWH.


Demystifying values-affirmation interventions: writing about social belonging is a key to buffering against identity threat.
Two experiments examined for the first time whether the specific content of participant-generated affirmation essays-in particular, writing about social belonging-facilitated an affirmation intervention's ability to reduce identity threat among negatively stereotyped students. Study 1, a field experiment, revealed that seventh graders assigned to a values-affirmation condition wrote about social belonging more than those assigned to a control condition. Writing about belonging, in turn, improved the grade point average (GPA) of Black, but not White students. In Study 2, using a modified "belonging-affirmation" intervention, we directly manipulated writing about social belonging before a math test described as diagnostic of math ability. The more female participants wrote about belonging, the better they performed, while there was no effect of writing about belonging for males. Writing about social belonging improved performance only for members of negatively stereotyped groups. Implications for self-affirmation theory and practice are discussed.


Protein Corona Analysis of Silver Nanoparticles Links to Their Cellular Effects.
The breadth of applications of nanoparticles and the access to food-associated consumer products containing nanosized materials lead to oral human exposure to such particles. In biological fluids nanoparticles dynamically interact with biomolecules and form a protein corona. Knowledge about the protein corona is of great interest for understanding the molecular effects of particles as well as their fate inside the human body. We used a mass spectrometry-based toxicoproteomics approach to elucidate mechanisms of toxicity of silver nanoparticles and to comprehensively characterize the protein corona formed around silver nanoparticles in Caco-2 human intestinal epithelial cells. Results were compared with respect to the cellular function of proteins either affected by exposure to nanoparticles or present in the protein corona. A transcriptomic data set was included in the analyses in order to obtain a combined multiomics view of nanoparticle-affected cellular processes. A relationship between corona proteins and the proteomic or transcriptomic responses was revealed, showing that differentially regulated proteins or transcripts were engaged in the same cellular signaling pathways. Protein corona analyses of nanoparticles in cells might therefore help in obtaining information about the molecular consequences of nanoparticle treatment.


Coordinate developmental regulation of purine catabolic enzyme expression in gastrointestinal and postimplantation reproductive tracts.
Using histochemical detection, we have visualized in situ the complete metabolic pathway for the degradation of purine nucleotides. From the tongue to the ileum, diverse epithelial cell types lining the lumen of the mouse gastrointestinal (GI) tract strongly coexpress each of the five key purine catabolic enzymes. Dramatic increases in the expression of each enzyme occurred during postnatal maturation of the GI tract. Using in situ hybridization, an intense accumulation of adenosine deaminase (ADA) mRNA was detected only within GI epithelial cells undergoing postmitotic differentiation. In a similar manner, at the developing maternal-fetal interface, high level expression of the purine catabolic pathway also occurred in a unique subset of maternal decidual cells previously known to express high levels of alkaline phosphatase and ADA. This induction occurred almost immediately after implantation in the periembryonic maternal decidual cells, shortly thereafter in antimesometrial decidual cells, and later in cells of the placental decidua basalis: all of which contain cell types thought to be undergoing programmed cell death. The expression of the pathway at the site of embryo implantation appears to be critical because its pharmacologic inhibition during pregnancy has been found to be embryolethal or teratogenic. Purine destruction at these nutritional interfaces (placenta and gastrointestinal tract) seem to override any potential economy of purine salvage, and may represent biochemical adaptation to nucleic acid breakdown occurring in the context of dietary digestion or extensive programmed cell death.


Recruitment and Retention of Women Living With HIV for Clinical Research: A Review.
Women are underrepresented in HIV clinical research. However, there has not been a review on how to effectively recruit and retain women living with HIV in research. The purpose of this review is to describe recruitment and retention methods and factors associated with research participation among women living with HIV in the U.S. We searched PubMed, CINAHL, and Google and synthesized studies using thematic analysis. The most common method of recruiting women with HIV into research was through community-based HIV clinics, and the greatest yield was from word of mouth and a university HIV research center. Attrition may occur early and can be addressed by focusing on retention as early as study planning. Barriers to research participation for women can be addressed through retention methods discussed. We conclude that building relationships with community members and women living with HIV, being flexible, and implementing many methods is important for recruitment and retention.


The Internet and drug safety: what are the implications for pharmacovigilance?
Use of the Internet is becoming widespread throughout the world. Its use in the domain of drug safety and pharmacovigilance is spreading rapidly. Governments and industry have taken the lead in developing extensive web sites. The US Food and Drug Administration (FDA), the European Agency for the Evaluation of Medicinal Products (EMEA) and other agencies have developed sites containing enormous amounts of information both on pharmacovigilance in general and on specific drugs in particular. Under the US 'Freedom of Information Act' the FDA has put major parts of its adverse event database on line. Regulatory documents are also available from the FDA site or from hyperlinks described in the site. The US Center for Drug Evaluation and Research updates its site most days and maintains a free automated e-mail announcement service of these updates. Similarly, the EMEA updates its site frequently and publishes extensive material including regulatory documents, guidelines, European Public Assessment Reports on newly approved medications and other useful information. A free update service by e-mail is also available. Although English is the primary language used on the EMEA site, some of the information is available in other languages. Pharmaceutical companies are not using the Internet for pharmacovigilance yet. Rather, the Internet is being used for promotion of their products and for informing consumers on general information on diseases, for financial and investor data and for employment opportunities, etc. Other organisations such as lobbies, consumer groups and medical journals are also beginning to use the Internet. The electronic transmission of safety information, using the standards developed by the International Conference on Harmonization, is currently being tested for the transmission of individual patient adverse event information between companies and governments. In addition, the FDA has begun to accept adverse events from healthcare providers and consumers directly on line using an electronic version of its MedWatch form. It is expected that these developments will change the nature of the way pharmacovigilance is carried out. Significant issues will arise from this including privacy concerns. The European Union's 1995 directive on 'the protection of individuals with regard to the processing of personal data and on the free movement of such data (95/46/EC)' went into effect in October 1998. The enabling legislation now being passed by the member states will produce significant changes in the way companies and governments handle individual patient data in order to assure the privacy and protection of individuals.


