Diffuse binding of Zn(2+) to the denatured ensemble of Cu/Zn superoxide dismutase 1.
The stability and structural properties of the metalloprotein superoxide dismutase 1 (SOD1) are found to depend critically on metal ions. Native SOD1 monomers coordinate one structural Zn(2+) and one redox-active Cu(2+/1+) to the active site. To do this, the Zn(2+) ions need to interact with the SOD1 protein on the denatured side of the folding barrier, prior to the formation of the folding nucleus. In this study, we have examined at residue level the nature of this early Zn(2+) binding by NMR studies on the urea denatured-state of SOD1. Nearly complete backbone chemical shift assignments were obtained in 9 M urea at physiological pH, conditions at which NMR studies are scarce. Our results demonstrate that SOD1 is predominantly unstructured under these conditions. Chemical-shift changes upon Zn(2+) titration show that denatured SOD1 retains a significant affinity to Zn(2+) ions, even in 9 M urea. However, the Zn(2+) interactions are not limited to the native metal-binding ligands in the two binding sites, but are seen for all His residues. Moreover, the native Cu(2+/1+) ligand H46 seems not to bind as well as the other His residues, while the nearby non-native H43 does bind, indicating that the binding geometry is relaxed. The result suggests that the Zn(2+)-binding observed to catalyze folding of SOD1 in physiological buffer is initiated by diffuse, non-specific coordination to the coil, which subsequently funnels by ligand exchange into the native coordination geometry of the folded monomer. Altogether, this diffuse binding is a result with fundamental implications for folding of metalloproteins in general.


Use of theoretical and conceptual frameworks in qualitative research.
To debate the definition and use of theoretical and conceptual frameworks in qualitative research. There is a paucity of literature to help the novice researcher to understand what theoretical and conceptual frameworks are and how they should be used. This paper acknowledges the interchangeable usage of these terms and researchers' confusion about the differences between the two. It discusses how researchers have used theoretical and conceptual frameworks and the notion of conceptual models. Detail is given about how one researcher incorporated a conceptual framework throughout a research project, the purpose for doing so and how this led to a resultant conceptual model. Concepts from Abbott (1988) and Witz ( 1992 ) were used to provide a framework for research involving two case study sites. The framework was used to determine research questions and give direction to interviews and discussions to focus the research. Some research methods do not overtly use a theoretical framework or conceptual framework in their design, but this is implicit and underpins the method design, for example in grounded theory. Other qualitative methods use one or the other to frame the design of a research project or to explain the outcomes. An example is given of how a conceptual framework was used throughout a research project. Theoretical and conceptual frameworks are terms that are regularly used in research but rarely explained. Textbooks should discuss what they are and how they can be used, so novice researchers understand how they can help with research design. Theoretical and conceptual frameworks need to be more clearly understood by researchers and correct terminology used to ensure clarity for novice researchers.


Vascular arginase contributes to arteriolar endothelial dysfunction in a rat model of hemorrhagic shock.
Hemorrhagic shock causes hypoperfusion of peripheral tissues and promotes endothelial dysfunction, which may lead to further tissue injury. Trauma increases extrahepatic activity of arginase, an enzyme which competes for l-arginine with nitric oxide synthase, and plays a key role in the development of endothelial dysfunction during aging, hypertension, and diabetes. However, the role of arginase in hemorrhage-induced endothelial dysfunction has not been studied. This study tests the hypothesis that arginase inhibition improves endothelial function after hemorrhage. Male Sprague-Dawley rats were implanted with indwelling arterial catheters for blood pressure measurements and blood removal. Awake animals were subjected to a 45% fixed volume controlled hemorrhage and blood pressure was monitored. Unbled rats served as controls. Skeletal muscle arterioles were isolated 24 hours after hemorrhage and cannulated in a pressure myograph system. To study endothelial function, arterioles were exposed to constant midpoint, but altered endpoint pressures, to establish graded levels of luminal flow and internal diameter was measured. Hemorrhage lowered mean arterial pressure that spontaneously recovered to 78% and 88% of baseline in 2 hours and 20 hours, respectively. Vascular arginase II and blood glucose levels were elevated, whereas hemoglobin and insulin levels were decreased 24 hours after blood loss. In posthemorrhage arterioles, flow-induced dilation was abolished. Acute in vitro treatment with an inhibitor of arginase, N-hydroxy-nor-l-arginine, restored flow-induced dilation to unbled control levels. Similarly, the arginase and nitric oxide synthase substrate, l-arginine, but not the inactive isomer, d-arginine, restored flow-induced dilation. These results indicate that arginase contributes to endothelial dysfunction in resistance vessels after significant hemorrhage.


Different effects of the glucosidase inhibitors 1-deoxynojirimycin, N-methyl-1-deoxynojirimycin and castanospermine on the glycosylation of rat alpha 1-proteinase inhibitor and alpha 1-acid glycoprotein.
The glucosidase inhibitors 1-deoxynojirimycin, N-methyl-1-deoxynojirimycin and castanospermine were used to inhibit oligosaccharide processing in primary cultures of rat hepatocytes. Their effect on the glycosylation of alpha 1-proteinase inhibitor (alpha 1PI) and alpha 1-acid glycoprotein (alpha 1AGP) was studied. Of the three glucosidase inhibitors examined, 1-deoxynojirimycin inhibited not only oligosaccharide trimming but also glycosylation de novo of newly synthesized proteins, resulting in the formation of alpha 1PI with two and three (normally carrying three) and alpha 1AGP with two to five (normally carrying six) oligosaccharide side chains. In the presence of the glucosidase inhibitors, glucosylated high-mannose-type oligosaccharides accumulated. Whereas most of the endoglucosaminidase-H-sensitive oligosaccharides formed in the presence of 1-deoxynojirimycin contained only one glucose residue, N-methyl-1-deoxynojirimycin and castanospermine led mainly to the formation of oligosaccharides with three glucose residues. None of the three glucosidase inhibitors completely prevented the formation of complex-type oligosaccharides. Thus, in their presence, alpha 1PI and alpha 1AGP with a mixture of both high-mannose and complex-type oligosaccharides were secreted.


Availability to rats of zinc from soybean seeds as affected by maturity of seed, source of dietary protein, and soluble phytate.
Male rats were used to assess the availability of zinc in soybean seeds (Glycine max, var. 'Amsoy') as affected by maturity of seed, dietary protein source, and exogenous dietary sodium phytate. Seeds were harvested from either 84- (immature) or 120-day-old (mature) plants grown in 65Zn-labeled nutrient solutions that contained either 0.066 or 0.262 ppm zinc as zinc sulfate. Increased zinc supply to plants increased the zinc content of seeds; immature seeds had higher concentrations of zinc than mature seeds. Phytic acid concentration averaged about 0.6 and 1.7% dry weight in immature and mature seeds, respectively. Seeds of each type were incorporated into meals fed to zinc-depleted rats. In experiment 1, rats fed mature, high-phytate seeds absorbed about 60% of the 65Zn in the seeds, whereas rats fed immature, low-phytate seeds absorbed about 89% of the 65Zn (P less than 0.05). In experiment 2, the source of dietary protein (egg albumen or soy protein) did not markedly affect 65Zn absorption by rats fed mature soybean seeds. In experiment 3, dietary sodium phytate (1.76% of diet as phytic acid) depressed (P less than 0.05) 65Zn absorption by about 16 and 44% from mature soybean seeds and zinc sulfate, respectively. Zinc in soybean seeds apparently was as readily available to rats as that reported for other legume and cereal seeds. Moreover, the nutritional quality of soybean seeds with respect to zinc apparently can be increased by increasing zinc supplies to plants.


Whole genome-based phylogenetic analysis of free-living microorganisms.
A phylogenetic 'tree of life' has been constructed based on the observed presence and absence of families of protein-encoding genes observed in 11 complete genomes of free-living microorganisms. Past attempts to reconstruct the evolutionary relation-ships of microorganisms have been limited to sets of genes rather than complete genomes. Despite apparent rampant lateral gene transfer among microorganisms, these results indicate a single robust underlying evolutionary history for these organisms. Broadly, the tree produced is very similar to the small subunit rRNA tree although several additional phylogenetic relationships appear to be resolved, including the relationship of Archaeoglobus to the methanogens studied. This result is in contrast to notions that a robust phylogenetic reconstruction of microorganisms is impossible due to their genomes being composed of an incomprehensible amalgam of genes with complicated histories and suggests that this style of genome-wide phylogenetic analysis could become an important method for studying the ancient diversification of life on Earth. Analyses using informational and operational subsets of the genes showed that this 'tree of life' is not dependent on the phylogenetically more consistent informational genes.


Culture, but more than culture: an exploratory study of the HIV vulnerability of Indian immigrants in Canada.
Explanations of immigrant health that ascribe to culture a fundamental causal role neglect the broader structural and contextual factors with which culture intersects. Based on a qualitative study of Indian immigrants' vulnerability to HIV in Canada, this paper presents a contextualised understanding of these individuals' understanding of, perceptions about, and responses to the HIV risk in their post-immigration lives. The study reveals that although culture - both traditional values and the norms of the diaspora community - appears to have constrained Indian immigrants' capacities to respond to the risk, this effect can be properly understood only by situating such constraint in the context of the settlement process that has shaped participants' living conditions, including their relationship with the diasporic community in Canada. We argue that HIV vulnerability should be conceptualised as a health inequality associated with broader systems of power relations (eg socio-economic marginalisation, gender inequality, discrimination, and racism). This more holistic conceptualisation of the intersection of culture, integration, and HIV vulnerability will facilitate exploration of HIV prevention strategies, through which interconnected inequalities of gender, race, and access to knowledge and resources can be challenged.


Cognitive and motor functioning in elderly glucocerebrosidase mutation carriers.
Mutations in the glucocerebrosidase (GBA) gene are a strong genetic risk factor for the development of Parkinson's disease and dementia with Lewy Bodies. However the penetrance of GBA mutations is low for these diseases in heterozygous carriers. The aim of this study was to examine the relationship between mutation status and cognitive and motor functioning in a sample of community-dwelling older adults. Using linear mixed effects models, we examined the effect of heterozygous mutation status on 736 community-dwelling older adults (≥70 years) without dementia or Parkinson's disease assessed over an average of 6 years, 28 of whom had a single GBA mutation (primarily N370S). Verbal memory was measured using the picture version of the Free and Cued Selective Reminding Test, and carriers showed significantly (p < 0.05) greater decline in verbal memory over time. There was no difference in motor function or any other cognitive domain. Taken together, these results suggest an effect, but an overall limited burden, of harboring a single GBA mutation in aging mutation carriers.


