A new model of traumatic axonal injury to determine the effects of strain and displacement rates.
Traumatic brain injury (TBI) continues to be a major health problem, with over 500,000 cases per year with a societal cost of approximately $85 billion in the US. Motor vehicle accidents are the leading cause of such injuries. In many cases of TBI widespread disruption of the axons occurs through a process known as diffuse axonal injury (DAI) or traumatic axonal injury (TAI). In the current study, an in vivo TAI model was developed using spinal nerve roots of adult rats. This model was used to determine functional and structural responses of axons to various strains and displacement rates. Fifty-six L5 dorsal nerve roots were each subjected to a predetermined strain range (<10%, 10-20% and >20%) at a specified displacement rate (0.01 mm/sec and 15 mm/sec) only once. Image analysis was used to determine actual strains on the roots during the pull. Neurophysiologic recordings were performed on the nerve root before and after stretch to determine functional changes in response to stretch, including conduction velocity (CV) and area of the evoked compound action potential (CAP). Structural changes including vascular injury, axotomy, and impaired axoplasmic transport (IAT) were evaluated using hematoxylin and eosin, Palmgren silver impregnation and beta-APP staining techniques, respectively. Results showed that CV and the area of the CAP decreased as strain and displacement rate increased. Also, threshold strains for complete nerve conduction loss were 16% and 9% at 0.01 mm/sec and 15 mm/sec rate, respectively. These threshold values indicate the rate dependency of functional injury and indicate that axons tolerate slow loading rates better than higher loading rates. Histological studies revealed increased spacing, tearing of axons, IAT and occurrence of hemorrhage to be strain and displacement rate dependent. Linear relationships existed between the increasing strain and the occurrence rate of axonal injury as evidenced by multiple indicators (IAT, hemorrhage, torn fibers or primary axotomy) at both rates. In conclusion, the results from this study indicate that the severity of both functional and structural injury increased with increases in strain and displacement rate.


Saccharomyces cerivisiae as a model system for kidney disease: what can yeast tell us about renal function?
Ion channels, solute transporters, aquaporins, and factors required for signal transduction are vital for kidney function. Because mutations in these proteins or in associated regulatory factors can lead to disease, an investigation into their biogenesis, activities, and interplay with other proteins is essential. To this end, the yeast, Saccharomyces cerevisiae, represents a powerful experimental system. Proteins expressed in yeast include the following: 1) ion channels, including the epithelial sodium channel, members of the inward rectifying potassium channel family, and cystic fibrosis transmembrane conductance regulator; 2) plasma membrane transporters, such as the Na(+)-K(+)-ATPase, the Na(+)-phosphate cotransporter, and the Na(+)-H(+) ATPase; 3) aquaporins 1-4; and 4) proteins such as serum/glucocorticoid-induced kinase 1, phosphoinositide-dependent kinase 1, Rh glycoprotein kidney, and trehalase. The variety of proteins expressed and studied emphasizes the versatility of yeast, and, because of the many available tools in this organism, results can be obtained rapidly and economically. In most cases, data gathered using yeast have been substantiated in higher cell types. These attributes validate yeast as a model system to explore renal physiology and suggest that research initiated using this system may lead to novel therapeutics.


Towards MRI guided surgical manipulator.
The advantages of surgical robots and manipulators are well recognized in the clinical and technical community. Precision, accuracy and the potential for telesurgery are the prime motivations in applying advanced robot technology in surgery. In this paper critical interactions between Magnetic Resonance Imaging equipment and mechatronic devices are discussed and a novel Magnetic Resonance compatible surgical robot is described. Experimental results of the effects from several passive (metallic materials) and active (ultrasound motors) mechanical elements are demonstrated. The design principles for Magnetic Resonance compatible robots are established and the compatibility of the proposed robot is assessed by comparing images taken with and without the robot's presence within Signa SP/I GE Medical Systems scanner. The results showed that, in principle, it is possible to construct precision mechatronic devices intended to operate inside MR scanner. Use of such a device will not cause image shift or significant degradation of signal-to-noise-ratio. An MR compatible surgical assist robot was designed and constructed. The robot is not affected by the presence of strong magnetic fields and is able to manoeuvre during imaging without compromising the quality of images. A novel image-guided robot control scheme was proposed. As a part of the control scheme, biomechanics-based organ deformation model was constructed and validated by in-vivo experiment. It has been recognised that for robust control of an image guided surgical robot the precise knowledge of the mechanical properties of soft organs operated on must be known. As an illustration, results in mathematical modelling and computer simulation of brain deformation are given. The novel MR compatible robot was designed to position and direct an axisymmetric tool, such as a laser pointer or a biopsy catheter. New Robot control system based on the prediction of soft organ deformation was proposed.


Heat sensitivity of double-stranded DNA-dependent protein kinase (DNA-PK) activity.
The heat sensitivity of DNA-PK activity in hybrid cells and the possible restoration of this activity with extracts from scid cells (defective in DNA-PKcs), sxi-3 cells (defective in Ku80) and V794 (sxi-3 parental wild-type cells) was analysed. Heat treatment of cells was performed in a water bath at 44 degrees C. The cell extract from scid cells or sxi-3 cells was added to heat-treated hybrid cell extracts, and the DNA-PK activity was assayed. When hybrid cells were heated at 44 degrees C for 15 min, DNA-PK activity was reduced to undetectable levels. The decreased DNA-PK activity could be restored in a concentration-dependent manner with the addition of scid cell extract. The sxi-3 cell extract could not restore heat-inactivated DNA-PK activity. DNA-PK was inactivated by heat treatment at 44 degrees C. Ku70/Ku80, but not Ku70 alone, could restore heat-inactivated DNA-PK.


Association of pain and itch with depth of invasion and inflammatory cell constitution in skin cancer: results of a large clinicopathologic study.
This study highlights a simple bedside evaluation of itch and pain for suspicious skin lesions. To examine the correlation of pain and itch with histologic features of skin cancers. This large, prospective, clinicopathologic study enrolled patients who filled out questionnaires that assessed itch and pain intensity of their skin tumors at the time of excision. Study participants were from the patient population presenting to the Department of Dermatology surgical unit at Wake Forest University Baptist Medical Center from July 1, 2010, through March 31, 2011. Study participants included 268 patients, representing 339 histopathologically confirmed cutaneous neoplasms. The following skin cancer subtypes were represented in this analysis: 166 basal cell carcinomas, 146 squamous cell carcinomas, and 27 melanomas. Itch and pain associated with skin cancer at the time of excision ranked on an 11-point (score range, 0-10) numerical visual analog scale and histopathologic analysis for each neoplasm (assessment of the amount and type of inflammation, ulceration, perineural invasion, and depth of invasion). The prevalence of itch and pain across all skin cancers was 36.9% and 28.2%, respectively. However, these symptoms were mostly absent in melanomas. Pain intensity was significantly associated with the degree of inflammation (mild or none vs moderate or marked; P < .001), presence of neutrophils in the inflammatory infiltrate (predominantly mononuclear vs mixed or neutrophilic; P = .003), presence of eosinophils (present vs absent; P = .007), ulceration (yes vs no; P = .003), perineural invasion (yes vs no; P < .001), depth of invasion (P = .001), and largest diameter length of skin lesion (P < .003). Itch intensity was significantly associated with the degree of inflammation (mild or none vs moderate or marked; P = .001) and the presence of eosinophils (present vs absent; P = .02). These findings support the theory that itch emanates from the upper layers of the skin, whereas pain is associated with deeper processes. This study also reports that a simple bedside assessment for the presence and intensity of pain or itch is an easily implementable tool for physicians evaluating suspicious skin lesions.


Impact of three-dimensional echocardiography in valvular heart disease.
Recent advances in the field of three-dimensional (3D) echocardiography have allowed improved visualization of cardiac structures. These advances have also provided valuable insights into cardiac function. The purpose of this review is to describe the recent developments in 3D echocardiography in assessing valvular heart disease. Application of 3D echocardiography to valvular heart disease has improved with advances made in both the hardware and software components of 3D ultrasound systems. The most significant advancement has been the development of a matrix transducer that is capable of rapid real-time 3D acquisition and rendering. There have been many studies evaluating 3D echocardiographic assessment of mitral valve disease, aortic valve disease, as well as congenital heart disease using both real-time 3D transthoracic echocardiography (TTE) as well as off-line reconstructed 3D images from transesophageal echocardiography (TEE) using post image processing. More recent studies have combined the structural 3D information with color Doppler 3D imaging, providing qualitative functional information. Developments in the field of 3D ultrasound imaging have allowed better qualitative assessment of valvular structures. The addition of color flow Doppler to the 3D imaging has provided improved visualization of regurgitant lesions and holds great promise for improved quantitative assessment of such lesions. The ongoing miniaturization of transducers and improvements in hardware and software components of ultrasound systems will certainly enhance both the ease of image acquisition as well as image quality, which should result in more precise quantitation of valvular dysfunction. However, clinical benefits of 3D echocardiography are yet to be demonstrated in properly conducted clinical trials, which are needed for wider acceptance of this technique.