Establishing Digital Biomarkers for Occupational Health Assessment in Commercial Salmon Fishermen: Protocol for a Mixed-Methods Study.
Commercial salmon fishing in Alaska is one of the most dangerous occupations in the United States. Between 1992 and 2008, the average annual industry mortality rate was 128 deaths per 100,000 workers, and despite an increase in industry regulations, there has not been a significant decrease in mortality rate since 2000. Unpredictable fishing openings and fierce competition for limited resources result in periods of intense sleep deprivation and physical strain during the short commercial salmon season in Alaska. We hypothesize that the combined effect of sleep deprivation, intense physical workload, and significant short-term chronic stress may be deleterious to health in both the short- and long-term among commercial salmon drift gillnet fishermen in Alaska. The objective of this protocol is to determine the feasibility of the study design to test this hypothesis. The study design uses mixed methods and includes biometric monitoring consisting of heart rate variability, respiration, and movement data collected via a personal, wearable biometric device. Additional methods include observational data on activity, including duration and quality of sleep, weather, catch, and financial gain, as well as the collection of salivary cortisol. As such, the study will provide a holistic assessment of individual stress on multiple simultaneous timescales: immediately and continuously through the personal wearable biometric device, on the minute-hour level through the multiple daily collections of salivary cortisol, and by the hour-day through the use of participant and environment observational data. Data collection was initiated in July 2017 and will extend through August 2019. Initial data collection has indicated that the methods outlined in this protocol are feasible and allow for effective collection of qualitative and quantitative data related to the psychological and physiological impact of Alaska commercial salmon fishing. We anticipate that the use of a biometric device will be crucial in establishing measures of stress and physical activity within a population and environment uniquely challenged by physical isolation, strong weather patterns, and the potential for significant financial gain by fishermen. The potential exists for individuals engaged long-term in the fishing industry, through repeated and extended exposure to periods of intense sleep deprivation and chronic stress, to be at increased risk of cardiovascular disease. DERR1-10.2196/10215.


Emergence of a Plasmid-Encoded Resistance-Nodulation-Division Efflux Pump Conferring Resistance to Multiple Drugs, Including Tigecycline, in Klebsiella pneumoniae.
Transporters belonging to the chromosomally encoded resistance-nodulation-division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria. However, the cotransfer of large gene clusters encoding RND-type pumps from the chromosome to a plasmid appears infrequent, and no plasmid-mediated RND efflux pump gene cluster has yet been found to confer resistance to tigecycline. Here, we identified a novel RND efflux pump gene cluster, designated tmexCD1-toprJ1, on plasmids from five pandrug-resistant Klebsiella pneumoniae isolates of animal origin. TMexCD1-TOprJ1 increased (by 4- to 32-fold) the MICs of tetracyclines (including tigecycline and eravacycline), quinolones, cephalosporins, and aminoglycosides for K.pneumoniae, Escherichia coli, and Salmonella TMexCD1-TOprJ1 is closely related (64.5% to 77.8% amino acid identity) to the MexCD-OprJ efflux pump encoded on the chromosome of Pseudomonas aeruginosa In an IncFIA plasmid, pHNAH8I, the tmexCD1-toprJ1 gene cluster lies adjacent to two genes encoding site-specific integrases, which may have been responsible for its acquisition. Expression of TMexCD1-TOprJ1 in E. coli resulted in increased tigecycline efflux and in K. pneumoniae negated the efficacy of tigecycline in an in vivo infection model. Expression of TMexCD1-TOprJ1 reduced the growth of E. coli and Salmonella but not K. pneumoniaetmexCD1-toprJ1-positive Enterobacteriaceae isolates were rare in humans (0.08%) but more common in chicken fecal (14.3%) and retail meat (3.4%) samples. Plasmid-borne tmexCD1-toprJ1-like gene clusters were identified in sequences in GenBank from Enterobacteriaceae and Pseudomonas strains from multiple continents. The possibility of further global dissemination of the tmexCD1-toprJ1 gene cluster and its analogues in Enterobacteriaceae via plasmids may be an important consideration for public health planning.IMPORTANCE In an era of increasing concerns about antimicrobial resistance, tigecycline is likely to have a critically important role in the treatment of carbapenem-resistant Enterobacteriaceae, the most problematic pathogens in human clinical settings-especially carbapenem-resistant K.pneumoniae Here, we identified a new plasmid-borne RND-type tigecycline resistance determinant, TMexCD1-TOprJ1, which is widespread among K. pneumoniae isolates from food animals. tmexCD1-toprJ1 appears to have originated from the chromosome of a Pseudomonas species and may have been transferred onto plasmids by adjacent site-specific integrases. Although tmexCD1-toprJ1 still appears to be rare in human clinical isolates, considering the transferability of the tmexCD1-toprJ1 gene cluster and the broad substrate spectrum of TMexCD1-TOprJ1, further dissemination of this mobile tigecycline resistance determinant is possible. Therefore, from a "One Health" perspective, measures are urgently needed to monitor and control its further spread. The current low prevalence in human clinical isolates provides a precious time window to design and implement measures to tackle this.


Fused-Ring Pyrrole-Based Near-Infrared Emissive Organic RTP Material for Persistent Afterglow Bioimaging.
Organic near-infrared room temperature phosphorescence (RTP) materials offer remarkable advantages in bioimaging due to their characteristic time scales and background noise elimination. However, developing near-infrared RTP materials for deep tissue imaging still faces challenges since the small band gap increases the non-radiative decay, resulting in weak emission and short phosphorescence lifetime. Here, fused-ring pyrrole-based structures were employed as the guest molecules for the construction of long wavelength RTP materials. Compared to the decrease of the singlet energy level, the triplet energy level showed a more effectively decrease with the increase of the conjugation of the substituent groups. Moreover, the sufficient conjugation of fused ring structures in the guest molecule suppresses the non-radiative decay of triplet excitons. Therefore, a near-infrared RTP material (764 nm) was achieved for deep penetration bioimaging. Tumor cell membrane is used to coat RTP nanoparticles (NPs) to avoid decreasing the RTP performance compared to traditional coating by amphiphilic surfactants. RTP NPs with tumor-targeting properties show favorable phosphorescent properties, superior stability, and excellent biocompatibility. These NPs are applied for time-resolved luminescence imaging to eliminate background interference with excellent tissue penetration. This study provides a practical solution to prepare long-wavelength and long-lifetime RTP materials and their applications in bioimaging.


Lung cancer patients who are asymptomatic at diagnosis show favorable prognosis: a korean Lung Cancer Registry Study.
The outcomes of lung cancer patients who were asymptomatic at diagnosis have never been reported as part of a large-scale study. A national survey of lung cancer in South Korea registered a total of 8788 patients diagnosed in 2005. We report the results herein, with an emphasis on the prognosis of the asymptomatic lung cancer patients. Adenocarcinoma was the most frequent (36.1%) histopathologic type, followed by squamous cell carcinoma (32.1%), large cell carcinoma (1.5%), and small cell carcinoma (13.5%). In most cases, lung cancer was detected with subjective symptoms, but 6.5% of cases had no symptoms indicative of lung cancer at the time of diagnosis. Compared to symptomatic patients, asymptomatic patients were younger, more often female, non-smokers, and more frequently presented with adenocarcinoma. Initial treatments were surgery (22.1%), radiation therapy (7.8%), chemo-radiation therapy (5.4%), and chemotherapy (38%), while 26.6% of patients were recorded to have supportive care only. Asymptomatic patients received surgery in 60.0% of cases, and they showed significantly longer survival times than symptomatic patients. Absence of symptoms at diagnosis significantly reduced the risk of death from non-small cell lung cancer, regardless of patient age, patient gender, stage at diagnosis, smoking history, or whether treatment was performed, but did not reduce the risk of death from small cell lung cancer. Adenocarcinoma has grown to be the leading histopathologic type of lung cancer in South Korea. Absence of symptom at diagnosis is a favorable prognostic factor for patients with non-small cell lung cancer.