Current strategies in the treatment of Parkinson's disease and a personalized approach to management.
Parkinson's disease is a progressive, neurodegenerative disorder affecting millions of people worldwide. Given the aging population, the prevalence of the disease is expected to increase substantially. The mainstay of treatment has been dopamine replacement therapy with carbidopa, levodopa, dopamine agonists, monoamine oxidase type B inhibitors, catechol-O-methyltransferase inhibitors and amantadine. Nonmotor features, such as cognitive impairment, mood disorders, autonomic dysfunction, gastrointestinal and genitourinary dysfunction, have a substantial impact on Parkinson's disease patients and their quality of life. This review will provide an overview on medications currently available for management of both motor and nonmotor symptoms of Parkinson's disease. Focus will be placed on recent and evolving studies evaluating symptomatic and neuroprotective effects of medications, and how such studies may impact the future management of Parkinson's disease.


Fluoride gels for preventing dental caries in children and adolescents.
Topically applied fluoride gels have been widely used as a caries-preventive intervention in dental surgeries and school-based programs for over two decades. To determine the effectiveness and safety of fluoride gels in the prevention of dental caries in children and to examine factors potentially modifying their effect. Multiple electronic database searches, reference lists of articles, journal handsearch, selected authors and manufacturers. Randomized or quasi-randomized controlled trials with blind outcome assessment, comparing fluoride gel with placebo or no treatment in children up to 16 years during at least one year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces (D(M)FS). Inclusion decisions, quality assessment and data extraction were duplicated in a random sample of one third of studies, and consensus achieved by discussion or a third party. Study authors were contacted for missing data. The primary outcome measure was the prevented fraction (PF), that is the caries increment in the treatment group expressed as a percentage of the control group. Random effects meta-analyses were performed where data could be pooled. Potential sources of heterogeneity were examined in random effects meta-regression analyses. Twenty-five studies were included, involving 7747 children. For the 23 that contributed data for meta-analysis, the D(M)FS pooled prevented fraction estimate was 28% (95% CI, 19% to 37%; p<0.0001). There was clear heterogeneity, confirmed statistically (p<0.0001). The effect of fluoride gel varied according to type of control group used, with D(M)FS PF on average being 19% (95% CI, 5% to 33%; p<0.009) higher in non-placebo controlled trials. A funnel plot of the 23 studies indicated a relationship between prevented fraction and study precision. Only two trials reported on adverse events. There is clear evidence of a caries-inhibiting effect of fluoride gel. The best estimate of the magnitude of this effect, based on the 14 placebo-controlled trials, is a 21% reduction (95% CI, 14 to 28%) in D(M)FS. This corresponds to an NNT of 2 (95% CI, 1 to 3) to avoid 1 D(M)FS in a population with a caries increment of 2.2 D(M)FS/year, or an NNT of 24 (95% CI, 18 to 36) based on an increment of 0.2 D(M)FS/year. There is little information concerning deciduous dentition, on adverse effects or on acceptability of treatment. Future trials should include assessment of potential adverse effects.


Treatment of abdominal malignant neoplasms using regional chemotherapy with hemofiltration.
The regional delivery of high-dose chemotherapy for malignant neoplasms of the limb with the isolated regional perfusion technique was first described in the late 1950s. Recently, the use of concomitant hemofiltration for rapid systemic drug removal permits the use of higher regional drug levels in treating patients with advanced abdominal malignant neoplasms without complete vascular isolation. Twenty-five patients successfully underwent 42 treatments of high-dose intra-arterial chemotherapy with concomitant hemofiltration at Tulane University Medical Center Hospital, New Orleans, La, from 1989 through 1990. One patient (4%) achieved a complete response. Two patients (8%) had partial responses following high-dose intra-arterial chemotherapy with concomitant hemofiltration and their residual disease was resected for cure. Seven patients (28%) achieved a partial response, 11 (44%) had stable disease, and four (16%) had progression of disease.


Molecular mechanisms of fibrinolysis.
The molecular mechanisms that finely co-ordinate fibrin formation and fibrinolysis are now well defined. The structure and function of all major fibrinolytic proteins, which include serine proteases, their inhibitors, activators and receptors, have been characterized. Measurements of real time, dynamic molecular interactions during fibrinolysis of whole blood clots can now be carried out in vitro. The development of gene-targeted mice deficient in one or more fibrinolytic protein(s) has demonstrated expected and unexpected roles for these proteins in both intravascular and extravascular settings. In addition, genetic analysis of human deficiency syndromes has revealed specific mutations that result in human disorders that are reflective of either fibrinolytic deficiency or excess. Elucidation of the fine control of fibrinolysis under different physiological and pathological haemostatic states will undoubtedly lead to novel therapeutic interventions. Here, we review the fundamental features of intravascular plasmin generation, and consider the major clinical syndromes resulting from abnormalities in fibrinolysis.


Tail morphology in the Western Diamond-backed rattlesnake, Crotalus atrox.
The shaker muscles in the tails of rattlesnakes are used to shake the rattle at very high frequencies. These muscles are physiologically specialized for sustaining high-frequency contractions. The tail skeleton is modified to support the enlarged shaker muscles, and the muscles have major anatomical modifications when compared with the trunk muscles and with the tail muscles of colubrid snakes. The shaker muscles have been known for many years to consist of three large groups of muscles on each side of the tail. However, the identities of these muscles and their serial homologies with the trunk muscles were not previously known. In this study, we used dissection and magnetic resonance imaging of the tail in the Western Diamond-backed Rattlesnake, Crotalus atrox, to determine that the three largest muscles that shake the rattle are the M. longissimus dorsi, the M. iliocostalis, and the M. supracostalis lateralis. The architecture of these muscles differs from their serial homologs in the trunk. In addition, the rattlesnake tail also contains three small muscles. The M. semispinalis-spinalis occurs in the tail, where it is a thin, nonvibratory, postural muscle that extends laterally along the neural spines. An additional muscle, which derives from fusion of the M. interarticularis inferior and M. levator costae, shares segmental insertions with the M. longissimus dorsi and M. iliocostalis. Several small, deep ventral muscles probably represent the Mm. costovertebrocostalis, intercostalis series, and transversohypapophyseus. The architectural rearrangements in the tail skeleton and shaker muscles, compared with the trunk muscles, probably relate to their roles in stabilizing the muscular part of the tail and to shaking the rattle at the tip of the tail. Based on comparisons with the tail muscles of a colubrid snake described in the literature, the derived tail muscle anatomy in rattlesnakes evolved either in the pitvipers or within the rattlesnakes. J. Morphol., 2008. (c) 2008 Wiley-Liss, Inc.


Smoothed particle hydrodynamics simulation of shear-induced powder migration in injection moulding.
We present the application of the smoothed particle hydrodynamics (SPH) discretization scheme to Phillips' model for shear-induced particle migration in concentrated suspensions. This model provides an evolution equation for the scalar mean volume fraction of idealized spherical solid particles of equal diameter which is discretized by the SPH formalism. In order to obtain a discrete evolution equation with exact conservation properties we treat in fact the occupied volume of the solid particles as the degree of freedom for the fluid particles. We present simulation results in two- and three-dimensional channel flow. The two-dimensional results serve as a verification by a comparison to analytic solutions. The three-dimensional results are used for a comparison with experimental measurements obtained from computer tomography of injection moulded ceramic microparts. We observe the best agreement of measurements with snapshots of the transient simulation for a ratio D(c)/D(η)=0.1 of the two model parameters.


Changes in brain natriuretic peptide levels and bioelectrical impedance measurements after treatment with high-dose furosemide and hypertonic saline solution versus high-dose furosemide alone in refractory congestive heart failure: a double-blind study.
The aim of this study was to evaluate the effect of a new treatment for refractory congestive heart failure (CHF) on brain natriuretic peptide (BNP) plasma levels and hydration station. The study was aimed at evaluating the effects of the combination of high-dose furosemide and small-volume hypertonic saline solution (HSS) in refractory CHF patients. A total of 94 patients (34 women/60 men) with refractory CHF (age 55 to 80 years) were enrolled. They had to have an ejection fraction <35%, serum creatinine <2 mg/dl, blood urea nitrogen <60 mg/dl, a reduced urinary volume, and a low natriuresis (<500 ml/24 h and <60 mEq/24 h, respectively). Patients were divided (double-blind) into two groups: group 1 (18 women/30 men) received an intravenous furosemide (500 to 1,000 mg) plus HSS twice a day in 30 min. Group 2 (16 women/30 men) received an intravenous bolus of furosemide (500 to 1,000 mg/twice a day) alone, for four to six days. At entry, body weight, blood pressure, heart rate, and laboratory parameters were checked during hospitalization; BNP levels were measured on admission, 6 and 30 days after discharge, while on admission and 6 days after, impedance plethysmography was performed. The HSS group received 120 mmol of Na intake versus 80 mmol in non-HSS group. Fluid intake of 1,000 was given to both groups. The groups were similar for clinical characteristics. A significant increase in daily diuresis and natriuresis was observed in HSS group, p < 0.05. The BNP values showed significant intragroup and intergroup differences, 6 and 30 days after treatment. The patients from the HSS group reached a better hydration state than the non-HSS group after six days. In addition, the HSS group showed a significant reduction in hospitalization time and readmission rate. Our data show that the HSS group reached dry weight more rapidly, a significantly faster reduction in BNP levels, shorter hospitalization stay, and lower incidence in readmissions in the 30-day study period.


