Glutamate decarboxylase and GABA in pancreatic islets: lessons from knock-out mice.
The GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) is expressed in pancreatic beta-cells and GABA has been suggested to play a role in islet cell development and function. Mouse beta-cells predominantly express the larger isoform of the enzyme, GAD67, and very low levels of the second isoform, GAD65. Yet GAD65 has been shown to be a target of very early autoimmune T-cell responses associated with beta-cell destruction in the non-obese diabetic (NOD) mouse model of Type 1 diabetes. Mice deficient in GAD67, GAD65 or both were used to assess whether GABA is important for islet cell development, and whether GAD65 is required for initiation of insulitis and progression to Type 1 diabetes in the mouse. Lack of either GAD65 or GAD67 did not effect the development of islet cells and the general morphology of islets. When GAD65-/-(129/Sv) mice were backcrossed into the NOD strain for four generations, GAD65-deficient mice developed insulitis similar to GAD65+/+ mice. Furthermore, at the low penetrance of diabetes in this backcross, GAD65-deficient mice developed disease at the same rate and incidence as wildtype mice. The results suggest that GABA generated by either GAD65 or GAD67 is not critically involved in islet formation and that GAD65 expression is not an absolute requirement for development of autoimmune diabetes in the NOD mouse.


Moralized Health-Related Persuasion Undermines Social Cohesion.
Integrating theory and research on persuasion, moralization, and intergroup relations, the present research aims to highlight the far-reaching impact of health-related persuasion on society. I propose that governments' health-related persuasion leads to the emergence of new social norms, and in particular moral norms. Importantly, moral norms provide strong behavioral imperatives and are seen as binding for group members. This suggests that moralized persuasion has a strong potential to divide society along the lines of citizens who conform to and citizens who deviate from health-related moral norms. Thus, departing from the traditional focus on targets of persuasion, the present research focuses on those holding a moralized view on health and lifestyle. Key aspects of social cohesion as defined by the OECD (2011) have been tested across four studies. The main hypothesis tested is that those conforming to the norm (e.g., non-smokers, normal weight people, people with healthy lifestyles) will stigmatize those deviating from the norm (e.g., smokers, overweight people, people with unhealthy lifestyles). Flowing from stigmatization, less inclusion, lower solidarity with and greater endorsement of unequal treatment of those deviating from the moral norm are predicted. Four survey studies (total N = 1568) examining the proposed associations among non-smokers, normal weight people, and employees with healthy lifestyles are presented. The studies provide unanimous support for the hypothesis, with meta-analysis providing further support for the reliability of the findings. Consistent across studies, social cohesion indicators were negatively affected by health moralization through stigmatization of those deviating from health-related moral norms. Findings highlight an under-acknowledged potential of moralized health-related persuasion to divide society, thereby undermining cohesion and the achievement of important societal goals. In the discussion, limitations and relevant routes for future research are highlighted. Recommendations are derived for policy makers, institutions, employers, and individuals.


Continuing dilemmas concerning aortic valve replacement in patients with advanced left ventricular systolic dysfunction.
Aortic valve replacement in patients with aortic stenosis or aortic regurgitation who have severe left ventricular (LV) systolic dysfunction continues to be associated with a high mortality risk despite surgical, cardiological and anesthetic improvements over time. As a result of earlier surgical referral, however, fewer patients with aortic regurgitation (AR) and advanced LV failure present for operation today. Favorable operative and long-term results, and data demonstrating recovery of LV systolic function if patients are referred prior to the onset of systolic dysfunction have largely solved this problem in the context of AR. On the other hand, patients with critical aortic stenosis (AS) and severe LV systolic dysfunction constitute a more heterogeneous and even more challenging group. On one side of the continuum, patients with truly critical AS and low ejection fraction due to LV 'afterload mismatch' (depressed ejection performance resulting from excessively high systolic LV wall stress secondary to a very tight valve) generally respond well to aortic valve replacement, which immediately normalizes LV afterload. Conversely, patients with 'critical' aortic stenosis and advanced LV systolic dysfunction who present with a low transvalvular gradient and cardiac output constitute a subgroup at high operative risk, which also has a suboptimal prognosis after aortic valve replacement. This clinical situation has been termed the 'Gorlin Conundrum', and is punctuated by a low mean transvalvular gradient and low flow. The reason for the low transvalvular gradient is not always known, but can be secondary to some type of coexistent cardiomyopathy. Patients with only mild pathologic aortic valve sclerosis/stenosis and markedly depressed LV systolic function are frequently judged to have 'critical' aortic stenosis (AVA < 0.8 cm2 or AVAI < 0.4 cm2/m2) due to inherent flaws in the Gorlin equation and limitations of the Doppler continuity equation. Although alternative diagnostic techniques have been proposed, e.g. aortic valve resistance, stroke work loss, none has yet proven to be totally reliable. The suboptimal results of aortic valve replacement in low-gradient AS patients underscore our difficulty in currently predicting which patients will benefit from valve replacement. Newer diagnostic techniques, including dobutamine echocardiography, and novel new findings regarding the basic molecular mechanisms responsible for contractile dysfunction in pressure overload hypertrophy may ultimately improve the results of surgical treatment in these patients.