The number of deformed joints as a surrogate measure of damage in rheumatoid arthritis.
To evaluate the reliability and validity of the number of deformed joints (NDJ) as a surrogate measure of joint damage in rheumatoid arthritis (RA). We tested interrater reliability and validity in determining the NDJ as a surrogate for joint damage in consecutive patients with RA. We rated each of 48 joints as normal or abnormal in terms of alignment and range of motion, and expressed the results as the total number of deformed joints. We compared the NDJ with the severity of damage on a plain radiograph of the hands, scored using Sharp's technique, as the gold standard measure of joint damage. We also compared the correlation between the NDJ and radiographic joint damage, on the one hand, and disease duration, performance-based measures of physical function, and the self-reported level of disability. The interrater reliability of the NDJ was excellent, with an intraclass correlation among four examiners of 0.94. To assess validity of the NDJ, we studied 273 RA patients from 5 clinical settings. Their average NDJ was 14 (range 0-43), and their average Sharp's score for joint space narrowing and erosions combined was 106 (range 4-309). The NDJ and the total Sharp's score were highly correlated (r = 0.83). Both measures were correlated to a similar degree with disease duration (r = 0.51 for each measure), grip strength (r = -0.49 for NDJ, and r = -0.51 for Sharp's score), walking velocity (r = -0.44 for NDJ, and r = -0.45 for Sharp's score), the timed button test (r = -0.62 for NDJ, and r = -0.57 for Sharp's score), and the Modified Health Assessment Questionnaire (r = 0.38 for NDJ, and r = 0.38 for Sharp's score). Both the Sharp's score and the NDJ worsened significantly in 38 patients for whom 1-2 year followup data were available. The NDJ is reliable and is strongly associated with the standard measure of joint damage in RA. Because it is easily performed in a clinical setting, it could be used as an economical surrogate of joint damage in studies of the long-term outcome of RA.


The Role of External Inputs and Internal Cycling in Shaping the Global Ocean Cobalt Distribution: Insights From the First Cobalt Biogeochemical Model.
Cobalt is an important micronutrient for ocean microbes as it is present in vitamin B12 and is a co-factor in various metalloenzymes that catalyze cellular processes. Moreover, when seawater availability of cobalt is compared to biological demands, cobalt emerges as being depleted in seawater, pointing to a potentially important limiting role. To properly account for the potential biological role for cobalt, there is therefore a need to understand the processes driving the biogeochemical cycling of cobalt and, in particular, the balance between external inputs and internal cycling. To do so, we developed the first cobalt model within a state-of-the-art three-dimensional global ocean biogeochemical model. Overall, our model does a good job in reproducing measurements with a correlation coefficient of >0.7 in the surface and >0.5 at depth. We find that continental margins are the dominant source of cobalt, with a crucial role played by supply under low bottom-water oxygen conditions. The basin-scale distribution of cobalt supplied from margins is facilitated by the activity of manganese-oxidizing bacteria being suppressed under low oxygen and low temperatures, which extends the residence time of cobalt. Overall, we find a residence time of 7 and 250 years in the upper 250 m and global ocean, respectively. Importantly, we find that the dominant internal resupply process switches from regeneration and recycling of particulate cobalt to dissolution of scavenged cobalt between the upper ocean and the ocean interior. Our model highlights key regions of the ocean where biological activity may be most sensitive to cobalt availability.


The BBaRTS Healthy Teeth Behaviour Change Programme for preventing dental caries in primary school children: study protocol for a cluster randomised controlled trial.
Oral health behaviours such as establishing twice-daily toothbrushing and sugar control intake need parental self-efficacy (PSE) to prevent the development of childhood dental caries. A previous study has shown that behaviour change techniques (BCTs) delivered via a storybook can improve parental self-efficacy to undertake twice-daily toothbrushing. to determine whether an intervention (BBaRTS, Bedtime Brush and Read Together to Sleep), designed to increase PSE; delivered through storybooks with embedded BCTs, parenting skills and oral health messages, can improve child oral health compared to (1) an exactly similar intervention containing no behaviour change techniques, and (2) the BBaRTS intervention supplemented with home supply of fluoride toothpaste and supervised toothbrushing on schooldays. A 2-year, three-arm, multicentre, cluster randomised controlled trial. children (estimated 2000-2600) aged 5-7 years and their families from 60 UK primary schools. Test group 1: a series of eight children's storybooks developed by a psychologist, public health dentist, science educator, children's author and illustrators, with guidance from the Department for Education (England). The books feature animal characters and contain embedded dental health messages, parenting skills and BCTs to promote good oral health routines focused on controlling sugar intake and toothbrushing, as well as reading at bedtime. Books are given out over 2 years. Test group 2: as Test group 1 plus home supplies of fluoride toothpaste (1000 ppmF), and daily supervised toothbrushing in school on schooldays. Active Control group: series of eight books with exactly the same stories, characters and illustrations, but without BCTs, dental health messages or parenting skills. Annual child dental examinations and parental questionnaires will be undertaken. A sub-set of participants will be invited to join an embedded study of the child's diet and salivary microbiota composition. dental caries experience in permanent teeth at age 7-8 years. A multi-disciplinary team was established to develop the BBaRTS Children's Healthy Teeth Programme. The books were developed in partnership with the Department for Education (England), informed by a series of focus groups with children, teachers and parents. ISRCTN21461006 (date of registration 23 September 2015).


[Prophylaxis of thrombohemorrhagic complications in surgical treatment of chemoresistant pulmonary tuberculosis].
Analysis of thrombohemorrhagic complications was conducted in 98 patients, operated on for various forms of chemoresistant pulmonary tuberculosis. To prevent such complications it is necessary to prescribe heparin in minimal doses or fraxiparine preoperatively and intraoperatively. It permits to lower the prethrombotic background significantly, to prevent thrombohemorrhagic complications, and in their incidence--to eliminate thrombotic and hemorrhagic clinical features with minimal losses.