Synthetic Nuclease-Producing Microbiome Achieves Efficient Removal of Extracellular Antibiotic Resistance Genes from Wastewater Effluent.
Antibiotic resistance gene (ARG) transmission poses significant threats to human health. The effluent of wastewater treatment plants is demonstrated as a hotspot source of ARGs released into the environment. In this study, a synthetic microbiome containing nuclease-producing Deinococcus radiodurans was constructed to remove extracellular ARGs. Results of quantitative polymerase chain reaction (qPCR) showed significant reduction in plasmid RP4-associated ARGs (by more than 3 orders of magnitude) and reduction of indigenous ARG sul1 and mobile genetic element (MGE) intl1 (by more than 1 order of magnitude) in the synthetic microbiome compared to the control without D. radiodurans. Metagenomic analysis revealed a decrease in ARG and MGE diversity in extracellular DNA (eDNA) of the treated group. Notably, whereas eight antibiotic-resistant plasmids with mobility risk were detected in the control, only one was detected in the synthetic microbiome. The abundance of the nuclease encoding gene exeM, quantified by qPCR, indicated its enrichment in the synthetic microbiome, which ensures stable eDNA degradation even when D. radiodurans decreased. Moreover, intracellular ARGs and MGEs and pathogenic ARG hosts in the river receiving treated effluent were lower than those in the river receiving untreated effluent. Overall, this study presents a new approach for removing extracellular ARGs and further reducing the risk of ARG transmission in receiving rivers.


The microsomal/peroxidase antigen: modulation of its expression in thyroid cells.
Evidence has accumulated in the last few years that the expression of the microsomal/peroxidase antigen (M/TPO-Ag) in thyroid cells is induced by TSH, through pathways which involve intracellular cAMP accumulation and protein synthesis. These data have been found true in any thyroid system studied so far, both in terms of immunologic and enzymatic activity of TPO. TSH and cAMP also increase the levels of the specific mRNA for TPO in thyroid cells from different species. Whether this phenomenon is due to a direct transcriptional regulation of the TPO gene, as shown in dog thyroid cells, or to posttranscriptional effects, as it would appear in FRTL-5 cells, remains to be clarified by future experiments. Thyroid stimulating antibody (TSAb) of Graves' disease also stimulates the expression of M/TPO-Ag. This finding gives further support to the relevance of TSAb in the pathogenesis of hyperthyroidism and explains the well known observation that the "microsomal" antigen is particularly abundant in glands of Graves' patients. The modulation of M/TPO-Ag surface expression by TSH can explain the decrease of circulating anti-MAb observed during L-thyroxine therapy in hypothyroid patients with Hashimoto's thyroiditis. Other agents, such as methimazole and sodium iodide, which influence thyroid cell function, do not directly interfere with the expression of M/TPO-Ag. Cytokines, such as gamma-interferon, interleukin-1, and interleukin-6 have been shown to inhibit the TSH-induced increase of TPO mRNA, but further investigations are required to elucidate the exact role of cytokines in the regulation of M/TPO-Ag expression.


Nosocomial dermatitis and pruritus caused by pigeon mite infestation.
We report an outbreak of pigeon mite infestation involving two patients, two nurses, and one physician on a medical ward in a municipal hospital. The index patient developed a diffuse, pruritic erythematous maculopapular rash on his trunk and extremities. Dermanyssus gallinae, a nonburrowing, blood-sucking avian mite was identified on the patient and his bedding. A second patient who complained of scalp pruritus had mites present on her pillow and bed linen. The intern taking care of both patients, and two nurses who had contact with these patients, had mite infestation. Pigeons roosting on the air conditioners and near the doors connecting the patients' rooms to a sunporch were the source of the mites. The outbreak abated after control measures were instituted that prevented pigeons from roosting on the porch. This outbreak illustrates an unusual cause of nosocomial pruritic dermatitis that may be misdiagnosed as scabies or pediculosis. Physicians and health care personnel working in metropolitan areas are alerted to mites as a cause of pruritic dermatitis that may be chronic, recurrent, or unresponsive to ectoparasiticides.


Adult cardiac progenitor cell aggregates exhibit survival benefit both in vitro and in vivo.
A major hurdle in the use of exogenous stems cells for therapeutic regeneration of injured myocardium remains the poor survival of implanted cells. To date, the delivery of stem cells into myocardium has largely focused on implantation of cell suspensions. We hypothesize that delivering progenitor cells in an aggregate form would serve to mimic the endogenous state with proper cell-cell contact, and may aid the survival of implanted cells. Microwell methodologies allow for the culture of homogenous 3D cell aggregates, thereby allowing cell-cell contact. In this study, we find that the culture of cardiac progenitor cells in a 3D cell aggregate augments cell survival and protects against cellular toxins and stressors, including hydrogen peroxide and anoxia/reoxygenation induced cell death. Moreover, using a murine model of cardiac ischemia-reperfusion injury, we find that delivery of cardiac progenitor cells in the form of 3D aggregates improved in vivo survival of implanted cells. Collectively, our data support the notion that growth in 3D cellular systems and maintenance of cell-cell contact improves exogenous cell survival following delivery into myocardium. These approaches may serve as a strategy to improve cardiovascular cell-based therapies.


Do 1-year outcomes predict 2-year outcomes for adult deformity surgery?
Health-related quality-of-life (HRQOL) measures are being used more frequently in the evaluation of the adult deformity patient. This is due in part to the validation of the deformity-specific Scolios Research Society-22 (SRS-22). Hence, relationships between HRQOL outcomes and traditional measures of success such as deformity correction, fusion healing, and complications are being established. To examine the pattern of HRQOL outcome responses after adult deformity surgery. Analysis of prospective multicenter cohort. Two hundred and eighty-three adult deformity patients with preoperative, 1-, and 2-year postoperative outcome measures. SRS-22, Short Form-12 (SF-12), Oswestry Disability Index (ODI), and back and leg pain numeric rating scale scores. Preoperative versus postoperative health status measures were evaluated by matched-pairs sample t test statistics and post hoc analysis of variance (ANOVA) findings. SRS-22 improved from a mean 3.03 points at baseline to 3.21 points at 6 months, 3.71 points at 1 year, and 3.70 points at 2 years post-op. Mean ODI score was 37.0 points pre-op and improved to 27.0 points at 6 months, and 22.8 points at 1 and 2 years post-op. Mean SF-12 physical component score was 33.7 points at baseline, improving to 36.9 points at 6 months, 40.6 points at 1 year, and 40.5 points at 2 years post-op. Paired samples analysis comparing 6-month and 1-year post-op scores showed deterioration for numeric rating scale leg pain (p=0.05). There was a trend for improvement in SF-12 physical component score (p=0.06). Significant improvement between 6 months and 1 year post-op was noted for ODI (p=0.02) and SRS total score (p<0.0001). Comparison of 1- versus 2-year postoperative scores revealed no statistically significant differences for any of the HRQOL parameters. This study supports the application of HRQOL measures, including the deformity-specific SRS-22, as a valuable tool in the assessment of adult deformity patients. Change in outcome score stabilized after the 1-year postoperative interval, for most patients.


Examining delusional ideation: Relationships with race and socioeconomic status.
Race and socioeconomic status (SES) are commonly cited as risk factors for psychosis and psychotic-like experiences (PLEs). However, few studies have investigated the relationships between race and SES with specific domains of PLEs. Specifically, little work has examined the relationships between race and SES with delusional ideation, severity (preoccupation, conviction, distress), and delusional themes. Using cross-sectional, general population data (N = 727) from the Nathan Kline Institute-Rockland (NKI-Rockland) database, we investigated racial differences in delusional ideation and severity between Black and White participants, including differences in delusional themes. Then, we investigated SES's relationship with delusional thinking and the interaction between race and SES on delusional thinking. Black American participants endorsed higher delusional ideation with stronger severity than White Americans. A significant interaction between race and delusional theme revealed that Black Americans endorse significantly more delusional ideation in themes of grandiosity, religiosity, and referential-guilt. Black Americans endorse greater delusional severity in grandiose and religious ideations. Black Americans endorse stronger preoccupation and conviction - but not distress-in their referential-guilt ideation. SES was not significantly associated with delusional thinking, nor did SES moderate the significant relationships between race and delusional ideation. These results illuminate the clear racial disparity that exist in delusional ideation within a general population, which did not extend to SES in this dataset. Future work should investigate deeper into the contributory factors to these racial disparities, particularly whether they are based in psychological and/or cultural differences or are the result of assessment/measurement bias.


Autoimmune Congenital Heart Block: A Review of Biomarkers and Management of Pregnancy.
Autoimmune Congenital Heart Block (CHB) is an immune-mediated disease due to transplacental passage of circulating anti-Ro/SSA and anti-La/SSB autoantibodies. It occurs in 2% of anti-Ro/SSA-exposed pregnancies, and recurrence rate is nine times higher in subsequent pregnancies. Aim of this review is to identify biomarkers of CHB and treatment strategies. The Ro-system is constituted by two polypeptides targeted by the anti-Ro52 and anti-Ro60 autoantibodies. The central portion of Ro52 (p200), more than the full amino-acid sequence of Ro-52, is recognized to be the fine specificity of anti-Ro associated to the highest risk of cardiac damage. If anti-p200 antibody should be tested, as biomarker of CHB, over standard commercial ELISAs is still debated. Recent studies indicate that type I-Interferon (IFN) can activate fibroblasts in fetal heart. In the mother the anti-Ro/La antibodies activate the type I IFN-signature, and maternal IFN-regulated genes correlate with a similar neonatal IFN-gene expression. Evaluation of maternal IFN-signature could be used as novel biomarker of CHB. The measurement of "mechanical" PR interval with weekly fetal echocardiogram (ECHO) from 16 to at least 24 weeks of gestation is strongly recommended for CHB prenatal diagnosis. However, ECHO screening presents some limitations due to difficult identification of first-degree block and possible occurrence of a complete block from a normal rhythm in few days. Maternal administration of Hydroxychloroquine from the tenth week of gestation, modulating toll-like receptor and autoantibody-dependent type I IFN activation on the fetus, has an important role in preventing CHB in pregnant women with high risk for recurrent CHB.


Role of carbohydrate moieties in peanut (Arachis hypogaea) peroxidases.
The activities of a cationic (C.PRX) and an anionic peroxidase isolated from peanut (Arachis hypogaea)-cell suspension culture were drastically reduced when they were deglycosylated with glycopeptidase F or oxidized by 10 mM-periodate. In contrast with the controls, the deglycosylated or the oxidized peroxidases were much more susceptible to proteolytic degradation. In radiolabelling experiments with [35S]methionine, the non-glycosylated C.PRX was synthesized in the tunicamycin-treated cultures and secreted into the medium. Examination of the C.PRX polypeptides by SDS/polyacrylamide-gel electrophoresis followed by fluorography showed that the non-glycosylated form had an Mr of approx. 31,000, which is about 78% of that of the glycosylated form. Our results suggest that carbohydrates may not be essential for peroxidase secretion, but that stabilization of the peroxidase molecules and acquisition by these isoenzymes of a catalytically active conformation is linked directly or indirectly to glycosylation.