[New developments in understanding the compensatory hematological reactions and their outcomes in local fractionated therapeutic gamma irradiation].
We have carried out a study of the bone marrow status in both irradiated and non-irradiated zones of 56 patients with stage I-II Hodgkin's disease in complete 9-12 (33 patients, group 1) and 18-23 (23 patients, group 2) year remission after therapeutic irradiation of the supradiaphragmatic lymphatic collectors at a dose of 40 Gy with irradiation of the spleen (33 patients) or splenectomy (23 patients). The total count of myelokaryocytes, myelogram, a relative and absolute content of lymphoid cells, immature granulocytes and elements of erythroid series were calculated in the aspirates from the exposed to radiotherapy sternum and non-irradiated upper portion of the ileum. The number of granulocyte-macrophage (CFU-GM) and stromal (CFU-F) precursor cells were defined using in vitro culture technique. There was a complete annihilation of the bone marrow in the irradiated zones, when the dose exceeded 35 Gy in 3-4 weeks. The concentration of myelokaryocytes, immature granulocytes, erythronormoblasts, CFU-GM, CFU-F in non-exposed bone marrow were significantly lower in all patients of group 2 than in normal subjects and in group 1 patients. Absolute lymphoid count in patients with 18-23 year remission was found to be normal but was considerably reduced in comparison to patients of group 1. These changes may be the result of the previous hyperactivity of the non-irradiated bone marrow which could be a cause of stem cell compartment depletion. The differential calculation of compact and diffuse subpopulations of CFU-F revealed a significant reduction of compact colony-forming CFU-F in both irradiated and unexposed bone marrow. Almost all the stromal precursor cells from irradiated zone formed diffuse colonies in cultures. These results confirm experimental data concerning greater radiosensitivity and proliferative potential of CFU-F, forming compact colonies versus diffuse colony-forming CFU-F. Aplasia of the irradiated bone marrow and hypoplasia of the non-irradiated bone marrow 18-23 years after radiotherapy completion coexisted with normal circulating CFU-GM and granulocyte blood count suggesting a compensatory mechanism involving a mitotic amplification between the progenitor cell and the final differentiated cell.


The cell wall sensors Mtl1, Wsc1, and Mid2 are required for stress-induced nuclear to cytoplasmic translocation of cyclin C and programmed cell death in yeast.
Mtl1 is a member of a cell wall sensor family that monitors cell wall integrity in budding yeast. In response to cell wall stress, Mtl1 activates the cell wall integrity (CWI) MAP kinase pathway which transmits this signal to the nucleus to effect changes in gene expression. One target of the CWI MAP kinase is cyclin C, a negative regulator of stress response genes. CWI activation results in cyclin C relocalization from the nucleus to the cytoplasm where it stimulates programmed cell death (PCD) before it is destroyed. This report demonstrates that under low oxidative stress conditions, a combination of membrane sensors, Mtl1 and either Wsc1 or Mid2, are required jointly to transmit the oxidative stress signal to initiate cyclin C destruction. However, when exposed to elevated oxidative stress, additional pathways independent of these three sensor proteins are activated to destroy cyclin C. In addition, N-glycosylation is important for Mtl1 function as mutating the receptor residue (Asn42) or an enzyme required for synthesis of N-acetylglucosamine (Gfa1) reduces sensor activity. Finally, combining gfa1-1 with the cyclin C null allele induces a severe synthetic growth defect. This surprising result reveals a previously unknown genetic interaction between cyclin C and plasma membrane integrity.


Current role of cryoamputation.
Cryoamputation or physiologic amputation has been used at our institution for more than 30 years. From 1971 through 1989, 891 major lower extremity amputations were performed in 750 patients. With the use of dry ice or mechanical refrigeration, 320 (36%) physiologic amputations were performed in 292 patients. After physiologic amputation, the initially elevated white blood cell count and temperature decreased. Complications of physiologic amputation were unusual; 3% of patients developed minor freezing above the tourniquet, which did not alter the amputation level, while 1% had purulence at the level of surgical amputation that required delayed stump closure. The overall operative mortality rate in patients who underwent physiologic amputation was 11%, which was equivalent to the rate in patients undergoing primary amputation. Revision was required in 9% of amputations after preliminary physiologic amputation compared with 17% of primary amputations. Physiologic amputation is a simple technique, controls local infection, avoids emergency surgery, and allows for medical stabilization prior to surgery. Amputation revision after physiologic amputation is required less often than after primary amputation, while the mortality rate is comparable to that of patients undergoing primary amputation.


Integration of computational tools, data analysis and social science into food safety risk assessment.
The EU-FORA Fellowship Programme 'Integration of tools and social science into food safety risk assessments' was proposed by the Food Standards Agency (FSA), the government department responsible for food safety in the UK. The working programme was organised into four modules, covering different areas of risk assessment, including microbiological risk assessment, chemical risk assessment, exposure assessment, risk prioritisation and the integration of risk assessment with social science. During this period, the fellow had the unique opportunity to gain experience in different fields of risk assessment, namely how to conduct a systematic review, to assess the risk of microbiological and chemical hazards, to make use of modelling tools for exposure assessment and risk prioritisation, to write scientific reports for committees and networks at the national level and to understand the role of social science in risk assessment. In addition, the fellow was able to attend several meetings, seminars, courses and workshops that helped him to gain further insight in the field of food science. The complete programme enabled a fast learning curve that allowed the fellow to have an overview of the different tools that can be employed in the wide field of food safety risk assessment, in order to acquire skills and competences that can be used in his future career.


Comparison of results for serologic testing and a polymerase chain reaction assay to determine the prevalence of stray dogs in eastern Tennessee seropositive to Ehrlichia canis.
To determine the prevalence of stray dogs in eastern Tennessee seropositive to Ehrlichia canis and examine the correlation between results for an ELISA, indirect immunofluorescent antibody (IFA) test, and polymerase chain reaction (PCR) assay. Blood samples obtained from 90 adult dogs admitted to an animal shelter in eastern Tennessee. Serum samples were analyzed for antibodies against E. canis by use of a commercially available ELISA kit, 2 IFA tests, and a PCR assay; testing was performed at the University of Tennessee (TN) and North Carolina State University (NCSU). The PCR amplification was performed by use of DNA extracted from EDTA-anticoagulated blood and primers designed to amplify DNA of Ehrlichia spp. Antibodies against E. canis were detected in only 1 dog by use of the ELISA. By IFA testing at TN, 10 of 90 (11%) dogs were seroreactive against E. canis antigens, all of which had medium to high titers to E. canis. Only 5 of the 10 TN seroreactors were also reactive against E. canis antigens in IFA tests conducted at NCSU, and all 5 had low to medium titers. The DNA of Ehrlichia spp was not amplified in any blood samples by use of PCR assays conducted at the TN or NCSU. The discordant ELISA, IFA, and PCR results obtained in this study were unexpected and may have been related to exposure of dogs to an Ehrlichia species other than E. canis, such as E. ewingii.


[Diagnostic value of small concentrations of troponin in patients with myocardial infarction].
We have reviewed here studies of measurement of small concentrations of troponin in patients with myocardial infarction conducted in 2010-2011 which were most significant for the clinic. Troponin is a most specific and sensitive cardiomarker appearance of which in blood serum evidence for a necrotic process in cardiac muscle. We discuss the problem of interpretation of small troponin concentrations by clinicians as well as the states in which appearance of the cardiomarker in blood serum has noncardiac origin. We also discuss novel possibilities of application of troponin as a prognostic marker in patients with stable or unstable angina after revascularization procedures.


Typing of feline calicivirus isolates from different clinical groups by virus neutralisation tests.
One hundred and thirteen isolates of feline calicivirus originating from seven different clinical groups were typed by virus neutralisation tests using eight different cat antisera. The clinical groups comprised 'healthy' cats, cases of acute oral/respiratory disease, chronic stomatitis, acute febrile lameness syndrome, vaccine reactions (clinical disease seen within 21 days of vaccination) and vaccine breakdowns (clinical disease seen more than 21 days after but within one year of vaccination). Isolates from the vaccine reaction cases were grouped into those associated with acute oral/respiratory disease alone and those associated with the lameness syndrome, and the latter group was further subdivided according to the vaccine used. Two groups appeared significantly different from others with some of the antisera. Thus the lameness vaccine reaction isolates associated with vaccine B were significantly different from the isolates from all the other clinical groups, including other lameness isolates, with a number of the antisera. In addition, the chronic stomatitis isolates were significantly different from those from the 'healthy' and the acute oral/respiratory disease groups with one or two of the antisera. Eighty-five to 88 per cent of the isolates were neutralised by antisera raised against F9 or F9-like vaccine strains at a dilution of 1 in 2. Twenty antibody units of such antisera neutralised 42 to 80 per cent of the isolates. A bivalent antiserum raised against a vaccine F9 strain and field strain LS015 neutralised 96 per cent of the isolates at a dilution of 1 in 2, and 20 antibody units neutralised 68 per cent of isolates. Antisera to field strain F65 neutralised all the remaining isolates at a dilution of 1 in 2 and 44 per cent of the remaining isolates at a dilution of 20 antibody units. Therefore, strains LS015 and F65 may be of use in the production of a polyvalent feline calicivirus vaccine, together with the widely used strain F9.


[Longitudinal assessment of body composition by different methods as product of a integral intervention for treating obesity in Chilean children school].
In Chile, the main nutritional problem of children, is obesity. The alarming increase in childhood obesity, has generated an urgent need to develop prevention and treatment programs, unfortunately, the results have been disappointing because they have not achieved the expected impact on the nutritional status of the target population. For this it is necessary to use other strategies, such as incorporating exercise of muscle strength. To determine the impact of an integral intervention (exercise, nutritional education and psychological support) in the body composition of obese school children after the intervention and post-intervention. The sample consisted of 61 obese children (BMI = p 95) of both sex, between 8 and 13 years old, who participated in an integral intervention for treating childhood obesity in the short term (3 months) and medium term (12 months). Body composition was assessed by isotope dilution, plethysmography, radiographic absorptiometry and four-compartment model of Fuller. There was a significant increase over time in FFM (kg) by 4C in both sex, GC (%) by isotope dilution in boys was reduced in the post-intervention, while in girls decreased significantly over time and FFM (kg) by isotope dilution significantly increased in both sex. According to the magnitude and direction of change in time, there was only significant difference by sex in FFM (%) by isotope dilution, the increase was significantly higher in boys a result of the intervention (p = 0,000). An intervention that includes programmed exercise improves body composition. However, its effect is reversed in the medium term if training ceases. This reaffirms the need for sustainability of interventions over time.