Synergistic Antiviral Effects of Metal Oxides and Carbon Nanotubes.
In this research, the synergistic antiviral effects of carbon nanotubes (CNTs) and metal oxides (MO) in the form of novel hybrid structures (MO-CNTs) are presented. Raw CNTs, Ni(OH)2, Fe2O3 and MnO2, as well as Ni(OH)2-CNT, Fe2O3-CNT and MnO2-CNT were explored in this study against Escherichia. coli MS2 bacteriophage, which was used as a virus surrogate. The nano particles were synthesized and characterized using field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), particle size analysis, Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). Kinetic parameters such as the LD50 (lethal dose to kill 50% of the population), T50 and T80 (time taken to kill 50% and 80% of the population), SGR (specific growth rate) and IRD (initial rate of deactivation of the population) were also studied to examine the antiviral efficacy of these nanomaterials. Among all the nanomaterials, Ni(OH)2-CNT was the most effective antiviral agent followed by Fe2O3-CNT, MnO2-CNT, raw CNTs, Ni(OH)2, Fe2O3 and MnO2. When comparing the metal oxide-CNTs to the raw CNTs, the average enhancement was 20.2%. The average antiviral activity enhancement of the MO-CNTs were between 50 and 54% higher than the MO itself. When compared to the raw CNTs, the average enhancement over all the MO-CNTs was 20.2%. The kinetic studies showed that the LD50 of Ni(OH)2-CNT was the lowest (16µg/mL), which implies that it was the most toxic of all the compounds studied. The LD50 of Ni(OH)2, Fe2O3 and MnO2 were 17.3×, 14.5× and 10.8× times greater than their corresponding hybrids with the CNTs. The synergistic mechanism involved the entrapment of phage viruses by the nano structured CNTs leading to structural damage along with toxicity to phage from the release of MO ions. The metal oxide-CNT nano hybrids developed in this project are promising candidates in applications such as antiviral coatings, nanocomposites, adsorbents and as components of personal protection gears.


Feather colour affects the aggressive behaviour of chickens with the same genotype on the dominant white (I) locus.
Aggression in chickens is a serious economic and animal welfare issue in poultry farming. Pigmentation traits have been documented to be associated with animal behaviour. Chicken pecking behaviour has been found to be related to feather colour, with premelanosome protein 17 (PMEL17) being one of the candidate genes. In the present study, we performed a genotypic and phenotypic association analysis between chicken plumage colour (red and white) and aggressive behaviour in an F1 hybrid group generated by crossing the autosomal dominant white-feathered breed White Leghorn (WL) and the red-feathered breed Rhode Island Red (RIR). In genetic theory, all the progeny should have white feathers because WL is homozygous autosomal dominant for white feathers. However, we found a few red-feathered female chickens. We compared the aggressiveness between the red and white females to determine whether the feather colour alone affected the behaviour, given that the genetic background should be the same except for feather colour. The aggressiveness was recorded 5 days after sexual maturity at 26 weeks. Generally, white plumage hens showed significantly higher aggressiveness compared to the red ones in chasing, attacking, pecking, and threatening behaviour traits. We assessed three candidate feather colour genes-PMEL17, solute carrier family 45 member 2 (SLC45A2), and SRY-box 10 (SOX10)-to determine the genetic basis for the red and white feather colour in our hybrid population; there was no association between the three loci and feather colour. The distinct behavioural findings observed herein provide clues to the mechanisms underlying the association between phenotype and behaviour in chickens. We suggest that mixing red and white chickens together might reduce the occurrence of aggressive behaviours.


Differential induction of FosB isoforms throughout the brain by fluoxetine and chronic stress.
Major depressive disorder is thought to arise in part from dysfunction of the brain's "reward circuitry", consisting of the mesolimbic dopamine system and the glutamatergic and neuromodulatory inputs onto this system. Both chronic stress and antidepressant treatment regulate gene transcription in many of the brain regions that make up these circuits, but the exact nature of the transcription factors and target genes involved in these processes remain unclear. Here, we demonstrate induction of the FosB family of transcription factors in ∼25 distinct regions of adult mouse brain, including many parts of the reward circuitry, by chronic exposure to the antidepressant fluoxetine. We further uncover specific patterns of FosB gene product expression (i.e., differential expression of full-length FosB, ΔFosB, and Δ2ΔFosB) in brain regions associated with depression--the nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus--in response to chronic fluoxetine treatment, and contrast these patterns with differential induction of FosB isoforms in the chronic social defeat stress model of depression with and without fluoxetine treatment. We find that chronic fluoxetine, in contrast to stress, causes induction of the unstable full-length FosB isoform in the NAc, PFC, and hippocampus even 24 h following the final injection, indicating that these brain regions may undergo chronic activation when fluoxetine is on board, even in the absence of stress. We also find that only the stable ΔFosB isoform correlates with behavioral responses to stress. These data suggest that NAc, PFC, and hippocampus may present useful targets for directed intervention in mood disorders (ie, brain stimulation or gene therapy), and that determining the gene targets of FosB-mediated transcription in these brain regions in response to fluoxetine may yield novel inroads for pharmaceutical intervention in depressive disorders.


[International survey of the status of dosimetry for controlling quality assurance in radiotherapy (WHO)].
The results of an IAEA/WHO 14-year survey on the precision of irradiation at a preset dose (2 Gy) in radiotherapy departments in different countries have shown that nearly in 40% of cases deviations from a preset dose exceeded the tolerant rate (+/- 5%). A conclusion has been made of the necessity to develop a program of quality guarantee in radiotherapy at national and international levels.


A re-examination of adult mouse nicotinic acetylcholine receptor channel activation kinetics.
1. During routine sequencing of our mouse muscle alpha subunit acetylcholine receptor channel (AChR) cDNA clones, we detected a discrepancy with the GenBank database entry (accession X03986). At nucleotides 1305-7 (residue 433, in the M4 domain) the database lists GTC which encodes a valine, while our putative 'wild-type' cDNA had the nucleotides GCC, which encodes an alanine. No other sequence differences were found. 2. PCR amplification of genomic DNA confirmed that the BALB/C mouse alpha subunit gene has a T nucleotide at position 1306, and, therefore, that the protein has a V at position 433 in the M4 segment. 3. In order to determine the functional consequences of this difference, either wild-type (V433) or mutant (A433) alpha subunits were co-expressed in HEK cells with mouse beta, epsilon and delta subunits. Single-channel currents were recorded in cell-attached patches, and rate and equilibrium constants were estimated from open and closed durations obtained from a range of ACh concentrations. No significant differences were found between the activation rate constants or equilibrium constants of the V433 and A433 variants. 4. Kinetic modelling of alphaV433 AChR suggests that the two transmitter binding sites have similar dissociation equilibrium constants for acetylcholine ( approximately 160 microM in 142 mM extracellular KCl). 5. Diliganded AChRs occupy a closed state that has a lifetime of approximately 1 ms. The rate constants for entering and leaving this state do not vary with the ACh concentration. 6. The kinetics of a mutant AChR that causes a slow channel congenital myaesthenic syndrome, alphaG153S, was re-examined. The properties of this mutant were similar with a V or an A at position alpha433.