Structure-activity relationships of 7-deaza-6-benzylthioinosine analogues as ligands of Toxoplasma gondii adenosine kinase.
Several 7-deaza-6-benzylthioinosine analogues with varied substituents on aromatic ring were synthesized and evaluated against Toxoplasma gondii adenosine kinase (EC.188.8.131.52). Structure-activity relationships indicated that the nitrogen atom at the 7-position does not appear to be a critical structural requirement. Molecular modeling reveals that the 7-deazapurine motif provided flexibility to the 6-benzylthio group as a result of the absence of H-bonding between N7 and Thr140. This flexibility allowed better fitting of the 6-benzylthio group into the hydrophobic pocket of the enzyme at the 6-position. In general, single substitutions at the para or meta position enhanced binding. On the other hand, single substitutions at the ortho position led to the loss of binding affinity. The most potent compounds, 7-deaza- p-cyano-6-benzylthioinosine (IC 50 = 5.3 microM) and 7-deaza- p-methoxy-6-benzylthioinosine (IC 50 = 4.6 microM), were evaluated in cell culture to delineate their selective toxicity.


Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives.
The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 PEX genes; defects in 14 of these have been shown to cause PBD. Three broad phenotypic groups are described on a spectrum of severity: Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate and infantile Refsum disease is less severe. Another group is Rhizomelic chondrodysplasia punctata spectrum. Recently, atypical phenotypes have been described, indicating that the full spectrum of these disorders remains to be identified. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome functions and PEX gene sequencing. There are no targeted therapies, although management protocols have been suggested and research endeavors continue. In this review we will discuss peroxisome biology and PBD, and research contributions to pathophysiology and treatment.


Surgical removal of fragmented coronoid processes and fractured anconeal process in an older dog with evidence of severe degenerative joint disease.
A 10-year-old Labrador Retriever was admitted because of severe unilateral (left) forelimb lameness of 6 weeks' duration. Computerized tomography revealed bilateral fragmented coronoid processes (FCP) and unilateral fracture of the anconeal process. Surgery on the left elbow to remove the loose anconeal process and FCP resolved the severe lameness and improved the dog's overall activity, compared with that of the preceding 2 years. Unstable FCP can develop late in life, and a degenerative anconeal process may fracture. Surgical removal of loose fragments in a severely arthritic joint may be beneficial.


Exploration into the origins and mobilization of di-hydrofolate reductase genes and the emergence of clinical resistance to trimethoprim.
Trimethoprim is a synthetic antibacterial agent that targets folate biosynthesis by competitively binding to the di-hydrofolate reductase enzyme (DHFR). Trimethoprim is often administered synergistically with sulfonamide, another chemotherapeutic agent targeting the di-hydropteroate synthase (DHPS) enzyme in the same pathway. Clinical resistance to both drugs is widespread and mediated by enzyme variants capable of performing their biological function without binding to these drugs. These mutant enzymes were assumed to have arisen after the discovery of these synthetic drugs, but recent work has shown that genes conferring resistance to sulfonamide were present in the bacterial pangenome millions of years ago. Here, we apply phylogenetics and comparative genomics methods to study the largest family of mobile trimethoprim-resistance genes (dfrA). We show that most of the dfrA genes identified to date map to two large clades that likely arose from independent mobilization events. In contrast to sulfonamide resistance (sul) genes, we find evidence of recurrent mobilization in dfrA genes. Phylogenetic evidence allows us to identify novel dfrA genes in the emerging pathogen Acinetobacter baumannii, and we confirm their resistance phenotype in vitro. We also identify a cluster of dfrA homologues in cryptic plasmid and phage genomes, but we show that these enzymes do not confer resistance to trimethoprim. Our methods also allow us to pinpoint the chromosomal origin of previously reported dfrA genes, and we show that many of these ancient chromosomal genes also confer resistance to trimethoprim. Our work reveals that trimethoprim resistance predated the clinical use of this chemotherapeutic agent, but that novel mutations have likely also arisen and become mobilized following its widespread use within and outside the clinic. Hence, this work confirms that resistance to novel drugs may already be present in the bacterial pangenome, and stresses the importance of rapid mobilization as a fundamental element in the emergence and global spread of resistance determinants.


Triclosan blocks MMP-13 expression in hormone-stimulated osteoblasts.
Matrix metalloproteinase-13 (MMP-13) is an important enzyme for the modulation of bone turnover and gingival recession. Elevated levels of MMP-13 are associated with alveolar bone resorption, periodontal ligament breakdown, and gingival attachment loss, which are the clinical symptoms of periodontal disease. Evidence continues to suggest that periodontal disease contributes to oral tissue breakdown and is linked to numerous systemic conditions. Triclosan (TCN) is a long-standing, proven antibacterial and anti-inflammatory agent found in the only Food and Drug Administration-approved dentifrice for the treatment of plaque and gingivitis. This study examines the inhibitory effects of TCN on lipopolysaccharide-, parathyroid hormone (PTH)-, and prostaglandin E2 (PGE2)-induced expression of MMP-13 in UMR 106-01 cells, an osteoblastic osteosarcoma cell line. The cells were stimulated with PTH or PGE2 to induce MMP-13 mRNA expression, and real-time reverse transcription-polymerase chain reaction was performed to determine gene expression levels. Western blot analysis assessed the presence or absence of protein degradation or inhibition of protein synthesis. MMP-13 promoter reporter assay was used to explore possible direct effects of TCN on the MMP-13 promoter. TCN significantly reduced PTH or PGE2 elevated expression of MMP-13 in osteoblastic cells without affecting basal levels of the mRNA. Surprisingly, TCN enhanced the expression of c-fos and amphiregulin mRNA. A promoter assay indicated that TCN directly inhibits the activation of the PTH-responsive minimal promoter of MMP-13. The present study appears to have identified a nuclear mechanism of action of TCN that accounts for the ability of TCN to inhibit PTH- or PGE2-induced MMP-13 expression in osteoblastic cells.


Type III hyperlipoproteinemia: defective metabolism of an abnormal apolipoprotein E.
The apolipoprotein E isolated from plasma of individuals with type III hyperlipoproteinemia (HLP) shows an abnormal pattern when it is examined by isoelectric focusing. Compared to apolipoprotein E from normal subjects, apolipoprotein E isolated from subjects with type III HLP had a decreased fractional catabolic rate in vivo in both type III HLP patients and normal individuals. The delayed catabolism of apolipoprotein E in type III HLP patients may be responsible for the lipid and lipoprotein abnormalities characteristic of these patients.


The evolution of changes in primary care delivery underlying the Veterans Health Administration's quality transformation.
Suffering from waning demand, poor quality, and reform efforts enabling veterans to "vote with their feet" and leave, the Veterans Health Administration (VA) health care system transformed itself through a series of substantive changes. We examined the evolution of primary care changes underlying VA's transformation. We used 3 national organizational surveys from 1993, 1996, and 1999 that measured primary care organization, staffing, management, and resource sufficiency to evaluate changes in VA primary care delivery. Only rudimentary primary care was in place in 1993. Primary care enrollment grew from 38% in 1993 to 45% in 1996, and to 95% in 1999 as VA adopted team structures and increased the assignment of patients to individual providers. Specialists initially staffed primary care until generalist physicians and nonphysican providers increased. Primary care-based quality improvement and authority expanded, and resource sufficiency (e.g., computers, space) grew. Provider notification of admissions and emergency department, urgent-care visit, and sub-specialty-consult results increased nearly 5 times. Although VA's quality transformation had many underlying causes, investment in primary care development may have served as an essential substrate for many VA quality gains.


Correlation Between Paramedic Disaster Triage Accuracy in Screen-Based Simulations and Immersive Simulations.
Background: Disaster triage is an infrequent, high-stakes skill set used by emergency medical services (EMS) personnel. Screen-based simulation (SBS) provides easy access to asynchronous disaster triage education. However, it is unclear if the performance during a SBS correlates with immersive simulation performance. Methods: This was a nested cohort study within a randomized controlled trial (RCT). The RCT compared triage accuracy of paramedics and emergency medical technicians (EMTs) who completed an immersive simulation of a school shooting, interacted with an SBS for 13 weeks, and then completed the immersive simulation again. The participants were divided into two groups: those exposed vs. those not exposed to 60 Seconds to Survival© (60S), a disaster triage SBS. The aim of the study was to measure the correlation between SBS triage accuracy and immersive simulation triage accuracy. Improvements in triage accuracy were compared among participants in the nested study before and after interacting with 60S, and with improvements in triage accuracy in a previous study in which immersive simulations were used as an educational intervention. Results: Thirty-nine participants completed the SBS; 26 (67%) completed at least three game plays and were included in the evaluation of outcomes of interest. The mean number of plays was 8.5 (SD =7.4). Subjects correctly triaged 12.4% more patients in the immersive simulation at study completion (73.1% before, 85.8% after, P = 0.004). There was no correlation between the amount of improvement in overall SBS triage accuracy, instances of overtriage (P = 0.101), instances of undertriage (P = 0.523), and improvement in the second immersive simulation. A comparison of the pooled data from a previous immersive simulation study with the nested cohort data showed similar improvement in triage accuracy (P = 0.079). Conclusions: SBS education was associated with a significant increase in triage accuracy in an immersive simulation, although triage accuracy demonstrated in the SBS did not correlate with the performance in the immersive simulation. This improvement in accuracy was similar to the improvement seen when immersive simulation was used as the educational intervention in a previous study.


Nephrotic syndrome in children-a clinical study.
The clinical and biochemical features of 54 children with Nephrotic Syndrome seen over a period of 6 years and the response to Prednisolone therapy in 43 cases is presented. The disease was more prevalent in male children and the highest incidence was observed at the age of 3 years. An excellent response to steroid therapy was obtained in cases with a recent onset of disease and no nephritic features.