Antiplatelet therapy and percutaneous coronary intervention in patients with acute coronary syndrome and thrombocytopenia.
Platelets are crucial in the pathogenesis of acute coronary syndrome. Treatment for acute coronary syndrome usually involves antiplatelet, anticoagulant, and antithrombotic therapy, and the performance of percutaneous coronary intervention. All of the medications are associated with bleeding sequelae and are typically withheld from patients who have thrombocytopenia. The safety of antiplatelet therapy and percutaneous coronary intervention in patients who have acute coronary syndrome and thrombocytopenia is unknown, and there are no guidelines or randomized studies to suggest a treatment approach in such patients. Acute coronary syndrome is uncommon in patients who have thrombocytopenia; however, it occurs in up to 39% of patients who have both thrombocytopenia and cancer. Herein, we present the cases of 5 patients with acute coronary syndrome, thrombocytopenia, and cancer who underwent percutaneous coronary intervention with stenting. Before intervention, their platelet counts ranged from 17 to 72 x 10(9)/L. One patient underwent preprocedural platelet transfusion. All were given aspirin, alone or with clopidogrel. One patient experienced melena (of colonic origin). No other patient experienced bleeding sequelae. Aside from the occasional use of antiplatelet and thrombolytic agents in patients with thrombocytopenia, no therapeutic recommendation can be made until data are available on a larger patient population. Until then, treatment should conform to specific clinical circumstances. Approaches to the treatment of acute coronary syndrome in patients with thrombocytopenia might be better directed toward the evaluation of platelet function rather than toward absolute platelet count, and the risk-benefit equation of invasive procedures and antithrombotic therapies may need to incorporate this information.


Nuts and Cardio-Metabolic Disease: A Review of Meta-Analyses.
Accumulating epidemiological and intervention evidence suggest that nut consumption is associated with reduced incidence of some cardiometabolic diseases. However, to date no review of meta-analyses of epidemiological and intervention studies has evaluated the effects of nut consumption on cardiometabolic disease. Design/Results: Electronic searches for meta-analyses of epidemiological and intervention studies were undertaken in PubMed®/MEDLINE®. Meta-analyses of prospective studies show that nut consumption appears to be associated with reduced all-cause mortality by 19⁻20% (n = 6), cardiovascular disease (CVD) incidence (19%; n = 3) and mortality (25%; n = 3), coronary heart disease (CHD) incidence (20⁻34%; n = 2) and mortality (27⁻30%; n = 2) and stroke incidence (10⁻11%; n = 7) and mortality (18%; n = 2). No association between nut consumption and the risk of type 2 diabetes mellitus (T2DM) was observed in meta-analyses of prospective studies, whereas a decrease in fasting blood glucose ranging from 0.08 to 0.15 mmol/L was observed in 3 meta-analyses of intervention studies. In the interventions, nut consumption also had favorable effects on total cholesterol (0.021 to 0.28 mmol/L reduction from 8 meta-analyses of interventions) and low-density lipoprotein cholesterol (0.017 to 0.26 mmol/L reduction from 8 meta-analyses of interventions) and endothelial function (0.79 to 1.03% increase in flow-mediated dilation from 4 meta-analyses of interventions). Nut consumption did not significantly affect body weight. Nut consumption had no effect on inflammatory markers in intervention studies. The effect on blood pressure was inconsistent. A higher nut consumption was associated with a lower incidence of hypertension in prospective studies, while nut consumption did not improve blood pressure in intervention studies. Nut consumption appeared to be associated with lower all-cause mortality and CVD and CHD mortality. There was no association between nut consumption and the incidence of T2DM although fasting blood glucose is decreased in intervention studies. In intervention studies nuts lower total cholesterol and low-density lipoprotein cholesterol (LDL-C).


Fetal growth indicators and perfluorinated chemicals: a study in the Danish National Birth Cohort.
Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are widespread persistent organic pollutants that have been associated with reduced birth weight at doses expected in many pregnant populations. The authors randomly selected 1,400 pregnant women and their newborns from the Danish National Birth Cohort (1996-2002) to investigate whether these compounds reduce organ growth. PFOS and PFOA were measured in maternal blood samples taken early in pregnancy. Placental weight, birth length, and head and abdominal circumferences were measured shortly after birth by trained midwives or nurses. Maternal PFOA levels in early pregnancy were associated with smaller abdominal circumference and birth length. For each ng/ml increase in PFOA, birth length decreased by 0.069 cm (95% confidence interval: 0.024, 0.113) and abdominal circumference decreased by 0.059 cm (95% confidence interval: 0.012, 0.106). An inverse association was also observed between PFOA and placental weight and head circumference, and a positive association was observed with newborn ponderal index, but none of these associations was statistically significant. Maternal PFOS levels were not associated with any of the five fetal growth indicators. These findings suggest that fetal exposure to PFOA but not PFOS during organ development may affect the growth of organs and the skeleton.


Kohki tea protects the rabbit bladder from ischemia/reperfusion-induced contractile dysfunction.
Results of several studies indicated that ischemia/reperfusion is an etiological factor in obstructive bladder dysfunction. Kohki tea pretreatment was shown to reduce the dysfunctions induced by partial outlet obstruction in rabbits. The current study was designed to determine if pretreatment of rabbits with Kohki tea could prevent the contractile dysfunctions induced by bilateral ischemia followed by reperfusion. New Zealand white rabbits were separated into several groups; one half of each group was pretreated by oral gavage for 3 weeks with Kohki tea and the other half was treated with vehicle (water). Experimental groups were subjected to bilateral ischemia for either 1 or 3 h followed by reperfusion for either 1 h or 1 week (4 groups). The results from the experimental groups were compared to the groups of rabbits receiving sham operations. Under all experimental conditions, Kohki tea significantly reduced the contractile dysfunctions induced by ischemia and ischemia followed by reperfusion. This data is consistent with the concept that Kohki tea acts by protecting the bladder smooth muscle and mucosa from cellular damage caused by ischemia/reperfusion.


Incidence and Predictors of Atrial Fibrillation Progression.
Background The incidence and predictors of atrial fibrillation (AF) progression are currently not well defined, and clinical AF progression partly overlaps with rhythm control interventions (RCIs). Methods and Results We assessed AF type and intercurrent RCIs during yearly follow-ups in 2869 prospectively followed patients with paroxysmal or persistent AF. Clinical AF progression was defined as progression from paroxysmal to nonparoxysmal or from persistent to permanent AF. An RCI was defined as pulmonary vein isolation, electrical cardioversion, or new treatment with amiodarone. During a median follow-up of 3 years, the incidence of clinical AF progression was 5.2 per 100 patient-years, and 10.9 per 100 patient-years for any RCI. Significant predictors for AF progression were body mass index (hazard ratio [HR], 1.03; 95% CI, 1.01-1.05), heart rate (HR per 5 beats/min increase, 1.05; 95% CI, 1.02-1.08), age (HR per 5-year increase 1.19; 95% CI, 1.13-1.27), systolic blood pressure (HR per 5 mm Hg increase, 1.03; 95% CI, 1.00-1.05), history of hyperthyroidism (HR, 1.71; 95% CI, 1.16-2.52), stroke (HR, 1.50; 95% CI, 1.19-1.88), and heart failure (HR, 1.69; 95% CI, 1.34-2.13). Regular physical activity (HR, 0.80; 95% CI, 0.66-0.98) and previous pulmonary vein isolation (HR, 0.69; 95% CI, 0.53-0.90) showed an inverse association. Significant predictive factors for RCIs were physical activity (HR, 1.42; 95% CI, 1.20-1.68), AF-related symptoms (HR, 1.84; 95% CI, 1.47-2.30), age (HR per 5-year increase, 0.88; 95% CI, 0.85-0.92), and paroxysmal AF (HR, 0.61; 95% CI, 0.51-0.73). Conclusions Cardiovascular risk factors and comorbidities were key predictors of clinical AF progression. A healthy lifestyle may therefore reduce the risk of AF progression.


Filamentous Phages as Building Blocks for Bioactive Hydrogels.
Filamentous bacteriophages (bacterial viruses) are semiflexible proteinous nanofilaments with high aspect ratios for which the surface chemistry can be controlled with atomic precision via genetic engineering. That, in addition to their ability to self-propagate and replicate a nearly monodisperse batch of biologically and chemically identical nanofilaments, makes these bionanofilaments superior to most synthetic nanoparticles and thus a powerful tool in the bioengineers' toolbox. Furthermore, filamentous phages form liquid crystalline structures at high concentrations; these ordered assemblies create hierarchically ordered macro-, micro-, and nanostructures that, once cross-linked, can form hierarchically ordered hydrogels, hydrated soft material with a variety of physical and chemical properties suitable for biomedical applications (e.g., wound dressings and tissue engineering scaffolds) as well as biosensing, diagnostic assays. We provide a critical review of these hydrogels of filamentous phage, and their physical, mechanical, chemical, and biological properties and current applications, as well as an overview of limitations and challenges and outlook for future applications. In addition, we present a list of design parameters for filamentous phage hydrogels to serve as a guide for the (bio)engineer and (bio)chemist interested in utilizing these powerful bionanofilaments for designing smart, bioactive materials and devices.


Challenging Opinion 75.
Opinion 75 issued by the Judicial Commission is based on an interpretation of the Rules of the International Code of Nomenclature of Bacteria (the Code) that failed to take into consideration changes made to the Code by the Judicial Commission prior to consideration of the original Request for an Opinion. Furthermore, closer examination of the Request indicates a number of contradictions that have been carried over into the published Opinion. The Judicial Commission is therefore requested to re-examine Opinion 75.


Effect of medication dosing frequency on adherence in chronic diseases.
To systematically review available data on the effect of daily medication dosing frequency on medication adherence in chronic disease states, as assessed by precise medication event monitoring systems (MEMS). Systematic review of relevant literature published between January 1986 and August 2007. Four electronic databases were searched to identify appropriate studies. Study selection criteria included prospective study design, patient population with quiescent chronic disease, medication intervention prescribed to each treatment arm for at least 6 weeks, and the use of MEMS to measure adherence. Data were extracted on the chronic disease being treated, the frequency of medication dosing, and the proportion of days with correct number of doses. Twenty studies met the selection criteria. All studies reported higher adherence rates in patients using less frequently dosed medications, and these differences were statistically significant (P <.05) in 75% (15 of 20) of studies. For 5 of 6 studies comparing once-daily versus thrice-daily dosing, patients receiving once-daily dosing had 22% to 41% more adherent days compared with patients receiving thrice-daily dosing. For studies comparing once-daily versus twice-daily dosing, patients receiving once-daily dosing had 2% to 44% more adherent days compared with patients receiving twice-daily dosing, with most studies clustering around 13% to 26%. Patients are more compliant with once-daily compared with twice-daily or thrice-daily treatment regimens.