The antitumor monoclonal antibody 806 recognizes a high-mannose form of the EGF receptor that reaches the cell surface when cells over-express the receptor.
Overexpression of the EGFR is commonly caused by EGFR gene amplification and is sometimes associated with expression of a variant EGFR (de2-7 EGFR or EGFRvIII) bearing an internal deletion in its extracellular domain. mAb 806 is a novel EGFR antibody with significant antitumor activity that recognizes both the de2-7 EGFR and a subset of the wild-type (wt) EGFR when overexpressed, but does not bind the EGFR expressed in normal tissues. Recently, we demonstrated that the mAb 806 epitope is restricted to a short cysteine loop of the EGFR (amino acids 287-302) that is only available for antibody binding in a transitional form of the receptor, which occurs as the receptor changes from its inactive tethered conformation to a dimeric untethered form. The truncation associated with the de2-7 EGFR mutation renders this receptor constitutively untethered, leading to increased binding of mAb 806. We now show that mAb 806 preferentially binds the immature high-mannose wt and de2-7 EGFR precursors normally located in the endoplasmic reticulum, indicating that this form of the wt EGFR is also constitutively untethered. Using the unique specificity of mAb 806, we clearly demonstrated the presence of these high-mannose EGFR precursors on the cell surface. Given that the high-mannose forms of the wt EGFR must be untethered they may contribute to the spontaneous EGFR signaling reported in cells overexpressing the receptor. These precursor forms of the EGFR thus represent novel tumor targets and contribute to the exceptional selectivity of mAb 806 for EGFR when overexpressed in cancer cells. As our observations are likely to apply to other receptors overexpressed in cancer, they suggest a strategy for developing antitumor antibodies even when the target receptor is expressed in normal tissue.


Sexually divergent DNA methylation patterns with hippocampal aging.
DNA methylation is a central regulator of genome function, and altered methylation patterns are indicative of biological aging and mortality. Age-related cellular, biochemical, and molecular changes in the hippocampus lead to cognitive impairments and greater vulnerability to neurodegenerative disease that varies between the sexes. The role of hippocampal epigenomic changes with aging in these processes is unknown as no genome-wide analyses of age-related methylation changes have considered the factor of sex in a controlled animal model. High-depth, genome-wide bisulfite sequencing of young (3 month) and old (24 month) male and female mouse hippocampus revealed that while total genomic methylation amounts did not change with aging, specific sites in CG and non-CG (CH) contexts demonstrated age-related increases or decreases in methylation that were predominantly sexually divergent. Differential methylation with age for both CG and CH sites was enriched in intergenic and intronic regions and under-represented in promoters, CG islands, and specific enhancer regions in both sexes, suggesting that certain genomic elements are especially labile with aging, even if the exact genomic loci altered are predominantly sex-specific. Lifelong sex differences in autosomal methylation at CG and CH sites were also observed. The lack of genome-wide hypomethylation, sexually divergent aging response, and autosomal sex differences at CG sites was confirmed in human data. These data reveal sex as a previously unappreciated central factor of hippocampal epigenomic changes with aging. In total, these data demonstrate an intricate regulation of DNA methylation with aging by sex, cytosine context, genomic location, and methylation level.


Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies.
Cell-based immunotherapy in settings of allogeneic stem cell transplantation or donor leukocyte infusion has curative potential, especially in hematologic malignancies. However, this approach is severely restricted due to graft-versus-host disease (GvHD). This limitation may be overcome if target antigens are molecularly defined and effector cells are specifically selected. We chose formin-related protein in leukocytes 1 (FMNL1) as a target antigen after intensive investigation of its expression profile at the mRNA and protein levels. Here, we confirm restricted expression in peripheral blood mononuclear cells (PBMCs) from healthy donors but also observe overexpression in different leukemias and aberrant expression in transformed cell lines derived from solid tumors. We isolated allorestricted T-cell clones expressing a single defined TCR recognizing a particular HLA-A2-presented peptide derived from FMNL1. This T-cell clone showed potent antitumor activity against lymphoma and renal cell carcinoma cell lines, Epstein-Barr virus (EBV)-transformed B cells, and primary tumor samples derived from patients with chronic lymphocytic leukemia (CLL), whereas nontransformed cells with the exception of activated B cells were only marginally recognized. Allorestricted TCRs with specificity for naturally presented FMNL1-derived epitopes may represent promising reagents for the development of adoptive therapies in lymphoma and other malignant diseases.


Oxidation of protoporphyrinogen in the obligate anaerobe Desulfovibrio gigas.
The anaerobic oxidation of protoporphyrinogen to protoporphyrin was demonstrated in extracts of Desulfovibrio gigas. Protoporphyrin formation occurred in the presence of nitrite, hydroxylamine, sulfite, thiosulfate, ATP plus sulfate, NAD+, NADP+, flavin adenine dinucleotide, flavin mononucleotide, fumarate, 2,6-dichlorophenol-indophenol, methyl viologen, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. With dialyzed cell extracts, highest activities were observed with sulfite, NAD+, and NADP+ as electron acceptors. The enzyme for protoporphyrinogen oxidation was localized in the membrane of D. gigas and displayed optimal activity at pH 7.3 and 28 degrees C.


Pharmacogenetics of lithium prophylaxis in mood disorders: analysis of COMT, MAO-A, and Gbeta3 variants.
We studied the possible association between the prophylactic efficacy of lithium in mood disorders and the following gene variants: catechol-O-methyltransferase (COMT) G158A, monoamine oxydase A (MAO-A) 30-bp repeat, G-protein beta 3-subunit (Gbeta3) C825T. A total of 201 subjects affected by bipolar (n = 160) and major depressive (n = 41) disorder were followed prospectively for an average of 59.8 months and were typed for their gene variants using PCR techniques. COMT, MAO-A, and Gbeta3 variants were not associated with lithium outcome, even when possible stratification effects such as sex, polarity, age at onset, duration of lithium treatment, and previous episodes were included in the model. The pathways influenced by those variants are not therefore involved with long-term lithium outcome in our sample.


Cholera vaccination in urban Haiti.
Successful and sustained efforts have been made to curtail the major cholera epidemic that occurred in Haiti in 2010 with the promotion of hygiene and sanitation measures, training of health personnel and establishment of treatment centers nationwide. Oral cholera vaccine (OCV) was introduced by the Haitian Ministry of Health as a pilot project in urban and rural areas. This paper reports the successful OCV pilot project led by GHESKIO Centers in the urban slums of Port-au-Prince where 52,357 persons received dose 1 and 90.8% received dose 2; estimated coverage of the at-risk community was 75%. This pilot study demonstrated the effort, community mobilization, and organizational capacity necessary to achieve these results in a challenging setting. The OCV intervention paved the way for the recent launching of a national cholera vaccination program integrated in a long-term ambitious and comprehensive plan to address Haiti's critical need in water security and sanitation.