Association between pulmonary function and peak oxygen uptake in elderly: the Generation 100 study.
Although reduced function of the respiratory system limits peak oxygen uptake in diseases affecting the lungs or airways, the healthy respiratory system is thought to have a spare capacity for oxygen transport and uptake, and is not considered a limiting factor for peak oxygen uptake in healthy people. However, lung function declines with age and could theoretically limit peak oxygen uptake in elderly. We examined the association between peak oxygen uptake and lung function indices in an elderly population with the hypothesis that lung function indices would be associated with VO2peak up to a threshold value situated above the lower limits of normal lung function for our population. Spirometry, gas diffusion tests and incremental work tests were performed in 1443 subjects (714 women) aged 69-77 years. Association between lung function indices and peak oxygen uptake was studied with hockey-stick regression. Forced expiratory volume in 1 s (FEV1) had a positive association with peak oxygen uptake up to, but not above, a threshold value of 2.86 l for men, and 2.13 l for women (lower limit of normal 2.73 and 1.77 l respectively). A corresponding threshold was found for diffusing capacity of the lung for carbon monoxide (DLCO) for men at 9.18 mmol/min/kPa (lower limit of normal 6.84 mmol/min/kPa). DLCO for women and DLCO divided by alveolar volume (DLCO/VA) for both sexes had a significant linear relationship to VO2peak (p < 0.05), but no significant threshold value was found in these associations. Threshold values for FEV1 for both sexes and DLCO for men were identified. These lung function indices had a positive association with VO2peak up to these threshold values, but not above. The identified threshold values were above lower limits of normal for FEV1 and DLCO.


Pilot study: specific immunotherapy in patients with Papular urticaria by Cimex lectularius.
Background. Papular urticaria is a chronic allergic reaction induced by insect bites. In México the most common causative arthropods reported are bed bugs, fleas and mosquitoes. Approximately 70% of people who are bitten by Cimex lectularius experience hypersensitive reactions, papular urticaria, extensive erythema, urticaria, and even anaphylaxis has been reported, pruritus is the major complaint, impairing quality of life and sleep. Immunotherapy has been used in mosquito bite papular urticaria resulting in improvement of skin lesions and possibly protecting against reactions to subsequent exposures to mosquitoes. Methods. Children, 4-10 years of age, with recurrent papular urticaria due to bedbugs not responsive to multiple treatments were included. An initial allergy assessment included clinical history, skin prick test (SPT), and specific IgE sensitisation was performed to confirmed bedbug sensitization. Twenty children were randomized to receive subcutaneous specific immunotherapy (SSI) with whole body bed bug extract or conventional treatment. The treatment was carried out over twelve months and the response was assessed using the Dermatology Quality of Life Index (DLQ), the immunotherapy satisfaction questionnaire (ESPIA questionnaire) and the 12-Item Pruritus Severity Scale (12-IPSS). The results from both the treated and control groups were compared. Results. The twenty patients were randomized, 12 to receive immunotherapy and 8 to receive conventional treatment for 12 months. Quality of life improved with a reduction in the DLQI score of 19.83 in the immunotherapy group versus 9 in the conventional treatment group (p = 0.03). Itch improved with a reduction in the 12-IPSS of 16.5 in the immunotherapy group versus 9.63 in the conventional treatment group (p = 0.02). After twelve months of treatment, all 12 patients who received immunotherapy, reported a decrease of persistent cutaneous lesions but the 8 on conventional treatment did not. A mean score of 95.75 (SD 3.3) was recorded for satisfaction with immunotherapy. Conclusions. Patients with papular urticaria by Cimex lectularius receiving allergen immunotherapy for 1 year showed a significant improvement compared with baseline and patients receiving conventional treatment regarding skin lesions, quality of life impairment, intensity of pruritus and satisfaction with immunotherapy.


Defining the short-term and long-term skin manifestations of COVID-19: insights after more than three years of the pandemic.
This review aimed to assess the impact of coronavirus disease 2019 (COVID-19) on skin health to establish a classification of the skin lesions that occur most frequently during the disease and whether a particular category of skin damage is more likely to occur both in the short term and in the long term. We conducted a literature search of the PubMed database. Ultimately, 109 articles were included in this review. The exact phrases∕syntax and connectors used for the database search∕query were as follows: "Coronavirus and skin", "COVID-19 and skin", "SARS-CoV-2 and skin", "Coronavirus cutaneous manifestations", "COVID-19 cutaneous manifestations", "SARS-CoV-2 cutaneous manifestations", "Coronavirus dermatology", "SARS-CoV-2 and dermatology", "COVID-19 and dermatology", "COVID-19 and skin eruption", "Coronavirus and skin rash", "COVID-19 and hair", "Coronavirus and hair", "Coronavirus and nails", "SARS-CoV-2 and hair", and "SARS-CoV-2 and nails". Only articles with abstracts referring strictly to cutaneous manifestations of COVID-19 were chosen. Articles without abstracts were not considered. We established six of the most frequently reported clinical patterns associated with COVID-19 and their probability of occurring during COVID-19 disease evolution based on the current literature reports. We did not identify the particular types of skin lesions that are most prone to long-term persistence; most such cases are rare, and no conclusion can be drawn based on them. Apart from classified COVID-19-related skin disorders, this pandemic has been a challenge for dermatologists and a wide range of cutaneous side effects related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) treatments have been reported. We are aware of other polymorphic clinical presentations, with novel data being reported periodically, but the pathophysiological mechanisms and evolution are largely unknown.


Pore-scale controls on calcite dissolution rates from flow-through laboratory and numerical experiments.
A combination of experimental, imaging, and modeling techniques were applied to investigate the pore-scale transport and surface reaction controls on calcite dissolution under elevated pCO2 conditions. The laboratory experiment consisted of the injection of a solution at 4 bar pCO2 into a capillary tube packed with crushed calcite. A high resolution pore-scale numerical model was used to simulate the experiment based on a computational domain consisting of reactive calcite, pore space, and the capillary wall constructed from volumetric X-ray microtomography images. Simulated pore-scale effluent concentrations were higher than those measured by a factor of 1.8, with the largest component of the discrepancy related to uncertainties in the reaction rate model and its parameters. However, part of the discrepancy was apparently due to mass transport limitations to reactive surfaces, which were most pronounced near the inlet where larger diffusive boundary layers formed around grains and in slow-flowing pore spaces that exchanged mass by diffusion with fast flow paths. Although minor, the difference between pore- and continuum-scale results due to transport controls was discernible with the highly accurate methods employed and is expected to be more significant where heterogeneity is greater, as in natural subsurface materials.


Seroprevalence of bactericidal antibodies against serogroup B and C Meningococci in a University Hospital.
Meningococcus serogroup B (MenB), clonal complex 32 (cc 32), was the Brazilian epidemic strain of meningococcal disease (MD) in the 1990's. Currently, meningococcus serogroup C (MenC), cc 103, is responsible for most of the cases of the disease in Brazil. The aim of this study was to investigate the seroprevalence of bactericidal antibody (SBA) against representative epidemic strains of MenC, (N753/00 strain, C:23:P1.22,14-6, cc103) and MenB, (Cu385/83 strain, B:4,7:P1.15,19, cc32) in students and employees of a university hospital in the State of Rio Grande do Sul (RS, Brazil). A second MenC strain (N79/96, C:2b:P1.5-2,10, cc 8) was used as a prototype strain of Rio de Janeiro's outbreak that occurred in the 1990's. Our previous study showed a 9% rate of asymptomatic carriers in these same individuals. A second goal was to compare the SBA prevalence in meningococcal carriers and non-carriers. Fifty-nine percent of the studied population showed protective levels of SBA titers (log2≥2) against at least one of the three strains. About 40% of the individuals had protective levels of SBA against N753/00 and Cu385/83 strains. Nonetheless, only 22% of the individuals showed protective levels against N79/96 strain. Significantly higher antibody levels were seen in carriers compared to non-carriers (P≤0.009). This study showed that, similar to other States in Brazil, a MenC (23:P1.22,14-6, cc103) strain with epidemic potential is circulating in this hospital. Close control by the Epidemiological Surveillance Agency of RS of the number of cases of MD caused by MenC strains in the State is recommended to prevent a new disease outbreak.


Contrast-enhanced ultrasonographic imaging diagnosis on assessment of vascularity in liver metastatic lesions.
To investigate the vasculature of rabbit liver metastatic lesions by color Doppler imaging and power Doppler imaging (PDI) techniques. Eight New Zealand rabbits with implanted VX2 liver tumors were used. All ultrasound examinations were performed with a HP 5500 color Doppler ultrasound scanner. Before and after the injection of contrast agent, the changes of gray scale and the periphery and intralesional blood flow of the liver metastatic lesion were carefully observed by B mode ultrasound, color Doppler flow imaging (CDFI) and PDI. Twelve lesions were found in the eight rabbits with implanted VX2 liver tumors, whose diameter ranged from 1.6 to 4.8 cm. Echoes of these lesions were not characterized and has lack of specificity. After the injection of contrast agent, the numbers of dot or strip-like flow messages increased both at the periphery and inside of these lesions under the mode of CDFI and PDI, and were more pronounced under PDI. Morphology of intralesional vessels extended, even branched and some signals were clearly found encircling the lesion. And some vessels were found penetrating into the center of the lesion. PDI after injection of self-made echo contrast agent can show a pronounced sensitivity than that of B mode ultrasound and CDFI in diagnosis of vascularity of a metastatic lesion.


Proficient use of low spatial frequencies facilitates face memory but shows protracted maturation throughout adolescence.
Face perception is characterized by configural processing, which depends on visual information in the low spatial frequency (LSF) ranges. However, it is unclear whether LSF content is equally important for face memory. The present study investigated how face information in the low and high SF range plays a role in the configural encoding of faces for short-term and long-term recall. Moreover, we examined how SF-dependent face memorization develops in female adolescence, by comparing children (9-10-year-olds), adolescents (12-13-year-olds and 15-16-year-olds), and young adults (21-32-year-olds). Results show that similar to face perception, delayed face recognition was consistently facilitated by LSF content. However, only adults were able to adequately employ configural LSF cues for short-term recall, analogous to the slow maturation of LSF-driven configural face perception reported by previous studies. Moreover, the insensitivity to face inversion of early adolescents revealed their inadequate use of configural face cues regardless of SF availability, corroborating previous reports on an adolescent "dip" in face recognition. Like face perception, face recognition has a protracted maturational course. In (female) adolescence, sensitivity to configural LSF cues is developed, which aids not only configural face perception but also face memorization.


Exosomal communication goes viral.
Exosomes are small vesicles secreted from cells that participate in intercellular communication events. Accumulating evidence demonstrates that host exosome pathways are hijacked by viruses and that virally modified exosomes contribute to virus spread and immune evasion. In the case of tumor viruses, recent findings suggest that alterations in normal exosome biology may promote the development and progression of cancer. These studies will be discussed in the context of our current knowledge of Epstein-Barr virus (EBV)-modified exosomes.