Visceral herpesvirus infections in leukemic patients receiving cytarabine.
Autopsy evidence of herpesvirus infection was found in visceral organs of four leukemic patients who had received large doses of cytarabine (cytosine arabinoside; Ara-C) shortly before their death. In three of these patients the infection was clinically unsuspected; in the fourth, cutaneous herpes zoster developed after administration of 300 mg of cytarabine daily for the preceding five days. Although cytarabine exhibits pronounced in vitro virucidal activity against herpes viruses and has been successfully used in clinical treatment of severe herpesvirus infections, the present findings and a review of the recent literature cast doubt on the antiviral effectiveness of this drug, particularly in already immunosuppressed patients, and suggest instead that such patients actually have an increased risk for development of disseminated herpesvirus infection owing to further depression of host defenses by the drug.


Two Childhood Pheochromocytoma Cases due to von Hippel-Lindau Disease, One Associated with Pancreatic Neuroendocrine Tumor: A Very Rare Manifestation
von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited disorder, characterized by hemangioblastomas of the retina and central nervous system (CNS); renal cysts; clear cell carcinoma; pheochromocytoma (PCC); endolymphatic sac tumors; cystadenomas of the epididymis in males; broad ligament of uterus in females; pancreatic cysts; cystadenomas; and neuroendocrine tumors. We report two cases of VHL disease that presented with PCC as the first manifestation. Further clinical developments during follow-up, hemangioblastoma of CNS in one case and a pancreatic neuroendocrine tumor (PNET) in the second case led to the diagnosis of VHL disease. Genetic analyses of the two cases revealed p.Arg161Gln (c.482G>A) and p.Leu129Pro (c.386T>G) heterozygous missense mutations in the VHL gene, respectively. In children, PCC may be the only and/or initial manifestation of VHL with delayed manifestations of the syndrome in other organs. PNET is a very rare manifestation of VHL disease. To the best of our knowledge, this is only the second reported case presenting with a combination of a PNET and bilateral PCC as components of childhood VHL disease. Pediatric patients diagnosed with PCC should be investigated for genetic causes and especially for VHL.


The built environment and health: fostering interprofessional collaboration for better policy recommendations.
This paper describes the initiation and proceedings of a national consultation organized to appraise issues in the local built environment affecting public health, using an interprofessional and intersectoral approach. The consultation was hosted as a part of the onsite session of an international fellowship program in interprofessional education and practice, organized by the Manipal FAIMER Institute for Leadership in Interprofessional Education, India. One hundred and eight delegates from across academic disciplines including the health professions, management, public health, architecture, and engineering, participated in this event. Plenary lectures and case studies highlighted the theoretical basics of built environment. Participants were also introduced to fundamental parameters for evaluating health-related aspects of the built environment. Delegates were then grouped into 18 teams and assigned to visit predetermined locations which they appraised and provided recommendations for. These were then thematically coded and synthesized for communication to relevant local municipal authorities. The consultation scope was limited by involving only academics in the appraisal process, and next steps include the engagement of local citizens and policy-makers to ensure the implementation of recommendations. This event illustrates how engaging interprofessional stakeholders can facilitate knowledge-driven development for promoting health equity, through action on the social determinants of health.


Nitrogen dioxide and respiratory infection: pilot investigations.
Laboratory and human studies have raised concern that exposure to nitrogen dioxide may increase the frequency and severity of respiratory infections in children and adults. Cooking with a natural-gas-fueled stove exposes a home's residents to short-term peaks of nitrogen oxides and to higher average levels of nitrogen oxides than are measured in homes with electric stoves. We have designed a longitudinal study of infants to determine if nitrogen dioxide exposure from cooking stoves increases the incidence or severity of respiratory infections during the first 18 months of life. Pilot investigations for the longitudinal study were conducted from 1984 through 1986. This report provides the results of the pilot investigations. The first study, conducted in 1984 and 1985, was designed to document (1) that appropriate subjects could be recruited; (2) that nitrogen dioxide concentrations in Albuquerque homes were in the range of interest; (3) that an infant's personal exposure to nitrogen dioxide could be estimated; and (4) that a valid, feasible approach for surveillance could be implemented. To accomplish these goals, the families of infants were recruited at two Albuquerque hospitals, and their homes were monitored for nitrogen dioxide using a passive sampling tube. With this approach, we successfully recruited 147 households; monitoring for nitrogen dioxide showed substantially higher levels in homes with gas stoves than in homes with electric stoves, as previously found in other U.S. cities. More detailed investigations in a sample of the homes showed that personal exposures of the infants, who did not attend day care, could be satisfactorily estimated by room concentrations. We also demonstrated that mothers would complete a daily calendar-diary on respiratory symptoms and provide information every two weeks on illnesses occurring since the previous surveillance call. The second pilot study, conducted in 1986, was designed to refine the system for illness surveillance. Additional goals were to test further the methods for exposure assessment and to evaluate recruitment of subjects through pediatric practices. We recruited 75 infants and followed them over a four-month period. Information from the surveillance system was compared with the clinical assessments of the project's nurse practitioner and the subjects' physicians, and with the results of viral cultures. We also evaluated biweekly versus weekly surveillance calls. Overall, the results of the second pilot study documented that a surveillance system for respiratory illness that incorporates calendar-diaries and biweekly telephone calls is a feasible, relatively unbiased, and sensitive method for studying respiratory illness in a large population of infants. We also found that subjects could be successfully recruited through a pediatric practice.(ABSTRACT TRUNCATED AT 400 WORDS)


Efficacy of a Self-Administered Home-Based Parent Intervention on Parenting Behaviors for Preventing Adolescent Substance Use.
A growing body of literature suggests that parenting practices characterized by careful monitoring, firm and consistent limit setting, and nurturing communication patterns with children are protective against adolescent substance use and other problem behaviors. Family-based prevention programs that promote these behaviors can be an effective way to prevent adolescent substance use. However, low participation rates remain problematic for many such programs, particularly programs that require parents to attend scheduled meetings outside the home. The purpose of this study was to determine the efficacy of a newly developed substance use prevention program when self-administered at home by parents of middle school students. As part of a randomized trial, 338 parents of middle school students either received the parent prevention program or served as control group participants. Parents completed self-report surveys at home that assessed parenting behaviors at pre-test, post-test, and one-year follow-up time points. A series of mixed model ANCOVAs were conducted, examining the post-test and one-year follow-up means for the parent outcomes, controlling for pre-test levels on these outcomes. Analyses showed that at the post-test assessment, intervention parents reported significant increases relative to controls in appropriate role modeling, disciplinary practices, family communication, and parental monitoring skills. At the one-year follow-up assessment, intervention effects on family communication skills remained significant and effects on parental role modeling were marginally significant. This study shows that a theoretically rich prevention program can be effectively self-administered by parents at home and improve key parenting skills that have been shown to prevent adolescent substance use.


Inactivation of D-serine dehydratase by alkylamines via a transimination of enzyme-linked cofactor.
The time-dependent inactivation of D-serine dehydratase by alkylamines was characterized. Evidence is presented indicating that inactivation proceeds via a transimination reaction analogous to the first step in the catalytic pathway. The product of alkylamine attack, an alkylamine pyridoxal 5'-phosphate Schiff base, readily dissociated from D-serine dehydratase to produce inactive apoenzyme. Reaction with alkylamines was shown to be a convenient way of producing apoenzyme which can be reconstituted with pyridoxal 5'-phosphate to fully active holoenzyme. Amino acids such as glycine and alanine, unlike alkylamines, did not resolve D-serine dehydratase but were competitive inhibitors of the enzyme. The inability of amino acids to resolve D-serine dehydratase from its cofactor was attributed to a failure of the amino acid-cofactor Schiff base to dissociate from the enzyme. Transimination of D-serine dehydratase with its substrate D-serine was at least 3.5 X 10(5) times faster than a nonenzymic model transimination reaction and more than 70 million times faster than the reaction of the enzyme with 2-hydroxyethylamine, indicating that the carboxyl group of the substrate is an important structural determinant for catalysis of the transimination step in the catalytic pathway. An analysis of the inhibitory effect of potassium ion on the rate and extent of inactivation of D-serine dehydratase by alkylamines indicated that K+ binding increased the affinity of the enzyme for its cofactor by at least 13-fold.


Rotavirus survival on human hands and transfer of infectious virus to animate and nonporous inanimate surfaces.
We tested the survival of the Wa strain of human rotavirus on the hands of volunteers and also studied infectious virus transfer between animate and inanimate (stainless steel disks) surfaces. The virus was diluted in a 10% suspension of feces, and 10 microliters (1 X 10(3) to 4 X 10(4) PFU) was placed on each of the four fingerpads of the left hand. One milliliter of 20% tryptose phosphate broth in Earle balanced salt solution was used for virus elution from each fingerpad, and the hands were disinfected with 70% ethanol before they were washed with an antiseptic soap and water. At 20, 60, and 260 min after inoculation, approximately 57, 43, and 7%, respectively, of the input infectious virus could be recovered. For virus transfer, the inoculum (2 X 10(4) to 8 X 10(4) PFU) was allowed to dry, and the donor surface was kept in contact with the recipient surface for 10 s at a pressure of approximately 1 kg/cm2. At 20 and 60 min after virus inoculation, 16.1 and 1.8%, respectively, of the input infectious virus could be transferred from the contaminated hand to a clean disk; when a clean hand was pressed against a contaminated disk, virus transfer was 16.8 and 1.6%, respectively. Contact between a contaminated and a clean hand 20 and 60 min after virus inoculation resulted in the transfer of 6.6 and 2.8%, respectively, of the input infectious virus. These findings indicate the potential vehicular role for human hands in the spread of rotaviral infections.