[Ultrastructural morphometry of liver parenchyma in hepatitic cirrhosis].
An ultrastructural morphometric study was carried out to detect differences in parenchymal structures between chronic viral hepatitis and hepatitic cirrhosis for more reliable diagnosis of cirrhosis in needle biopsy. Five human liver biopsy specimens were selected from each of the following five groups: chronic persistent hepatitis (CPH), mild chronic active hepatitis (MCAH), severe chronic active hepatitis (SCAH), active hepatitic cirrhosis (AHC) and inactive hepatitic cirrhosis (IHC). The ultrastructural changes in hepatitic cirrhosis which differed from those in chronic hepatitis were: (1) increase in the volume fraction (Vv) of hepatic intercellular space with increased Vv of collagen fibers and less microvilli in the space; (2) decrease in the Vv of perisinusoidal space with more collagen fibers and less microvilli; (3) decreased Vv and surface density (Sv) of RER in hepatocytes; (4) decreased Vv without change in Sv of mitochondria of hepatocytes.


Spin correlations and magnetic order in nonsuperconducting Nd(2-x)Ce(x)CuO(4+/-delta).
We report quantitative neutron scattering measurements of the evolution with doping of the Néel temperature, the antiferromagnetic correlations, and the ordered moment of as-grown, nonsuperconducting Nd(2-x)Ce(x)CuO(4+/-delta) (0</=x</=0.18). The instantaneous correlation length can be effectively described by our quantum Monte Carlo calculations for the randomly site-diluted nearest-neighbor spin-1/2 square-lattice Heisenberg antiferromagnet. However, quantum fluctuations have a stronger effect on the ordered moment, which decreases more rapidly than for the quenched-disorder model.


The relationship between perceived exertion and physiologic indicators of stress during graded arm exercise in persons with spinal cord injuries.
To examine the relationship between psychologic cues of somatic stress and physiologic responses to exercise in persons with paraplegia and tetraplegia. Repeated measures with 2 comparison groups. Academic medical center. Forty-two subjects between 18 and 69 years of age with motor-complete spinal cord injury (SCI) resulting in paraplegia or tetraplegia (American Spinal Injury Association grades A and B). Not applicable. Subjects underwent peak graded arm ergometry during which heart rate, oxygen consumption (VO2), minute ventilation (VE), and ratings of perceived exertion (RPE) (Borg Categorical 6-20 Scale) were measured at successive work rate increments from baseline to fatigue. There were inconsistent associations among the outcomes. For subjects with tetraplegia, RPE related positively to heart rate at the initial work rate, but there were no other significant correlations. For subjects with paraplegia, RPE did not correlate significantly with heart rate, VO2, or VE. VO2 and Ve related positively at the first and last work rates. In general, heart rate, VO2, and Ve increased as the exercise intensity increased, and were more pronounced in subjects with paraplegia. While RPE values increased with increasing work rates for each group, we found no differences between groups. Our findings contradict the well-accepted relationships between RPE and both heart rate and VO2 during exercise by people without disabilities, and challenge the use of RPE as a valid psychophysiologic index of perceived exertion in persons with SCI.


Cognitive-behavioral stress management relieves anxiety, depression, and post-traumatic stress disorder in parents of pediatric acute myeloid leukemia patients: a randomized, controlled study.
Cognitive-behavioral stress management (CBSM) is an effective psychological intervention to relieve psychological and symptomatic distress. This study aimed to investigate the effect of CBSM in anxiety, depression, and post-traumatic stress disorder (PTSD) in parents of pediatric acute myeloid leukemia (AML) patients. Totally, 56 pediatric AML patients and 100 parents were randomized into the CBSM group (28 patients and 49 parents) and the normal control (NC) group (28 patients and 51 parents) to receive corresponding interventions for 10 weeks. The questionnaire scores were assessed at month M0, M1, M3, and M6. In parents of pediatric AML patients, self-rating anxiety scale score at M1 (p = 0.034), M3 (p = 0.010), and M6 (p = 0.003), as well as anxiety at M3 (p = 0.036) and M6 (p = 0.012) were decreased in the CBSM group versus the NC group. Self-rating depression scale score at M3 (p = 0.022) and M6 (p = 0.002), as well as depression at M6 (p = 0.019) were declined in the CBSM group versus the NC group. Symptom checklist-90 (a psychotic status questionnaire) score at M3 (p = 0.031) and M6 (p = 0.019) were declined in the CBSM group versus the NC group. Regarding PTSD, the impact of the events scale-revised score at M3 (p = 0.044) and M6 (p = 0.010) were decreased in the CBSM group versus the NC group. By subgroup analyses CBSM (versus NC) improved all outcomes in parents with anxiety at M0 and depression at M0 (all p < 0.050), but could not affect the outcomes in parents without anxiety or depression at M0 (all p > 0.050). CBSM reduces anxiety, depression, and PTSD in parents of pediatric AML patients.


Prevalence of Hypertension and its Determinants among Policemen in a City of Haryana, India.
Noncommunicable diseases (NCDs) kill 40 million people each year, equivalent to 70% of all deaths globally. Cardiovascular diseases account for most NCD deaths or 17.7 million people annually. Police work has been regarded by some researchers as one of the most stressful occupations in the world, and coronary heart disease has been identified as a major cause of mortality in this population. A cross-sectional study was carried out during July 2016-June 2017 among 450 policemen posted in Rohtak city of Haryana selected randomly. The investigator made two measurements of blood pressure. Data were collected using predesigned, pretested, semi-structured interview schedule, and analyzed using the Statistical Package for the Social Sciences version 20.0. Of 450 participants, 164 (36.4%) participants were found to be hypertensive. Age of study participants, duration of service, rank, and education are significantly associated with the prevalence of hypertension (HTN) among policemen. HTN in policemen has emerged as an important public health problem. Knowledge of risk factors for HTN may give tracks for prevention in this population. Therefore, it is the need of hour to devise a sound screening strategy to diagnose HTN among policemen and devise a comprehensive strategy for the management of HTN.