Non-invasive prenatal testing for aneuploidy: current status and future prospects.
Non-invasive prenatal testing (NIPT) for aneuploidy using cell-free DNA in maternal plasma is revolutionizing prenatal screening and diagnosis. We review NIPT in the context of established screening and invasive technologies, the range of cytogenetic abnormalities detectable, cost, counseling and ethical issues. Current NIPT approaches involve whole-genome sequencing, targeted sequencing and assessment of single nucleotide polymorphism (SNP) differences between mother and fetus. Clinical trials have demonstrated the efficacy of NIPT for Down and Edwards syndromes, and possibly Patau syndrome, in high-risk women. Universal NIPT is not cost-effective, but using NIPT contingently in women found at moderate or high risk by conventional screening is cost-effective. Positive NIPT results must be confirmed using invasive techniques. Established screening, fetal ultrasound and invasive procedures with microarray testing allow the detection of a broad range of additional abnormalities not yet detectable by NIPT. NIPT approaches that take advantage of SNP information potentially allow the identification of parent of origin for imbalances, triploidy, uniparental disomy and consanguinity, and separate evaluation of dizygotic twins. Fetal fraction enrichment, improved sequencing and selected analysis of the most informative sequences should result in tests for additional chromosomal abnormalities. Providing adequate prenatal counseling poses a substantial challenge given the broad range of prenatal testing options now available.


The Utility of a Wireless Implantable Hemodynamic Monitoring System in Patients Requiring Mechanical Circulatory Support.
Proper timing of left ventricular assist device (LVAD) implantation in advanced heart failure patients is not well established and is an area of intense interest. In addition, optimizing LVAD performance after implantation remains difficult and represents a significant clinical need. Implantable hemodynamic monitoring systems may provide physicians with the physiologic information necessary to improve the timing of LVAD implantation as well as LVAD performance when compared with current methods. The CardioMEMS Heart sensor Allows for Monitoirng of Pressures to Improve Outcomes in NYHA Class III heart failure patients (CHAMPION) Trial enrolled 550 previously hospitalized patients with New York Heart Association (NYHA) class III heart failure. All patients were implanted with a pulmonary artery (PA) pressure monitoring system and randomized to a treatment and control groups. In the treatment group, physicians used the hemodynamic information to make heart failure management decisions. This information was not available to physicians for the control group. During an average of 18 month randomized follow-up, 27 patients required LVAD implantation. At the time of PA pressure sensor implantation, patients ultimately requiring advanced therapy had higher PA pressures, lower systemic pressure, and similar cardiac output measurements. Treatment and control patients in the LVAD subgroup had similar clinical profiles at the time of enrollment. There was a trend toward a shorter length of time to LVAD implantation in the treatment group when hemodynamic information was available. After LVAD implantation, most treatment group patients continued to provide physicians with physiologic information from the hemodynamic monitoring system. As expected PA pressures declined significantly post LVAD implant in all patients, but the magnitude of decline was higher in patients with PA pressure monitoring. Implantable hemodynamic monitoring appeared to improve the timing of LVAD implantation as well as optimize LVAD performance when compared with current methods. Further studies are necessary to evaluate these findings in a prospective manner.


Pharmacological manipulation of peritoneal transport in CAPD.
Various endogenous compounds and drugs influence different determinants of peritoneal transport. Catecholamines affect vascular diameter and mesenteric blood flow. Several gastrointestinal hormones were found to induce splanchnic vasodilation and to augment the effective vascular surface. Different prostanoids, histamine, and bradykinin influence peritoneal mass transfer by increasing vascular permeability. Vasodilative acting drugs, diuretics and surface active compounds were found to augment peritoneal solute clearances and water efflux by acting on peritoneal vessels or the serosal surface of the peritoneal membrane. Hyperosmolar dialysis solutions increase ultrafiltration and contribute to total peritoneal clearance by convective transport. The present paper aims to summarize the current knowledge on pharmacological and physiological manipulation of peritoneal transport function and to show some ways of its clinical use.


Differential diagnoses for persistent pain after root canal treatment: a study in the National Dental Practice-based Research Network.
Pain present 6 months after root canal treatment (RCT) may be of odontogenic or nonodontogenic origin. This is important because treatments and prognoses are different; therefore, the aim of this study was to provide specific diagnoses of patients reporting pain 6 months after receiving initial orthograde RCT. We enrolled patients from the Midwest region of an existing prospective observational study of pain after RCT. Pain at 6 months was defined as ≥1 day of pain and average pain intensity of at least 1 of 10 over the preceding month. An endodontist and an orofacial pain practitioner independently performed clinical evaluations, which included periapical and cone-beam computed tomographic radiographs, to determine diagnoses. Thirty-eight of the 354 eligible patients in the geographic area (11%) met the pain criteria, with 19 (50%) consenting to be clinically evaluated. As the sole reason for pain, 7 patients (37%) were given odontogenic diagnoses (4 involving the RCT tooth and 3 involving an adjacent tooth). Eight patients (42%) were given nonodontogenic pain diagnoses (7 from referred temporomandibular disorder pain and 1 from persistent dentoalveolar pain disorder). Two patients (11%) had both odontogenic and nonodontogenic diagnoses, whereas 2 (11%) no longer fit the pain criteria at the time of the clinical evaluation. Patients reporting "tooth" pain 6 months after RCT had a nonodontogenic pain diagnosis accounting for some of this pain, with temporomandibular disorder being the most frequent nonodontogenic diagnosis. Dentists should have the necessary knowledge to differentiate between these diagnoses to adequately manage their patients.


Personality and coping with a common stressor: cardiac catheterization.
The association between coping and personality was examined in a sample of 204 cardiac catheterization patients who were asked to evaluate the use of specific coping strategies used to deal with their cardiac catheterization. Personality, as measured by the NEO Five-Factor Inventory (FFI), was moderately correlated with coping measures. In multivariate analyses, after considering confounding factors, Neuroticism was positively and Extraversion was negatively related to avoidance coping and Neuroticism was negatively associated with counting one's blessings as a coping strategy. Personality was not related to either problem solving or seeking social support coping strategies for individuals experiencing a cardiac catheterization. However, important covariates were associated with coping strategies. Not being married was negatively correlated with use of seeking social support and not having a confidant was negatively related with seeking social support and positively with avoidance. These results suggest that there are specific relationships between personality and coping, but these relationships are, for the most part, moderate in persons coping with a cardiac catheterization, and that coping processes are associated with individual differences in available social resources.


PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression.
PD-L1 (programmed death ligand 1, B7-H1) is a cell surface glycoprotein that can impair T-cell function. PD-L1 is aberrantly expressed by multiple human malignancies and has been shown to carry a highly unfavorable prognosis in patients with kidney cancer. The role of PD-L1 was evaluated as a mechanism for local stage progression in urothelial carcinoma (UC) of the bladder. Using immunohistochemistry, PD-L1 expression was evaluated in a cohort of 280 high-risk UCs of the bladder. PD-L1 was modeled as a predictor of bladder cancer stage using ordinal logistic regression. Other covariates evaluated as potential confounders included age, gender, tumor grade, and lymphocytic infiltration. Further, PD-L1 was evaluated as a potential mechanism of bacillus Calmette-Guerin (BCG) failure in the subset of high-risk nonmuscle-invasive tumors that received this treatment. PD-L1 expression was observed in 7% of pTa, 16% of pT1, 23% of pT2, 30% of pT3/4, and 45% of carcinoma in situ (CIS) tumors. PD-L1 expression was associated with high-grade tumors (odds ratio [OR] = 2.4, P = .009) and tumor infiltration by mononuclear cells (OR = 5.5, P = .004). We observed that the key determinants of stage progression in this cohort were World Health Organization/International Society of Urologic Pathology (WHO/ISUP) high-grade tumor pathology (OR = 4.77, 95% confidence interval [CI]: 2.73-8.34; P < .001) and PD-L1 expression (OR = 2.20, P = .012). PD-L1 expression was found to be extremely abundant in the BCG-induced bladder granulomata in 11 of 12 patients failing BCG treatment. Collectively, these data indicate that tumor PD-L1 may facilitate localized stage-advancement of UC and attenuate responses to BCG immunotherapy by neutralizing T cells that normally guard against cancer invasion from the epithelium into the bladder musculature.


Reversible sensorineural hearing loss after renal transplant immunosuppression with OKT3 (muromonab-CD3).
Reversible and irreversible ototoxicity has been documented following the administration of various therapeutic agents. Reversible hearing loss is a known complication following the administration of quinine, salicylates and other nonsteroidal anti-inflammatory drugs, and erythromycin. We report a case of reversible hearing loss following OKT3 (murine monoclonal antibody CD3) administration. OKT3, a monoclonal antibody used as an immunosuppressant following cadaveric renal transplants, was associated with a transient sensorineural hearing loss that reversed following discontinuation of OKT3.


Nanometer-scale loop currents and induced magnetic dipoles in carbon nanotubes with defects.
In metallic carbon nanotubes with defects, the electric current flow is expected to have characteristic spatial patterns depending on the nature of the defects. Here, we show, using first-principles transport calculations, that locally rotating loop currents in nanometer scale can be generated near defects in carbon nanotubes by quantum interference of conducting and quasi-bound states of electrons. The loop currents appear at energies near transmission dips, having opposite directions at lower- and higher-energy sides of the transmission dips and disappearing exactly at the centers of the dips. Temporal modulations of gate voltage around a transmission dip can produce oscillating magnetic dipoles, inducing magnetic fields that reflect characteristics of defects. This generation of loop currents and magnetic dipoles by quantum interference can generally occur in any nanostructure and it is potentially useful for novel electronic and magnetic nanodevices.


Development and understanding of cobaloxime activity through electrochemical molecular catalyst screening.
Electrochemical molecular catalyst screening (EMoCS) has been developed. This technique allows fast analysis and identification of homogeneous catalytic species through tandem catalyst assembly and electrochemistry. EMoCS has been used to study molecular proton reduction catalysts made from earth abundant materials to improve their viability for water splitting systems. The efficacy of EMoCS is proven through investigation of cobaloxime proton reduction activity with respect to the axial ligand in aqueous solution. Over 20 axial ligands were analysed, allowing rapid identification of the most active catalysts. Structure-activity relationships showed that more electron donating pyridine ligands result in enhanced catalytic currents due to the formation of a more basic Co-H species. The EMoCS results were validated by isolating and assaying the most electroactive cobaloximes identified during screening. The most active catalyst, [Co(III)Cl(dimethyl glyoximato)2(4-methoxypyridine)], showed high electro- and photoactivity in both anaerobic and aerobic conditions in pH neutral aqueous solution.