Cognitive control in young heavy drinkers: An ERP study.
Substance use disorders have been frequently linked to an impaired cognitive control system. Whether this impaired control is also present in young adults who heavily drink alcohol is still subject to debate. The present study investigated possible impairments in cognitive control in heavy drinkers using behavioral and electrophysiological (EEG) measures. We studied behavioral performance on an inhibitory control and an error-processing task, using a GoNogo task and an Eriksen Flanker task respectively, while ERPs (Nogo-N2/P3 and ERN/Pe) were measured in a group of heavy alcohol drinkers (n=48) and a healthy control group of light drinkers (n=49). Results showed very few impairments in the heavy drinking group either at the behavioral or physiological level. One exception was the error-related Pe amplitude. This ERP component was reduced in heavy drinkers as compared to controls. Given that the Pe reflects a motivational component (i.e., the salience attributed to the making of errors) rather than a basic cognitive deficit, it can be concluded that heavy drinking in this population is not associated with major impaired cognitive control, but rather with impairments that are associated with aberrant attribution of salience to the making of errors. The present EEG findings are consistent with recent reviews and large scale epidemiological studies showing that heavy drinking, in contrast to substance use disorders, in young persons is not necessarily associated with major behavioral impairments in cognitive control.


Frontline Reporting from the Epicenter of a Global Pandemic: A Survey of the Impact of COVID-19 on Plastic Surgery Training in New York and New Jersey.
Since the first documented case of coronavirus disease of 2019 (COVID-19), the greater New York City area quickly became the epicenter of the global pandemic, with over 500,000 cases and 50,000 deaths. This unprecedented crisis affected all aspects of health care, including plastic surgery residency training. The purpose of this study was to understand the specific impact of the COVID-19 pandemic on plastic surgery residencies. A survey of all plastic surgery residency training programs in the greater New York City area was conducted. The impact to training during the peak months of infection (March and April of 2020) was evaluated using resident education as measured by case numbers, need for redeployment, and staff wellness as primary outcome variables. A total of 11 programs were identified in the region, and seven programs completed the survey, with a response rate 63.6 percent. When comparing productivity in March and April of 2019 to March and April of 2020, a total decrease in surgical volume of 64.8 percent (range, 19.7 to 84.8 percent) and an average of 940 (range, 50 to 1287) cancelled clinic visits per month were observed. These decreases directly correlated with the local county's COVID-19 incidence rates (p = 0.70). A total of 83 percent of programs required redeployment to areas of need, and correlation between local incidence of COVID-19 and the percentage of residents redeployed to non-plastic surgical clinical environments by a given program (ρ = 0.97) was observed. As the first COVID-19 wave passes the greater New York area and spreads to the rest of the country, the authors hope their experience will shed light on the effects of the ongoing COVID-19 pandemic, and inform other programs on what to expect and how they can try and prepare for future public health crises.


Two Factors, Five Factors, or Both? External Validation Studies of Negative Symptom Dimensions in Schizophrenia.
Negative symptom studies frequently use single composite scores as indicators of symptom severity and as primary endpoints in clinical trials. Factor analytic and external validation studies do not support this practice but rather suggest a multidimensional construct. The current study used structural equation modeling (SEM) to compare competing dimensional models of negative symptoms to determine the number of latent dimensions that best capture variance in biological, psychological, and clinical variables known to have associations with negative symptoms. Three independent studies (total n = 632) compared unidimensional, two-factor, five-factor, and hierarchical conceptualizations of negative symptoms in relation to cognition, psychopathology, and community functioning (Study 1); trait emotional experience and defeatist performance beliefs (Study 2); and glutamate and gamma-aminobutyric acid levels in the anterior cingulate cortex quantified using proton magnetic resonance spectroscopy (Study 3). SEM favored the five-factor and hierarchical models over the unidimensional and two-factor models regardless of the negative symptom measure or external validator. The five dimensions-anhedonia, asociality, avolition, blunted affect, and alogia-proved vital either as stand-alone domains or as first-order domains influenced by second-order dimensions-motivation and pleasure and emotional expression. The two broader dimensions sometimes masked important associations unique to the five narrower domains. Avolition, anhedonia, and blunted affect showed the most domain-specific associations with external variables across study samples. Five domains and a hierarchical model reflect the optimal conceptualization of negative symptoms in relation to external variables. Clinical trials should consider using the two dimensions as primary endpoints and the five domains as secondary endpoints.


A unified model of the excitability of mouse sensory and motor axons.
Non-invasive nerve excitability techniques have provided valuable insight into the understanding of neurological disorders. The widespread use of mice in translational research on peripheral nerve disorders and by pharmaceutical companies during drug development requires valid and reliable models that can be compared to humans. This study established a novel experimental protocol that enables comparative assessment of the excitability properties of motor and sensory axons at the same site in mouse caudal nerve, compared the mouse data to data for motor and sensory axons in human median nerve at the wrist, and constructed a mathematical model of the excitability of mouse axons. In a separate study, ischaemia was employed as an experimental manoeuvre to test the translational utility of this preparation. The patterns of mouse sensory and motor excitability were qualitatively similar to human studies under normal and ischaemic conditions. The most conspicuous differences between mouse and human studies were observed in the recovery cycle and the response to hyperpolarization. Modelling showed that an increase in temperature in mouse axons could account for most of the differences in the recovery cycle. The modelling also suggested a larger hyperpolarization-activated conductance in mouse axons. The kinetics of this conductance appeared to be much slower raising the possibility that an additional or different hyperpolarization-activated cyclic-nucleotide gated (HCN) channel isoform underlies the accommodation to hyperpolarization in mouse axons. Given a possible difference in HCN isoforms, caution should be exercised in extrapolating from studies of mouse motor and sensory axons to human nerve disorders.


Upregulation of endogenous neurotrophin levels in the brain by intranasal administration of carnosic acid.
The potential of intranasally administered carnosic acid to enhance the endogenous levels of neurotrophins [nerve growth factor and brain-derived neurotrophic factor] in the brain was investigated. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was used to enhance the aqueous solubility of carnosic acid. The effect of different concentrations of chitosan on the permeation of carnosic acid was investigated across the bovine olfactory mucosa using Franz diffusion cell setup. The formulations were administered [intranasal (i.n.)/subcutaneous route] in Sprague-Dawley rats, and the neurotrophins were sampled from the brain by microdialysis after the treatment period and measured by enzyme-linked immunosorbent assay. Phase solubility studies revealed that the solubility of carnosic acid was enhanced significantly with increase in the concentration of HP-β-CD. The neurotrophin levels were enhanced significantly upon i.n. administration of carnosic acid with chitosan, which was approximately 1.5-2-fold more over the parenteral route. Nose-to-brain delivery of carnosic acid along with chitosan is a potential approach for treating disorders associated with depletion of neurotrophins.


Speciation along a depth gradient in a marine adaptive radiation.
Oceans are home to much of the world's biodiversity, but we know little about the processes driving speciation in marine ecosystems with few geographical barriers to gene flow. Ecological speciation resulting from divergent natural selection between ecological niches can occur in the face of gene flow. Sister species in the young and ecologically diverse rockfish genus Sebastes coexist in the northeast Pacific, implying that speciation may not require geographical isolation. Here, I use a novel phylogenetic comparative analysis to show that rockfish speciation is instead associated with divergence in habitat depth and depth-associated morphology, consistent with models of parapatric speciation. Using the same analysis, I find no support for alternative hypotheses that speciation involves divergence in diet or life history, or that speciation involves geographic isolation by latitude. These findings support the hypothesis that rockfishes undergo ecological speciation on an environmental gradient.


A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials.
Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer's disease.


Synthesis and In Vitro Evaluation as Potential Anticancer and Antioxidant Agents of Diphenylamine-Pyrrolidin-2-one-Hydrazone Derivatives.
The title compounds were synthesized by the reaction of 5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide with various aldehydes bearing aromatic and heterocyclic moieties and acetophenones, and their cytotoxicity was tested via MTT assay against human triple-negative breast cancer MDA-MB-231, human melanoma IGR39, human pancreatic carcinoma Panc-1, and prostate cancer cell line PPC-1. Furthermore, the selectivity of compounds towards cancer cells compared to fibroblasts was also investigated. Four compounds were identified as the most promising anticancer agents out of a series of pyrrolidinone-hydrazone derivatives bearing a diphenylamine moiety. These compounds were most selective against the prostate cancer cell line PPC-1 and the melanoma cell lines IGR39, with EC50 values in the range of 2.5-20.2 µM against these cell lines. In general, the compounds were less active against triple-negative breast cancer MDA-MB-231 cell line, and none of them showed an inhibitory effect on the migration of these cells. In the 'wound healing' assay, N'-((5-nitrothiophen-2-yl)methylene)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide was identified as the most promising derivative that could be further developed as an antimetastatic agent. N'-(5-chloro- and N'-(3,4-dichlorobenzylidene)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazides most efficiently reduced the cell viability in IGR39 cell spheroids, while there was no effect of the investigated pyrrolidinone-hydrazone derivatives on PPC-1 3D cell cultures. Antioxidant activity determined via FRAP assay of N'-(1-(4-aminophenyl)ethylidene)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide was 1.2 times higher than that of protocatechuic acid.


Evaluating tinnitus in industrial hearing loss prevention programs.
This study evaluated the interference of tinnitus on the quality of life for noise-exposed workers enrolled in a hearing conservation program. Noise measurements, a questionnaire, a Brazilian version of the Tinnitus Handicap Inventory (THI), and pure-tone audiometry were conducted with 52 participants (mean age, 29 years) who suffered from tinnitus. THI results indicated that tinnitus had the greatest influence in the functional scale (54%). Significant correlations (p < .05) were observed between the periodicity of tinnitus and noise exposure level; degree of tinnitus and exposure to chemicals; total THI score and the scores of the catastrophic, emotional, and functional scales; score of the emotional scale and the functional scale; and results of the THI and the general state of health. An evaluation of tinnitus and its impact could benefit tinnitus sufferers in the workplace.