Developmental and hormonal regulation of NR2A mRNA in forebrain regions controlling avian vocal learning.
Developmental changes in the composition of NMDA receptors can alter receptor physiology as well as intracellular signal transduction cascades, potentially shifting thresholds for neural and behavioral plasticity. During song learning in zebra finches, NMDAR currents become faster, and transcripts for the modulatory NR2B subunit of this receptor decrease in lMAN, a region in which NMDAR activation is critical for vocal learning. Using in situ hybridization, we found that NR2A transcripts change reciprocally, increasing significantly in both lMAN (59%) and in another song region, Area X (38%), between posthatch day (PHD) 20 and 40, but not changing further at PHD60 or 80. In adjacent areas not associated with song learning, NR2A mRNA did not change between PHD20-80. Although early song deprivation (which extends the sensitive period for song learning) delays changes in NR2B gene expression and NMDAR physiology within the lMAN, it did not alter NR2A mRNA levels measured at PHD40, 45, or 60. Early testosterone (T) treatment, which disrupts vocal development and accelerates the maturation of both NR2B levels and NMDAR physiology in lMAN, also significantly increased NR2A transcripts measured at PHD35 in lMAN. In Area X, a similar effect of T approached significance. Together with our previous studies, these results show that in a pathway critical for vocal plasticity, the ratio of NR2A:NR2B mRNA rises abruptly early during the sensitive period for song learning. Furthermore, androgen regulation of NMDAR gene expression may alter thresholds for experience-dependent synaptic change.


Regional distribution of cocaine in postmortem brain of chronic human cocaine users.
We measured concentrations of cocaine and its major metabolites (benzoylecgonine, ecgonine methylester, norcocaine, and cocaethylene) in 15 autopsied brain regions of 14 human chronic cocaine users. Only slight differences were observed in concentrations of cocaine and its metabolites amongst the examined brain areas. Although it is likely that some postmortem redistribution of the drug must have occurred, our data are consistent with the possibility that behaviorally relevant doses of cocaine are widely distributed throughout the brain of humans who use the drug on a chronic basis. Consideration should therefore be given to the possible pharmacological and toxicological actions of cocaine in both striatal and extra-striatal brain areas in human users of the drug.


Munc18b/STXBP2 is required for platelet secretion.
Platelets are vital for hemostasis because they release their granule contents in response to vascular damage. Platelet exocytosis is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), whose interactions are governed by regulators, eg, Sec/Munc18 proteins. These proteins chaperone syntaxin t-SNAREs and are required for exocytosis. Platelets contain 3 Munc18 isoforms: Munc18a, Munc18b, and Munc18c. We report that Munc18b is the major isoform and is required for platelet secretion. Familial hemophagocytic lymphohistiocytosis type 5 (FHL5) is caused by defects in the Munc18b/STXBP2 gene. We confirm a previous report showing that platelets from FHL5 patients have defective secretion. Serotonin, ADP/ATP, and platelet factor 4 release was profoundly affected in the 2 biallelic patients and partially in a heterozygous patient. Release of lysosomal contents was only affected in the biallelic platelets. Platelets from the FHL5 biallelic patients showed decreased Munc18b and syntaxin-11 levels were significantly reduced; other syntaxins were unaffected. Munc18b formed complexes with syntaxin-11, SNAP-23, and vesicle-associated membrane protein-8 in human platelets. Other potential secretion regulators, Munc13-4 and Rab27, were also found associated. These data demonstrate a key role for Munc18b, perhaps as a limiting factor, in platelet exocytosis and suggest that it regulates syntaxin-11.


Triggers of acute attacks of gout, does age of gout onset matter? A primary care based cross-sectional study.
To determine the proportion of people with gout who self-report triggers of acute attacks; identify the commonly reported triggers, and examine the disease and demographic features associated with self-reporting any trigger(s) of acute attacks of gout. Individuals with gout were asked to fill a questionnaire enquiring about triggers that precipitated their acute gout attacks. Binary logistic regression was used to compute odds ratio (OR) and 95% confidence intervals (CI) to examine the association between having ≥1 self-reported trigger of acute gout and disease and demographic risk factors and to adjust for covariates. All statistical analyses were performed using STATA. 550 participants returned completed questionnaires. 206 (37.5%) reported at least one trigger of acute attacks, and less than 5% reported >2 triggers. Only 28.73% participants reported that their most recent gout attack was triggered by dietary or lifestyle risk factors. The most frequently self-reported triggers were alcohol intake (14.18%), red-meat or sea-food consumption (6%), dehydration (4.91%), injury or excess activity (4.91%), and excessively warm or cold weather (4.36% and 5.45%). Patients who had onset of gout before the age of 50 years were significantly more likely to identify a trigger for precipitating their acute gout attacks (aOR (95%CI) 1.73 (1.12-2.68) after adjusting for covariates. Most people with gout do not identify any triggers for acute attacks, and identifiable triggers are more common in those with young onset gout. Less than 20% people self-reported acute gout attacks from conventionally accepted triggers of gout e.g. alcohol, red-meat intake, while c.5% reported novel triggers such as dehydration, injury or physical activity, and weather extremes.


Probing the importance of ionic liquid structure: a general ionic liquid effect on an S(N)Ar process.
The effect of a range of ionic liquids, with systematic variations in the cation and anion, on the rate constant of an aromatic substitution process was investigated. Temperature-dependent kinetic data allowed calculation of activation parameters for the process in each solvent. These data demonstrate a generalised ionic liquid effect, with an increase in rate constant observed in each ionic solvent, though the microscopic origins of the rate constant enhancement differ with the nature of the ionic liquid.


Testing the original and the extended dual-pathway model of lack of control over eating in adolescent girls. A two-year longitudinal study.
Stice's (1994, 2001) dual pathway model proposed a mediational sequence that links body dissatisfaction to lack of control over eating through dieting and negative affect. Van Strien et al. (2005) extended the negative affect pathway of the original dual pathway model by adding two additional intervening variables: interoceptive deficits and emotional eating. The purpose of this study was to test and compare the original and extended model using prospective data. Both types of loss of control over eating (i.e., subjective and objective binge eating) were evaluated. Data collected from 361 adolescent girls, who were interviewed and completed self-report measures annually over a 2-year period, were analysed using structural equation modeling. Although both models provided a good fit to the data, the extended model fit the adolescent girls' sample data better and accounted for a greater proportion of variance in binge eating than the original model. All proposed mediational pathways of both models were supported and all indirect effects examined through bootstrap procedure were significant. Although our results confirmed the validity of both models and extended previous findings to an early- to middle adolescent group, the bi-directional relationship between dietary restriction and negative affect suggests that the association between these key risk factors for binge eating are more complex than outlined in both the original and extended dual-pathway models.