Site of hemodynamic effects of intrathecal alpha 2-adrenergic agonists.
Intrathecally administered alpha 2-adrenergic agonists produce analgesia in humans but may also produce hypotension and bradycardia. To further characterize hemodynamic depression produced by intrathecally administered alpha 2-adrenergic agonists, clonidine (100-1,500 micrograms) was injected into the cervical, thoracic, or lumbar intrathecal space of conscious sheep. Only thoracic intrathecal clonidine injection (100 or 300 micrograms) decreased blood pressure, whereas these doses did not affect blood pressure when injected at other sites. A greater clonidine dose (1,500 micrograms) increased blood pressure to a similar degree at all sites. Hypotension after thoracic intrathecal clonidine injection was inhibited by pretreatment with the alpha 2-adrenergic antagonist idazoxan (1 mg, intrathecally) or the depleter of acetylcholine stores hemicholinium-3 (2 mg, intrathecally), suggesting an action at alpha 2-adrenoceptors on cholinergic preganglionic sympathetic neurons. ST-91, a polar clonidine analog, did not decrease blood pressure after thoracic intrathecal injection. Intrathecal injection of the muscarinic receptor agonist carbamylcholine increased blood pressure. These data describe a complex action of intrathecal alpha 2-adrenergic agonists on hemodynamic parameters that is dependent on site of injection, drug dose, and drug lipophilicity; that can be explained by anatomic factors; and that may possibly be exploited to minimize hemodynamic depression from these agents.


Steroid receptors, cellular kinetics, and lymph node status as prognostic factors in breast cancer.
Steroid receptor status, cellular kinetics, abnormal proto-oncogene presence, and lymph node metastases all have been shown to provide prognostic information in breast cancer. The factors guide the choice of therapy and predict the course of the disease. Both disease-free survival and overall survival are predicted by these variables. Steroid receptors are the most reliable predictor of hormonal responsiveness. Lymph node involvement is crucial in determining the extent of the disease and the need for adjuvant therapy. Cellular kinetics and abnormal proto-oncogene presence predict tumor aggressiveness. Together these prognostic factors provide considerable information to the clinician.


Holins: the protein clocks of bacteriophage infections.
Two proteins, an endolysin and a holin, are essential for host lysis by bacteriophage. Endolysin is the term for muralytic enzymes that degrade the cell wall; endolysins accumulate in the cytosol fully folded during the vegetative cycle. Holins are small membrane proteins that accumulate in the membrane until, at a specific time that is "programmed" into the holin gene, the membrane suddenly becomes permeabilized to the fully folded endolysin. Destruction of the murein and bursting of the cell are immediate sequelae. Holins control the length of the infective cycle for lytic phages and so are subject to intense evolutionary pressure to achieve lysis at an optimal time. Holins are regulated by protein inhibitors of several different kinds. Holins constitute one of the most diverse functional groups, with >100 known or putative holin sequences, which form >30 ortholog groups.


Determinants of the exposure of Eurasian griffon vultures (Gyps fulvus) to fluoroquinolones used in livestock: The role of supplementary feeding stations.
Veterinary pharmaceuticals, including antibiotics, are emerging contaminants of concern worldwide. Avian scavengers are exposed to pharmaceuticals through consumption of livestock carcasses used for feeding wildlife for conservation purposes at supplementary feeding stations. Here we tested the hypothesis that griffon vultures (Gyps fulvus) would be more exposed to antibiotics (i.e., quinolones) when feeding on livestock carcasses from intensive farming than when they rely on carcasses from extensive farming or wild animals. We sampled 657 adult griffon vultures captured between 2008 and 2012. In addition, we sampled tissues from domestic livestock supplied at feeding stations in the study area between 2009 and 2019; pig (n = 114), sheep (n = 28), cow (n = 1) and goat (n = 2). Samples were analysed by liquid chromatography with electrospray ionization mass spectrometry (LC-ESI-MS). Quinolones were detected in plasma from 12.9% of the griffon vultures analysed. Quinolone prevalence in griffon vultures varied significantly among feeding stations but was also affected by the total amount of carcasses supplemented, especially the mass of pig carcasses. These results aligned with a 21.1% quinolone prevalence in pig carcasses sampled at feeding stations, wherein enrofloxacin and ciprofloxacin levels of up to 3359 ng/g and 1550 ng/g, respectively, were found. Given enrofloxacin pharmacokinetics in pig tissues, 5.3% of the analysed pigs may have died no more than one day after treatment. Quinolone presence in vultures was negatively associated with blood lead levels, which mostly originates from lead ammunition and indicates a higher consumption of game animal carcasses. Carcass disposal for feeding avian scavengers must always assess and manage the risks posed by veterinary pharmaceuticals, especially when livestock provided may have died soon after treatment.


Comparative fluorescence in situ hybridization mapping of a 431-kb Arabidopsis thaliana bacterial artificial chromosome contig reveals the role of chromosomal duplications in the expansion of the Brassica rapa genome.
Comparative genome studies are important contributors to our understanding of genome evolution. Most comparative genome studies in plants have been based on genetic mapping of homologous DNA loci in different genomes. Large-scale comparative physical mapping has been hindered by the lack of efficient and affordable techniques. We report here the adaptation of fluorescence in situ hybridization (FISH) techniques for comparative physical mapping between Arabidopsis thaliana and Brassica rapa. A set of six bacterial artificial chromosomes (BACs) representing a 431-kb contiguous region of chromosome 2 of A. thaliana was mapped on both chromosomes and DNA fibers of B. rapa. This DNA fragment has a single location in the A. thaliana genome, but hybridized to four to six B. rapa chromosomes, indicating multiple duplications in the B. rapa genome. The sizes of the fiber-FISH signals from the same BACs were not longer in B. rapa than those in A. thaliana, suggesting that this genomic region is duplicated but not expanded in the B. rapa genome. The comparative fiber-FISH mapping results support that chromosomal duplications, rather than regional expansion due to accumulation of repetitive sequences in the intergenic regions, played the major role in the evolution of the B. rapa genome.


Microglial activation and toll-like receptor 4-Dependent regulation of angiotensin II type I receptor-mu-opioid receptor 1 heterodimerization and hypertension in fructose-fed rats.
Our previous study reported that the heterodimer of Angiotensin II Type I Receptor (AT1R) and Mu-Opioid Receptor 1 (MOR1) involves Nitric Oxide (NO) reduction which leads to elevation of blood pressure. Secondly, we showed that Toll-like Receptor 4 (TLR4) may be involved in the heterodimerization of AT1R and MOR1 in the brainstem Nucleus Tractus Solitarii (NTS), which regulates systemic blood pressure and gastric nitric oxide through the insulin pathway. Here, we investigated the role of microglial activation and TLR4 in the heterodimerization of AT1R and MOR1. Hypertensive rats were established after four weeks of fructose consumption. SBP of rats was measured using non-invasive blood pressure method. PLA technique was utilized to determine protein-protein interaction in the nucleus tractus solitarii. Results showed that the level of MOR-1 and AT1R was induced significantly in the fructose group compared with control. PLA signal potentially showed that AT1R and MOR1 were formed in the nucleus tractus solitarii after fructose consumption. Meanwhile, the innate immune cell in the CNS microglia was observed in the nucleus tractus solitarii using biomarkers and was activated. TLR4 inhibitor CLI-095, was administered to animals to suppress the neuroinflammation and microglial activation. CLI-095 treatment reduced the heterodimer formation of AT1R and MOR1 and restored nitric oxide production in the nucleus tractus solitarii. These findings imply that TLR4-primed neuroinflammation involves formation of heterodimers AT1R and MOR1 in the nucleus tractus solitarii which leads to increase in systemic blood pressure.


Embryos derived from porcine skin-derived stem cells exhibit enhanced preimplantation development.
Ongoing research to identify the most suitable type of donor cell for nuclear transfer (NT) has suggested that less differentiated stem cells may be better donors than other somatic cell types. Recently, we have reported the isolation and characterization of porcine skin-originated sphere (PSOS) stem cells from fetal skin, making it possible to test this hypothesis in a nonrodent animal model. In the present study, we have investigated and compared the feasibility and preimplantation developmental efficiency of using fetal PSOS cells and fibroblasts as nuclear-transfer donors. The majority of fetal PSOS cells are in the G1/ G0 stage of the cell cycle, which is desirable for NT. During long-term in vitro culture, fetal PSOS cells had greater genome stability, with a lower frequency of abnormal karyotypes than fetal fibroblast cells. Embryos cloned from PSOS cells showed enhanced preimplantation development compared with fibroblast cloned embryos, which is indicated by an increased rate of blastocyst development and a higher total cell number in Day 7 blastocysts. The gene expression profile of genes critical for early development from eight-cell-stage PSOS NT embryos more closely resembled the pattern observed from in vivo-produced embryos compared with that of fibroblast-cloned embryos. Cumulatively, our data suggest that fetal PSOS cells may be better donor cells for NT in the pig.


Subthalamic and pallidal deep brain stimulation: are we modulating the same network?
The subthalamic nucleus and internal pallidum are main target sites for deep brain stimulation in Parkinson's disease. Multiple trials that investigated subthalamic versus pallidal stimulation were unable to settle on a definitive optimal target between the two. One reason could be that the effect is mediated via a common functional network. To test this hypothesis, we calculated connectivity profiles seeding from deep brain stimulation electrodes in 94 patients that underwent subthalamic and 28 patients with pallidal treatment based on a normative connectome atlas calculated from 1000 healthy subjects. In each cohort, we calculated connectivity profiles that were associated with optimal clinical improvements. The two maps showed striking similarity and were able to cross-predict outcomes in the respective other cohort (R = 0.37 at P < 0.001; R = 0.34 at P = 0.032). Next, we calculated an agreement map, which retained regions common to both target sites. Crucially, this map was able to explain an additional amount of variance in clinical improvements of either cohort when compared to the maps calculated on each cohort alone. Finally, we tested profiles and predictive utility of connectivity maps calculated from different motor symptom subscores with a specific focus on bradykinesia and rigidity. While our study is based on retrospective data and indirect connectivity metrics, it may deliver empirical data to support the hypothesis of a largely overlapping network associated with effective deep brain stimulation in Parkinson's disease irrespective of the specific target.