Survival-related profile, pathways, and transcription factors in ovarian cancer.
Ovarian cancer has a poor prognosis due to advanced stage at presentation and either intrinsic or acquired resistance to classic cytotoxic drugs such as platinum and taxoids. Recent large clinical trials with different combinations and sequences of classic cytotoxic drugs indicate that further significant improvement in prognosis by this type of drugs is not to be expected. Currently a large number of drugs, targeting dysregulated molecular pathways in cancer cells have been developed and are introduced in the clinic. A major challenge is to identify those patients who will benefit from drugs targeting these specific dysregulated pathways.The aims of our study were (1) to develop a gene expression profile associated with overall survival in advanced stage serous ovarian cancer, (2) to assess the association of pathways and transcription factors with overall survival, and (3) to validate our identified profile and pathways/transcription factors in an independent set of ovarian cancers. According to a randomized design, profiling of 157 advanced stage serous ovarian cancers was performed in duplicate using approximately 35,000 70-mer oligonucleotide microarrays. A continuous predictor of overall survival was built taking into account well-known issues in microarray analysis, such as multiple testing and overfitting. A functional class scoring analysis was utilized to assess pathways/transcription factors for their association with overall survival. The prognostic value of genes that constitute our overall survival profile was validated on a fully independent, publicly available dataset of 118 well-defined primary serous ovarian cancers. Furthermore, functional class scoring analysis was also performed on this independent dataset to assess the similarities with results from our own dataset. An 86-gene overall survival profile discriminated between patients with unfavorable and favorable prognosis (median survival, 19 versus 41 mo, respectively; permutation p-value of log-rank statistic = 0.015) and maintained its independent prognostic value in multivariate analysis. Genes that composed the overall survival profile were also able to discriminate between the two risk groups in the independent dataset. In our dataset 17/167 pathways and 13/111 transcription factors were associated with overall survival, of which 16 and 12, respectively, were confirmed in the independent dataset. Our study provides new clues to genes, pathways, and transcription factors that contribute to the clinical outcome of serous ovarian cancer and might be exploited in designing new treatment strategies.


Raised plasma urea levels after myocardial infarction.
Plasma and urine urea and creatinine levels were measured in 50 consecutive patients admitted to a coronary care unit. Forty of the patients had had myocardial infarction; their average plasma urea level increased substantially by the third day after admission, when 50% of the patients had an "abnormally" high plasma urea level. There was no change in plasma urea levels in ten patients who had not had a myocardial infarction. Results indicate that a rise in plasma urea level is common if not universal after myocardial infarction and is caused by either a fall in the glomerular filtration rate or an increased urea production rather than a mixture of the two.


Electrodeposition of quaternary alloys in the presence of magnetic field.
Electrodeposition of Ni-Co-Fe-Zn alloys was done in a chloride ion solution with the presence and absence of a Permanent Parallel Magnetic Field (PPMF). The PPMF was applied parallel to the cathode surface. The deposition profile was monitored chronoamperometrically. It was found that the electrodeposition current was enhanced in the presence of PPMF (9 T) compared to without PPMF. The percentage of current enhancement (Gamma%) was increased in the presence of PPMF, with results of Gamma% = 11.9%, 16.7% and 18.5% at -1.1, -1.2 and -1.3 V respectively for a 2400 sec duration. In chronoamperometry, the Composition Reference Line (CRL) for Ni was around 57%, although the nobler metals (i.e. Ni, Co) showed anomalous behaviour in the presence of Zn and Fe. The anomalous behaviour of the Ni-Co-Fe-Zn electrodeposition was shown by the Energy Dispersive X-Ray (EDX) results. From Atomic Force Microscopy (AFM) measurements, it was found that the surface roughness of the Ni-Co-Fe-Zn alloy films decreased in the presence of a PPMF.


Motor strategies and adiabatic invariants: The case of rhythmic motion in parabolic flights.
The role of gravity in human motor control is at the same time obvious and difficult to isolate. It can be assessed by performing experiments in variable gravity. We propose that adiabatic invariant theory may be used to reveal nearly conserved quantities in human voluntary rhythmic motion, an individual being seen as a complex time-dependent dynamical system with bounded motion in phase space. We study an explicit realization of our proposal: An experiment in which we asked participants to perform ∞- shaped motion of their right arm during a parabolic flight, either at self-selected pace or at a metronome's given pace. Gravity varied between 0 and 1.8 g during a parabola. We compute the adiabatic invariants in the participant's frontal plane assuming a separable dynamics. It appears that the adiabatic invariant in vertical direction increases linearly with g, in agreement with our model. Differences between the free and metronome-driven conditions show that participants' adaptation to variable gravity is maximal without constraint. Furthermore, motion in the participant's transverse plane induces trajectories that may be linked to higher-derivative dynamics. Our results show that adiabatic invariants are relevant quantities to show the changes in motor strategy in time-dependent environments.


Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens.
The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthracycline-based regimens. Between 1996 and 2009, 651 APL patients with available data on CD56 expression were included in 3 subsequent trials (PETHEMA LPA96 and LPA99 and PETHEMA/HOVON LPA2005). Seventy-two patients (11%) were CD56(+) (expression of CD56 in ≥ 20% leukemic promyelocytes). CD56(+) APL was significantly associated with high white blood cell counts; low albumin levels; BCR3 isoform; and the coexpression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. For CD56(+) APL, the 5-year relapse rate was 22%, compared with a 10% relapse rate for CD56(-) APL (P = .006). In the multivariate analysis, CD56 expression retained the statistical significance together with the relapse-risk score. CD56(+) APL also showed a greater risk of extramedullary relapse (P < .001). In summary, CD56 expression is associated with the coexpression of immaturity-associated and T-cell antigens and is an independent adverse prognostic factor for relapse in patients with APL treated with all-trans-retinoic acid plus idarubicin-derived regimens. This marker may be considered for implementing risk-adapted therapeutic strategies in APL. The LPA2005 trial is registered at http://www.clinicaltrials.gov as NCT00408278.


Youth Athletes' Perception of Existence and Prevalence of Aggression and Interpersonal Violence and Their Forms in Serbia.
Aggression and interpersonal violence (IV) against children and youth are issues in contemporary society. The current study reports on the youth athletes' perception of the aggression and IV prevalence and its manifestation forms in a Serbian context. The sample included athletes (N = 2091) between the age of 11 and 18 years. Data were collected through an ad-hoc questionnaire created by the authors. Respondents' answers to introductory questions about the frequency of IV indicated its absence (78.1%). However, the answers to the questions about specific forms of violent peer behavior indicated forms as well as the time and place where IV most often occurs. They underlined that IV takes place mainly after training or competition and during sports camps; and that the dressing room is the most favorable place for these behaviors. They also confirmed that the most prevalent subtypes of IV are psychological (roughly 40%) and physical (approximately 30%). The respondents' opinions and experiences about IV (psychological, physical, sexual) revealed that factors such as gender, location, and parents' education level may influence the IV manifestation. Highlighting the prevalence and the most frequently manifesting types of aggression and IV could help in awareness-raising of these social issues.


Adjustment among area youth after the Boston Marathon bombing and subsequent manhunt.
The majority of research on terrorism-exposed youth has examined large-scale terrorism with mass casualties. Limited research has examined children's reactions to terrorism of the scope of the Boston Marathon bombing. Furthermore, the extraordinary postattack interagency manhunt and shelter-in-place warning made for a truly unprecedented experience in its own right for families. Understanding the psychological adjustment of Boston-area youth in the aftermath of these events is critical for informing clinical efforts. Survey of Boston-area parents/caretakers (N = 460) reporting on their child's experiences during the attack week, as well as psychosocial functioning in the first 6 attack months. There was heterogeneity across youth in attack- and manhunt-related experiences and clinical outcomes. The proportion of youth with likely attack/manhunt-related posttraumatic stress disorder (PTSD) was roughly 6 times higher among Boston Marathon-attending youth than nonattending youth. Attack and manhunt experiences each uniquely predicted 9% of PTSD symptom variance, with manhunt exposures more robustly associated than attack-related exposures with a range of psychosocial outcomes, including emotional symptoms, conduct problems, hyperactivity/inattention, and peer problems. One-fifth of youth watched >3 hours of televised coverage on the attack day, which was linked to PTSD symptoms, conduct problems, and total difficulties. Prosocial behavior and positive peer functioning buffered the impact of exposure. Clinical efforts must maintain a broadened focus beyond simply youth present at the blasts and must also include youth highly exposed to the intense interagency pursuit and manhunt. Continued research is needed to understand the adjustment of youth after mass traumas and large-scale manhunts in residential communities.


Deubiquitinating enzymes regulate Hes1 stability and neuronal differentiation.
Hairy and enhancer of split 1 (Hes1), a basic helix-loop-helix transcriptional repressor protein, regulates the maintenance of neural stem/progenitor cells by repressing proneural gene expression via Notch signaling. Previous studies showed that Hes1 expression oscillates in both mouse embryonic stem cells and neural stem cells, and that the oscillation contributes to their potency and differentiation fates. This oscillatory expression depends on the stability of Hes1, which is rapidly degraded by the ubiquitin/proteasome pathway. However, the detailed molecular mechanisms governing Hes1 stability remain unknown. We analyzed Hes1-interacting deubiquitinases purified from mouse embryonic stem cells using an Hes1-specific antibody, and identified the ubiquitin-specific protease 27x (Usp27x) as a new regulator of Hes1. We found that Hes1 was deubiquitinated and stabilized by Usp27x and its homologs ubiquitin-specific protease 22 (Usp22) and ubiquitin-specific protease 51 (Usp51). Knockdown of Usp22 shortened the half-life of Hes1, delayed its oscillation, and enhanced neuronal differentiation in mouse developing brain, whereas mis-expression of Usp27x reduced neuronal differentiation. These results suggest that these deubiquitinases modulate Hes1 protein dynamics by removing ubiquitin molecules, and thereby regulate neuronal differentiation of stem cells.