Endogenous interleukin-6 enhances the renal injury, dysfunction, and inflammation caused by ischemia/reperfusion.
Here, we investigate the effects of renal ischemia/reperfusion (I/R) on the degree of renal injury, dysfunction, and inflammation in interleukin (IL)-6 knockout (IL-6(-/-)) mice and mice administered a monoclonal antibody against IL-6. IL-6(-/-) mice were subjected to bilateral renal artery occlusion (30 min) and reperfusion (24 h). At the end of experiments, indicators and markers of renal dysfunction, injury, and inflammation were measured. Kidneys were used for histological evaluation of renal injury. Renal expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and P-selectin, as well as nitration of proteins in the kidney, were determined using immunohistochemistry. In addition, wild-type mice were pretreated (24 and 1 h before ischemia) with an IL-6 antibody to mimic the effects that would be seen in IL-6(-/-) mice. IL-6(-/-) mice and wild-type mice administered the IL-6 antibody demonstrated significantly reduced plasma urea and creatinine levels, indicating reduction of renal dysfunction caused by I/R. Neutrophil infiltration was also significantly reduced in IL-6(-/-) mice and wild-type mice administered the IL-6 antibody subjected to renal I/R. Proinflammatory cytokines (tumor necrosis factor-alpha and IL-1beta) in renal tissues were significantly attenuated in IL-6(-/-) mice to levels seen in wild-type mice. IL-6(-/-) mice demonstrated reduced histological evidence of tubular injury and markedly reduced immunohistochemical evidence of ICAM-1, P-selectin, and nitrotyrosine when subjected to renal I/R. We propose that endogenous IL-6 enhances the degree of renal injury, dysfunction, and inflammation caused by I/R of the kidney by promoting the expression of adhesion molecules and subsequent oxidative and nitrosative stress.


Impact of Recurrence Score on type and duration of chemotherapy in breast cancer.
The use of Oncotype dx (Genomic Health, Redwood City, CA, U.S.A.) testing has been shown to change treatment decisions in approximately 30% of breast cancer (bca) cases, but research on how Recurrence Score testing has affected the type of chemotherapy offered is limited. We sought to determine if the availability of Oncotype dx testing resulted in a change to the type and duration of chemotherapy regimens used in the treatment of early-stage hormone receptor-positive bca. In a population-based cohort study, patients treated in the 2 years before the availability of Oncotype dx testing were compared with patients treated in the 2 years after testing availability. Charts were audited and divided into 2 groups: pre-Oncotype dx and post-Oncotype dx. The groups were compared for differences in duration of chemotherapy (12 weeks vs. >12 weeks), types of agents used (anthracycline vs. non-anthracycline), and myelosuppressive potential of the chosen regimen. Of 834 patients who fulfilled the enrolment criteria, 360 fell into the pre-Oncotype dx era, and 474, into the post-Oncotype dx era. An increase of 11.2 percentage points, to 69.5% from 58.3%, was observed in the proportion of patients receiving short-course compared with long-course chemotherapy (p = 0.068). The proportion of patients prescribed anthracycline-containing regimens declined in the post-Oncotype dx era (47.7% pre vs. 32.2% post, p = 0.016). The selection of more-myelosuppressive chemotherapy protocols increased in the post-Oncotype dx era (67.4% pre vs. 78.8% post, p = 0.044). In the present study, the availability of Oncotype dx testing was observed to influence the choice of chemotherapy type in the setting of early-stage bca.


Identification, Virulence, and Molecular Characterization of a Recombinant Isolate of Grass Carp Reovirus Genotype I.
The hemorrhagic disease of grass carp (HDGC) caused by grass carp reovirus (GCRV) still poses a great threat to the grass carp industry. Isolation and identification of the GCRV genotype I (GCRV-I) has been rarely reported in the past decade. In this study, a new GCRV was isolated from diseased fish with severe symptoms of enteritis and mild hemorrhages on the body surface. The isolate was further identified by cell culture, transmission electron, indirect immunofluorescence, and SDS-PAGE electrophoretic pattern analysis of genomic RNA. The results were consistent with the new isolate as a GCRV-I member and tentatively named GCRV-GZ1208. Both grass carp and rare minnow infected by the GCRV-GZ1208 have no obvious hemorrhagic symptoms, and the final mortality rate was ≤10%, indicating that it may be a low virulent isolate. GZ1208 possessed highest genomic homology to 873/GCHV (GCRV-I) and golden shiner reovirus (GSRV). Additionally, it was found a 90.7-98.3% nucleotide identity, a 96.4-100% amino acid identity, and <50% identity with GCRV-II and III genotypes. Interestingly, the sequences of some segments of GZ1208 were similar to GCRV-8733/GCHV, whereas the remaining segments were more closely related to GSRV, suggesting that a recombination event had occurred. Bootscan analysis of the complete genomic sequence confirmed this hypothesis, and recombination events between 873/GCHV and other GSRV-like viruses were also accompanied by gene mutations.


Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation: A Scientific Statement From the American Heart Association.
Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with substantial morbidity, mortality, and healthcare use. Great strides have been made in stroke prevention and rhythm control strategies, yet reducing the incidence of AF has been slowed by the increasing incidence and prevalence of AF risk factors, including obesity, physical inactivity, sleep apnea, diabetes mellitus, hypertension, and other modifiable lifestyle-related factors. Fortunately, many of these AF drivers are potentially reversible, and emerging evidence supports that addressing these modifiable risks may be effective for primary and secondary AF prevention. A structured, protocol-driven multidisciplinary approach to integrate lifestyle and risk factor management as an integral part of AF management may help in the prevention and treatment of AF. However, this aspect of AF management is currently underrecognized, underused, and understudied. The purpose of this American Heart Association scientific statement is to review the association of modifiable risk factors with AF and the effects of risk factor intervention. Implementation strategies, care pathways, and educational links for achieving impactful weight reduction, increased physical activity, and risk factor modification are included. Implications for clinical practice, gaps in knowledge, and future directions for the research community are highlighted.


The role of pharmacoeconomic modeling in evidence-based and value-based formulary guidelines.
To review evidence-based medicine (EBM) in the context of pharmacoeconomic (PE) decision making by health care organizations. Pharmacoeconomics involves processes similar to EBM, but it deals with decisions on the population rather than the patient level. The overall goal of PE is to provide the most efficient use of resources, taking into account both the cost and the value derived from a given technology. These evaluations assist health care decision making because both cost and effectiveness are considered. New therapies are increasingly complex in terms of administration, effects, and cost. As a result, PE models are likely to become more complex as well. At present, there is no standard threshold for what constitutes cost-effective therapy, so each organization is likely to have its own criterion for acceptance. Clinical trial results define the safety and efficacy of therapy but cannot determine whether a given technology represents a good buy for a specific organization. This requires PE analysis.


Alternative approaches to epilepsy treatment.
Complementary and alternative medicine (CAM) is a diverse group of health care practices and products that fall outside the realm of traditional Western medical theory and practice and that are used to complement or replace conventional medical therapies. The use of CAM has increased over the past two decades, and surveys have shown that up to 44% of patients with epilepsy are using some form of CAM treatment. This article reviews the CAM modalities of meditation, yoga, relaxation techniques, biofeedback, nutritional and herbal supplements, dietary measures, chiropractic care, acupuncture, Reiki, and homeopathy and what is known about their potential efficacy in patients with epilepsy.