Specificity of the reaction between rheumatoid factors and gamma globulin.
Rheumatoid factors in the sera of patients with rheumatoid arthritis appear to be specifically directed against genetically determined "antigens" in human gamma-globulin. At least eight rheumatoid factors of differing specificity exist; usually several are present in combination in the same serum. The different rheumatoid factors can be readily detected through their pattern of reactivity with anti-Rh antibodies from different individuals. Rheumatoid factors in diseases other than rheumatoid arthritis were found to have a more restricted specificity, contrasted to the broader reactivity of the factors in most rheumatoid arthritis sera. A specificity similar to that for incomplete antibodies was not demonstrated for the reaction of rheumatoid factors with aggregated gamma-globulin or with gamma-globulin to form the "22S complex." In certain instances, using the anti-Rh system, rheumatoid factors were found to react poorly with the patient's own gamma-globulin, compared to that of other individuals of different genetic gamma-globulin types. These results, as well as additional indirect evidence, indicate that the rheumatoid factors can possess isospecificity. However, a certain degree of autospecificity was also found which was most clearly evident through complex formation with the patients own gamma-globulin and in the reaction with aggregates. The relevance of these findings to possible isoantibody as well as autoantibody concepts is discussed.


DNA strand scission by activated bleomycin group antibiotics.
The bleomycins (BLMs) are a structurally related group of antitumor antibiotics used clinically for the treatment of certain malignancies. The mechanism of action of the BLM is believed to involve DNA strand scission, a process that requires O2 and an appropriate metal ion; the therapeutically relevant metal is probably iron or copper. DNA strand scission by activated Fe X BLM involves oxygenation C-4' of deoxyribose and leads to two sets of products. One set results from scission of the C-3'--C-4' bond of deoxyribose, with concomitant cleavage of the DNA chain. The other set of products consists of free bases and an alkali-labile lesion, the latter of which leads to DNA chain cleavage on subsequent treatment with base. The structures of all of these degradation products have now been established by direct comparison with authentic synthetic samples. Also studied was the activation of BLM with (mono)oxygen surrogates such as iodosobenzene. The chemistry of the activated BLM so formed was remarkably similar to that of activated cytochrome P-450 and structurally related metalloporphyrins, which suggests a mechanistic analogy between the two. Remarkably, both Fe X BLM and Cu X BLM were also shown to be activated by NADPH cytochrome P-450 reductase in a transformation that was dependent on metal ion, O2 and NADPH.


Respiratory sinus arrhythmia and submersion bradycardia in bottlenose dolphins (Tursiops truncatus).
Among the many factors that influence the cardiovascular adjustments of marine mammals is the act of respiration at the surface, which facilitates rapid gas exchange and tissue re-perfusion between dives. We measured heart rate (fH) in six adult male bottlenose dolphins (Tursiops truncatus) spontaneously breathing at the surface to quantify the relationship between respiration and fH, and compared this with fH during submerged breath-holds. We found that dolphins exhibit a pronounced respiratory sinus arrhythmia (RSA) during surface breathing, resulting in a rapid increase in fH after a breath followed by a gradual decrease over the following 15-20 s to a steady fH that is maintained until the following breath. RSA resulted in a maximum instantaneous fH (ifH) of 87.4±13.6 beats min-1 and a minimum ifH of 56.8±14.8 beats min-1, and the degree of RSA was positively correlated with the inter-breath interval (IBI). The minimum ifH during 2 min submerged breath-holds where dolphins exhibited submersion bradycardia (36.4±9.0 beats min-1) was lower than the minimum ifH observed during an average IBI; however, during IBIs longer than 30 s, the minimum ifH (38.7±10.6 beats min-1) was not significantly different from that during 2 min breath-holds. These results demonstrate that the fH patterns observed during submerged breath-holds are similar to those resulting from RSA during an extended IBI. Here, we highlight the importance of RSA in influencing fH variability and emphasize the need to understand its relationship to submersion bradycardia.


Rab36 regulates the spatial distribution of late endosomes and lysosomes through a similar mechanism to Rab34.
Small GTPase Rab36 is homologous to Rab34 with 56% amino acid sequence identity. Rab34 was characterized as a Golgi-associated Rab protein and regulates lysosomal positioning through interaction with RILP; however, the properties and functions of Rab36 have not been investigated. To investigate Rab36, we constructed EGFP-Rab36 wild type, the active GTP-bound mutant EGFP-Rab36Q116L and negative GDP-bound mutant EGFP-Rab36T71N. Expression of EGFP-Rab36 wild type revealed that Rab36 co-localized with Golgi markers GM130, Syntaxin 5 and TGN46 in Hela cells, indicating Rab36 is associated with Golgi apparatus. Over-expression of Rab36 induced late endosome and lysosome clustering around the Golgi apparatus, marked by LBPA, CD63, Lamp1 and Lamp2, without effects on early endosomal compartment marked by EEA1. GST-pulldown assay demonstrated that Rab36 can also interact with RILP. In addition, the binding region for Rab36 is in the C-terminal region (aa199-401) of RILP. Our data suggested that Rab36 may regulate the spatial distribution of late endosomes and lysosomes through a similar mechanism to Rab34.


Effects of Teucrium polium Ethyl acetate Extract on Serum, Liver and Muscle Triglyceride Content of Sucrose-Induced Insulin Resistance in Rat.
Possessing putative hypolipidemic effects, Teucrium polium (TP) have been traditionally used as a medicinal plant in Iran. The aim of the present study was to investigate this effect on the sucrose-induced insulin resistance male rat model. Thirty Wistar male rats weighting 180 ± 20 g were divided into five groups of six each. Four groups were given sucrose 50% in drinking water for 10 weeks. In 8(th) week of treatment, three groups of them were randomly selected and treated with Teucrium polium (T. polium) ethyl acetate extract (50, 100 and 200 mg/Kg for two weeks). Control animals were fed using normal rat chow. After ten weeks, blood samples were collected from the heart. Blood Glucose, insulin, leptin, lipid content and fasting insulin resistance index (FIRI) as well as liver and muscle glycogen and lipid contents were determined. Final data were analyzed by ANOVA and post-hoc Tukey's test. Liver glycogen contents and blood levels of glucose and insulin were significantly increased in high sucrose (HS) group compared with control group. A significant decrease was observed in blood glucose and insulin levels, FIRI, serum total lipid, triglyceride and VLDL-c as well as the liver triglyceride level, muscle and liver glycogen contents in 100 and 200 mg/Kg of TP-treated groups compared with HS group. Leptin level was significantly decreased in 50 and 100 mg/Kg groups compared with HS group. The treatment with T. polium ethyl acetate extract (TP-EAE) induced a dose-dependent reduction in serum, liver and muscle triglyceride (TG) and liver glycogen content levels, as well as serum insulin. These effects may be attributed, in part, to the hypolipidemic effect of TP flavonoids; otherwise, the hepatoprotective and antioxidant activity of TP-EAE may improve the liver function and reverse harmful sucrose effects.


Postcoronary Artery Bypass Graft Atrial Fibrillation Event Count and Survival: Differences by Sex.
New-onset atrial fibrillation (AF) after coronary artery bypass graft surgery (CABG) is associated with poor outcomes, but data on the effects of its characteristics are lacking and conflicting. We examined the effect number of post-CABG AF events has on long-term mortality risk, and whether this is sex dependent. Routinely collected Society of Thoracic Surgeons (STS) data were supplemented with details on new-onset post-CABG AF (detected in-hospital by continuous electrocardiogram/telemetry monitoring) and long-term survival for 9203 consecutive patients with isolated-CABG (2002-2010). With the use of Cox regression, we determined the propensity-adjusted (STS-recognized risk factors) effect of number of AF events on survival, testing for effect modification by sex and controlling for AF duration. AF occurred in 739 women (29.4%) and 2157 men (32.3%) (P < .001). Adjusted results showed 2 or more AF events significantly (P < .001) increased 5-year mortality risk, independently of total AF duration. However, mortality risk differed between the sexes (P < .001): women with 2 AF episodes had the greatest increase (hazard ratio [HR] = 2.98; 95% confidence interval [CI], 1.43-4.83; versus women without AF), followed by women and men with 4 or more AF events (HR = 2.76 [95% CI, 1.27-4.55] and HR = 2.73 [95% CI, 2.30-3.19], respectively). A single post-CABG AF episode was not associated with increased mortality risk. Both men and women who experienced 2 or more post-CABG AF episodes showed increased risk of 5-year mortality, independent of total AF duration. Although men's risk increased as the number of AF events increased, women's risk peaked at 2 AF events. Future research needs to determine whether this divergence stems from differences in treatment/management or underlying biology.


Bioaccumulation data from laboratory and field studies: are they comparable?
Once they are released into the environment, a number of chemicals are known to bioaccumulate in organisms, sometimes to concentrations that may threaten the individual or their predators. However, use of physical or chemical properties or results from laboratory bioaccumulation tests to predict concentrations sometimes found in wild organisms remains a challenge. How well laboratory studies and field measurements agree or disagree, and the cause of any discrepancies, is a subject of great interest and discussion from both a scientific and a regulatory perspective. A workshop sponsored by the ILSI Health and Environmental Sciences Institute, US Environmental Protection Agency, and the Society of Environmental Toxicology and Chemistry assembled scientists from academia, industry, and government to compare and contrast laboratory and field bioaccumulation data. The results of this workshop are summarized in a series of 5 articles published in this issue of Integrated Environmental Assessment and Management. The articles describe: 1) a weight-of-evidence approach that uses fugacity ratios to bring field measurements into the assessment of biomagnification potential for legacy chemicals; 2) a detailed comparison between laboratory and field data for the most commonly measured bioaccumulation endpoint, the biota-sediment accumulation factor; 3) a study that identifies and quantifies the differences between laboratory and field metrics of bioaccumulation for aquatic and terrestrial organisms; and 4) 2 reports on trophic magnification factors: the 1st addresses how trophic magnification factors are determined and interpreted and the 2nd describes how they could be used in regulatory assessments. Collectively, these articles present the workshop participants' current understanding and assessment of bioaccumulation science and make a number of recommendations on how to improve the collection and interpretation of bioaccumulation data.