Pharmacologic excitability of rat motor nerve endings: the effect of adrenalectomy on neostigmine-induced fasciculations.
Neostigmine-induced muscle fasciculations, quantitated as fasciculatory muscle action potentials, served as an indirect in vivo indicator of motor nerve ending (MNE) excitability. By this method, MNE excitability was depressed in adrenalectomized rats compared to matched intact controls. Daily or continuous administration of the mineralocorticoids aldosterone or desoxycorticosterone acetate restored MNE excitability toward normal; corticosterone, the endogenous corticosteroid having both mineralo- and glucocorticoid activity, was variably effective. There was a strong negative correlation (r = -0.95) between log plasma [K+]and the fasciculatory response to neostigmine. Dietary restriction of K in adrenalectomized rats lowered plasma [K+]to near normal and significantly increased MNE excitability. This effect of adrenalectomy on MNE excitability was further demonstrated by recording directly the neostigmine-induced repetitive neural discharges responsible for the muscle fasciculations. In adrenalectomized animals, neostigmine-induced neural discharges were reduced in intensity; restoration of neostigmine responsiveness was attained by lowering plasma [K+]through dietary restriction. Stimulus strength-duration relationships for both ventral and dorsal roots disclosed deficits in axonal excitability after adrenalectomy. These returned toward normal when plasma [K+]was lowered by K withdrawal from the diet. From these studies, it is concluded that 1) in adrenalectomized rats, peripheral nerve excitability, including the unmyelinated endings of motor nerve, is depressed; 2) mineralocorticoids play a significant role in restoring MNE excitability in these animals; 3) mineralocorticoid-induced changes in MNE excitability relate to the lowering of an elevated plasma [K+].


Sequence of Shiga toxin 2 phage 933W from Escherichia coli O157:H7: Shiga toxin as a phage late-gene product.
Lysogenic bacteriophages are major vehicles for the transfer of genetic information between bacteria, including pathogenicity and/or virulence determinants. In the enteric pathogen Escherichia coli O157:H7, which causes hemorrhagic colitis and hemolytic-uremic syndrome, Shiga toxins 1 and 2 (Stx1 and Stx2) are phage encoded. The sequence and analysis of the Stx2 phage 933W is presented here. We find evidence that the toxin genes are part of a late-phage transcript, suggesting that toxin production may be coupled with, if not dependent upon, phage release during lytic growth. Another phage gene, stk, encodes a product resembling eukaryotic serine/threonine protein kinases. Based on its position in the sequence, Stk may be produced by the prophage in the lysogenic state, and, like the YpkA protein of Yersinia species, it may interfere with the signal transduction pathway of the mammalian host. Three novel tRNA genes present in the phage genome may serve to increase the availability of rare tRNA species associated with efficient expression of pathogenicity determinants: both the Shiga toxin and serine/threonine kinase genes contain rare isoleucine and arginine codons. 933W also has homology to lom, encoding a member of a family of outer membrane proteins associated with virulence by conferring the ability to survive in macrophages, and bor, implicated in serum resistance.


The design and implementation of a workflow analysis tool.
Motivated by the use of scientific workflows as a user-oriented mechanism for building executable scientific data integration and analysis applications, this article introduces a framework and a set of associated methods for analysing the execution properties of scientific workflows. Our framework uses a number of formal modelling techniques to characterize the process and data behaviour of workflows and workflow components and to reason about their functional and execution properties. We use the framework to design the architecture of a customizable tool that can be used to analyse the key execution properties of scientific workflows at authoring stage. Our design is generic and can be applied to a wide variety of scientific workflow languages and systems, and is evaluated by building a prototype of the tool for the Discovery Net system. We demonstrate and discuss the utility of the framework and tool using workflows from a real-world medical informatics study.


Bilateral phacoemulsification and intraocular lens implantation in a great horned owl.
A great horned owl of estimated age < 1 year that was captured by wildlife rehabilitators was evaluated because of suspected cataracts. Nuclear and incomplete cortical cataracts were evident in both eyes. Ocular ultrasonography revealed no evidence of retinal detachment, and electroretinography revealed normal retinal function. For visual rehabilitation, cataract surgery was planned and intraocular lens design was determined on the basis of values obtained from the schematic eye, which is a mathematical model representing a normal eye for a species. Cataract surgery and intraocular lens placement were performed in both eyes. After surgery, refraction was within -0.75 diopters in the right eye and -0.25 diopters in the left eye. Visual rehabilitation was evident on the basis of improved tracking and feeding behavior, and the owl was eventually released into the wild. In raptors with substantial visual compromise, euthanasia or placement in a teaching facility is a typical outcome because release of such a bird is unacceptable. Successful intraocular lens implantation for visual rehabilitation and successful release into the wild are achievable.


The speed of human social interaction perception.
The ability to perceive others' social interactions, here defined as the directed contingent actions between two or more people, is a fundamental part of human experience that develops early in infancy and is shared with other primates. However, the neural computations underlying this ability remain largely unknown. Is social interaction recognition a rapid feedforward process or a slower post-perceptual inference? Here we used magnetoencephalography (MEG) decoding to address this question. Subjects in the MEG viewed snapshots of visually matched real-world scenes containing a pair of people who were either engaged in a social interaction or acting independently. The presence versus absence of a social interaction could be read out from subjects' MEG data spontaneously, even while subjects performed an orthogonal task. This readout generalized across different people and scenes, revealing abstract representations of social interactions in the human brain. These representations, however, did not come online until quite late, at 300 ms after image onset, well after feedforward visual processes. In a second experiment, we found that social interaction readout still occurred at this same late latency even when subjects performed an explicit task detecting social interactions. We further showed that MEG responses distinguished between different types of social interactions (mutual gaze vs joint attention) even later, around 500 ms after image onset. Taken together, these results suggest that the human brain spontaneously extracts information about others' social interactions, but does so slowly, likely relying on iterative top-down computations.


Factors associated with hepatitis C treatment adherence: an integrative review.
This integrative review examined factors associated with hepatitis C treatment adherence. The articles included were published in English, Spanish and Portuguese in the Lilacs, Medline, PsycINFO, Web of Science, Scopus and CINAHL databases, between 2000 and 2019. Initially, 540 publications were found and, after applying the study inclusion criteria, 22 articles were selected. Percentage non-adherence to treatment ranged from 12% to 32%. The variables identified as facilitating adherence were: receiving treatment for psychiatric disorders identified during treatment; knowing about medications and disease; receiving less complex treatment with greater likelihood of cure; fewer adverse events; social support; doctor-patient communication; and/or being in relationships. Barriers to adherence identified were: presence of depressive symptoms and other mental disorders; abuse of alcohol and psychoactive substances; education; age; ethnicity; unemployment; not having a steady partner; stigma; distance from health services; and the complexity and adverse effects of treatment. This review identified gaps in research on adherence.


Dobutamine effects on spontaneous variability of ventricular arrhythmias in patients with severe chronic heart failure: the Italian Multicenter Study.
Dobutamina Studio Italiano Multicentrico (Do.S.I.M.) is a prospective, randomized, multicenter interuniversity Italian study aimed at assessing the effects of dobutamine on spontaneous variability of ventricular arrhythmias in sinus rhythm NYHA class III-IV patients with congestive heart failure (CHF). Out of 74 pre-hoc estimated CHF patients, 68 (92%) were randomized electively to either being washed out of all active drugs except diuretics (group A) or to continue with the standard regimen including digitalis, diuretics and ACE-inhibitors (group B, standard therapy). In 63 patients, complete Holter data were obtained and are reported here. After 72 hours, in both groups, 48-hour Holter monitoring (Holter 1) was performed. The spontaneous variability of ventricular arrhythmias was assessed by calculating the natural logarithm of the sum of hourly incidences (during 48 consecutive hours) of index events such as the mean heart rate or the various forms of total and either sustained or non-sustained ventricular arrhythmias. The results were then grouped for the first and second 24-hour Holter periods. All patients were submitted to 10 microg/kg/min infusion of dobutamine for 72 hours and 48-hour Holter monitoring (Holter 2) was repeated 24 hours before the end of dobutamine infusion. The incidence of arrhythmia and the distribution of laboratory and echocardiographic variables was also studied in group A and B patients. The data of the two groups along with the intrapatient +/- 95% confidence intervals were pooled, both on and off dobutamine. There was no significant difference between Holter 1 and Holter 2 in the rates of index events in 63 patients with regard to pro-arrhythmic effects. Pro-arrhythmic effects were seen during dobutamine infusion in 21% of cases, an effect which subsided (to 5%) when dobutamine was discontinued. Interestingly, the positive inotropic effects of dobutamine (based on ejection fraction changes) were parallel (22%) to the pro-arrhythmic changes, although they persisted long after dobutamine discontinuation (18%). The pro-arrhythmic effects of dobutamine, both during (5%) as well as after (1%) drug infusion, were unrelated to heart rate changes. The prevalence and incidence of non-sustained ventricular tachycardia due to dobutamine were 47 and 29% respectively. In sinus rhythm patients with severe CHF, dobutamine had chronotropic effects and increased a depressed ejection fraction without significantly increasing arrhythmogenicity.


Olanzapine pharmacokinetics in pediatric and adolescent inpatients with childhood-onset schizophrenia.
Well-designed studies investigating how pediatric or adolescent patients with mental disorders respond to and metabolize the newer antipsychotic drugs are practically nonexistent. Without such data, clinicians have difficulty designing appropriate dosage regimens for patients in these age groups. The results from a study of olanzapine pharmacokinetics in children and adolescents are described. Eight inpatients (ages 10-18 years) with treatment-resistant childhood-onset schizophrenia received olanzapine (2.5-20 mg/day) over 8 weeks. Blood samples, collected during dose titration and at a steady state provided pharmacokinetic data. The final evaluation (week 8) included extensive sampling for 36 hours after a 20-mg dose. Olanzapine concentrations in these eight pediatric patients were of the same magnitude as those for nonsmoking adult patients with schizophrenia but may be as much as twice the typical olanzapine concentrations in patients with schizophrenia who smoke. Olanzapine pharmacokinetic evaluation gave an apparent mean oral clearance of 9.6 +/- 2.4 L/hr and a mean elimination half-life of 37.2 +/- 5.1 hours in these young patients. The determination of the initial olanzapine dose for adolescent patients should take into consideration factors such as the patient's size. In general, however, the usual dose recommendation of 5 to 10 mg once daily with a target dose of 10 mg/day is likely a good clinical guideline for most adolescent patients on the basis of our pharmacokinetics results.


Laser-induced breakdown spectroscopy (LIBS), part I: review of basic diagnostics and plasma-particle interactions: still-challenging issues within the analytical plasma community.
Laser-induced breakdown spectroscopy (LIBS) has become a very popular analytical method in the last decade in view of some of its unique features such as applicability to any type of sample, practically no sample preparation, remote sensing capability, and speed of analysis. The technique has a remarkably wide applicability in many fields, and the number of applications is still growing. From an analytical point of view, the quantitative aspects of LIBS may be considered its Achilles' heel, first due to the complex nature of the laser-sample interaction processes, which depend upon both the laser characteristics and the sample material properties, and second due to the plasma-particle interaction processes, which are space and time dependent. Together, these may cause undesirable matrix effects. Ways of alleviating these problems rely upon the description of the plasma excitation-ionization processes through the use of classical equilibrium relations and therefore on the assumption that the laser-induced plasma is in local thermodynamic equilibrium (LTE). Even in this case, the transient nature of the plasma and its spatial inhomogeneity need to be considered and overcome in order to justify the theoretical assumptions made. This first article focuses on the basic diagnostics aspects and presents a review of the past and recent LIBS literature pertinent to this topic. Previous research on non-laser-based plasma literature, and the resulting knowledge, is also emphasized. The aim is, on one hand, to make the readers aware of such knowledge and on the other hand to trigger the interest of the LIBS community, as well as the larger analytical plasma community, in attempting some diagnostic approaches that have not yet been fully exploited in LIBS.


Quantification of interplay and gradient effects for lung stereotactic ablative radiotherapy (SABR) treatments.
This study quantified the interplay and gradient effects on GTV dose coverage for 3D CRT, dMLC IMRT, and VMAT SABR treatments for target amplitudes of 5-30 mm using 3DVH v3.1 software incorporating 4D Respiratory MotionSim (4D RMS) module. For clinically relevant motion periods (5 s), the interplay effect was small, with deviations in the minimum dose covering the target volume (D99%) of less than ± 2.5% for target amplitudes up to 30 mm. Increasing the period to 60 s resulted in interplay effects of up to ± 15.0% on target D99% dose coverage. The gradient effect introduced by target motion resulted in deviations of up to ± 3.5% in D99% target dose coverage. VMAT treatments showed the largest deviation in dose metrics, which was attributed to the long delivery times in comparison to dMLC IMRT. Retrospective patient analysis indicated minimal interplay and gradient effects for patients treated with dMLC IMRT at the NCCI.


Insight into Organization of Gliadin and Glutenin Extracted from Gluten Modified by Phenolic Acids.
The changes in the secondary structure of individual gluten protein fractions (gliadin and glutenin) caused by the supplementation of model dough with eight phenolic acids were analysed. Gliadins and glutenins were extracted from gluten samples obtained from overmixed dough. The changes in the gliadin secondary structure depended on the amount of phenolic acid added to the dough. Higher acid concentrations (0.1% and 0.2%) led to a significant reduction in the amount of α-helices and to the formation of aggregates, non-ordered secondary structures, and antiparallel β-sheets. After the addition of acids at a lower concentration (0.05%), the disaggregation of pseudo-β-sheet structures and the formation of β-turns, hydrogen-bonded β-turns, and antiparallel β-sheets were detected. In the case of glutenin, most of the phenolic acids induced the formation of intermolecular hydrogen bonds between the polypeptide chains, leading to glutenin aggregation. When phenolic acids were added at a concentration of 0.05%, the process of protein folding and regular secondary structure formation was also observed. In this system, antiparallel β-sheets and β-turns were created at the expense of pseudo-β-sheets.


Essential Medicines List Implementation Dynamics: A Case Study Using Brazilian Federal Medicines Expenditures.
The aim was to analyse the implementation dynamics of the essential medicines list (EML). We used the government expenditures on medicines and Brazil as a case study. Drug purchases were considered as a proxy for utilization. The essential medicines (EMs) expenditures were followed over time by Brazilian National EMLs life-time and defined by broad therapeutic categories and by specific medicines. Brazil increased the number of the medicines during the last four editions of Brazilian National EMLs and the federal government expenditures on them. The EML implementation dynamics changed the distribution of expenditures on EMs. We identified a common set of 404 EMs present in all four editions of the Brazilian National EMLs. There was a proportional decrease in expenditures on anti-infectives for systemic use, blood and blood-forming organs and alimentary tract and metabolism, and increase in expenditures on antineoplastic and immunomodulating agents. The expenditures distribution per specific medicines revealed that a small set of EMs was responsible for 50% or more of expenditures considering Brazilian National EML life-time for all four periods. The increase in expenditures on EMs in Brazil was a consequence of the newer medicines incorporated over time in the Brazilian National EMLs. The use of the medicines expenditures as a source of data and the definition of an EML life-time permitted follow-up of the implementation dynamics of different versions of the Brazilian National EMLs. Our results have implications for policymakers and stakeholders to gain a better understanding of the role EMLs play in health system sustainability and in the provision of the most beneficial heath care.


The Arruga suture for retinal detachment 17 years on.
A brief description is given of the experience gained in the use of the 'Arruga suture' method in 64 eyes out of a total of 356 operated on for retinal detachment. The encouraging results in those eyes in which the method was used as a primary procedure and the absence of complications suggest that the 'Arruga suture' should be considered in selected cases of retinal detachment--particularly in cases of aphakic detachment.


NDV-D90 inhibits 17β-estradiol-mediated resistance to apoptosis by differentially modulating classic and nonclassic estrogen receptors in breast cancer cells.
Newcastle disease virus (NDV) is endowed with the oncolytic ability to kill tumor cells, while rarely causing side effects in normal cells. Both estrogen receptor α (ERα) and the G protein estrogen receptor (GPER) modulate multiple biological activities in response to estrogen, including apoptosis in breast cancer (BC) cells. Here, we investigated whether NDV-D90, a novel strain isolated from natural sources in China, promoted apoptosis by modulating the expression of ERα or the GPER in BC cells exposed to 17β-estradiol (E2). We found that NDV-D90 significantly killed the tumor cell lines MCF-7 and BT549 in a time- and dose-dependent manner. We also found that NDV-D90 exerted its effects on the two cell lines mainly by inducing apoptosis but not necrosis. NDV-D90 induced apoptosis via the intrinsic and extrinsic signaling pathways in MCF-7 cells (ER-positive cells) during E2 exposure not only by disrupting the E2/ERα axis and enhancing GPER expression but also by modulating the expression of several apoptosis-related proteins through ERα-and GPER-independent processes. NDV-D90 promoted apoptosis via the intrinsic signaling pathway in BT549 cells (ER-negative cells), possibly by impairing E2-mediated GPER expression. Furthermore, NDV-D90 exerted its antitumor effects in vivo by inducing apoptosis. Overall, these results demonstrated that NDV-D90 promotes apoptosis by differentially modulating the expression of ERα and the GPER in ER-positive and negative BC cells exposed to estrogen, respectively, and can be utilized as an effective approach to treating BC.


Knowledge and attitudes about depression among non-generalists and generalists.
The purpose of this study was to learn more about barriers to managing depression by comparing knowledge and attitudes about depression among physicians, internists, obstetrician-gynecologists, and a reference group of psychiatrists. Among the non-psychiatrists, we hypothesized that generalist physicians would have more favorable attitudes and greater knowledge about depression than non-generalists. Survey questionnaires were sent to resident and faculty physicians (N = 375) of two university-affiliated medical centers. The physicians were classified as non-generalists (medicine subspecialists, transitional year interns, and obstetrician-gynecologists), generalists (general internists and family physicians), and psychiatrists. A 33-item written questionnaire assessed knowledge and three attitudinal dimensions: attitudes attributed by physicians to patients; physicians' confidence in managing depression; and physicians' psychosocial orientation. A knowledge scale and an attitudes scale were scored by adding the number of knowledge items answered correctly and the more favorable attitudinal responses. Multivariable regression was used to identify physician characteristics among non-generalists and generalists associated with higher knowledge and attitudinal scores. Response rate was 82%. Sixty percent of the respondents were male, 63% were resident physicians, and 14% had advanced psychosocial training. Non-generalists and generalists had similar demographic characteristics, but psychiatrists were significantly more experienced. Psychiatrists had the most favorable attitudes, followed by generalists and non-generalists. Compared with non-generalists, generalists were more confident in prescribing antidepressants (62% vs 25%), more likely to report that treating depression is rewarding (71% vs 39%), and less likely to refer to a psychiatrist (58% vs 79%). Generalist classification, increased experience, and higher levels of psychosocial training were associated with more favorable attitudes. Knowledge scores were significantly higher for psychiatrists than for non-generalists and generalists. Among non-psychiatrists, correct responses for knowledge items were: treatment efficacy (61%), treatment duration (59%), > or = 5 DSM-III-R criteria (52%), and prevalence of depression (30%). Among those with incorrect responses, both non-generalists and generalists overestimated the prevalence (52%) and underestimated the efficacy of drug therapy (30%). Generalists and non-generalists have similar and relatively good basic knowledge about depression. Misperceptions about treatment efficacy, and attitudinal barriers, particularly among non-generalists, may compromise the physician's ability to diagnose and manage depression.