Hyper-Lapse From Multiple Spatially-Overlapping Videos.
Hyper-lapse video with high speed-up rate is an efficient way to overview long videos, such as a human activity in first-person view. Existing hyper-lapse video creation methods produce a fast-forward video effect using only one video source. In this paper, we present a novel hyper-lapse video creation approach based on multiple spatially-overlapping videos. We assume the videos share a common view or location, and find transition points where jumps from one video to another may occur. We represent the collection of videos using a hyper-lapse transition graph; the edges between nodes represent possible hyper-lapse frame transitions. To create a hyper-lapse video, a shortest path search is performed on this digraph to optimize frame sampling and assembly simultaneously. Finally, we render the hyper-lapse results using video stabilization and appearance smoothing techniques on the selected frames. Our technique can synthesize novel virtual hyper-lapse routes, which may not exist originally. We show various application results on both indoor and outdoor video collections with static scenes, moving objects, and crowds.


Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta-analysis of six cohort studies.
Concerns about teratogenicity and maternal and offspring complications restrict the use of lithium during pregnancy for the treatment of mood disorders. We aimed to investigate the association between in-utero lithium exposure and risk of pregnancy complications, delivery outcomes, neonatal morbidity, and congenital malformations. In this meta-analysis, primary data from pregnant women and their children from six international cohorts based in the community (Denmark, Sweden, and Ontario, Canada) and in clinics (the Netherlands, UK, and USA) were analysed. Pregnancies were eligible for analysis if the pregnancy resulted in a liveborn singleton between 1997 and 2015, if health-related information was available for both mother and infant, and if the mother had a mood disorder (bipolar disorder or major depressive disorder) or if she had been given lithium during pregnancy (at least two dispensations of lithium during pregnancy that were dispensed any time from 1 month before conception until the delivery, or a single lithium dispensation during pregnancy when there was at least one other lithium dispensation within 6 months before or after this date). Pregnancies during which the mother had been prescribed known teratogenic drugs were excluded. Pregnancies were grouped into a lithium-exposed group and a mood disorder reference group. The main outcome measures were pregnancy complications, delivery outcomes, neonatal readmission to hospital within 28 days of birth, and congenital malformations (major malformations and major cardiac malformations). Analyses were done at each site by use of a shared protocol. Adjusted odds ratios (aORs) and 95% CIs were calculated by use of logistic regression models, and site-specific prevalence rates and ORs were pooled by use of random-effects meta-analytical models. 22 124 eligible pregnancies were identified across the six cohorts, of which 727 pregnancies were eligible for inclusion in the lithium-exposed group (557 [77%] from register-based cohorts and 170 [23%] from clinical cohorts). Lithium exposure was not associated with any of the predefined pregnancy complications or delivery outcomes. An increased risk for neonatal readmission within 28 days of birth was seen in the lithium-exposed group compared with the reference group (pooled prevalence 27·5% [95% CI 15·8-39·1] vs 14·3% [10·4-18·2]; pooled aOR 1·62, 95% CI 1·12-2·33). Lithium exposure during the first trimester was associated with an increased risk of major malformations (pooled prevalence 7·4% [95% CI 4·0-10·7] vs 4·3% [3·7-4·8]; pooled aOR 1·71, 95% CI 1·07-2·72) but for major cardiac malformations the difference was not significant (2·1% [0·5-3·7] vs 1·6% [1·0-2·1]; pooled aOR 1·54, 95% CI 0·64-3·70). Considering both the effect sizes and the precision of the estimates in this meta-analysis, treatment decisions for pregnant women with mood disorders must weigh the potential for increased risks of lithium during pregnancy-in particular those associated with use of lithium during the first trimester-against its effectiveness at reducing relapse. None.


Immunocytochemical and neurochemical evidence for age-related loss of GABA in the inferior colliculus: implications for neural presbycusis.
The present study describes substantial, selective, age-related loss of the putative inhibitory neurotransmitter GABA in the central nucleus of the inferior colliculus (CIC) of rat based on immunocytochemical and neurochemical data. For immunocytochemistry, neurons in the CIC were immunolabeled using an antibody against a GABA conjugate in young adult (2- to 7-month-old) and aged (18- to 29-month-old) Fischer-344 rats. Computer-assisted morphometry was then used to generate maps of GABA-immunoreactive neurons in the CIC. The number of GABA-positive neurons was reduced 36% in the ventrolateral portion of the CIC of aged animals (93 neurons/mm2) compared to their matched young adult cohorts (145 neurons/mm2; p less than 0.01). For neurochemistry, basal and K(+)-evoked release of the endogenous amino acids GABA, glutamate (Glu), aspartate (Asp), and tyrosine (Tyr) from micropunches of the CIC were measured in 8 age-paired animals from the 2 age groups using high-performance liquid chromatography. Overflow of radiolabeled acetylcholine (3H-ACh) was also determined. In both age groups, K(+)-evoked release of GABA, Glu, Asp, and 3H-ACh from CIC punches was significantly enhanced above basal efflux (+200, +215, +163, and +309%, respectively), while Tyr release was unchanged. Evoked release of 3H-ACh and all amino acids except Tyr showed substantial Ca2+ dependence. A significant (p less than 0.05) age-related reduction in both basal (-35%) and K(+)-stimulated (-42%) efflux of GABA from the CIC was observed. A corresponding decrease in postrelease tissue content of GABA in CIC of aged rats was observed (-30%, p less than 0.05). In contrast, tissue content as well as basal and evoked release of Glu, Asp, Tyr, and 3H-ACh was similar between the 2 age groups. Age-related GABA neurochemical changes described in the CIC were not observed in the release of the other amino acids or 3H-ACh from either the rostral ventrolateral medulla or the somatosensory cortex, 2 brain regions involved in processing non-auditory sensory input. These data support previous findings that GABA, Glu, Asp, and ACh may subserve neurotransmission in the CIC. Additionally, these data provide clear evidence for a pronounced, region- and neurotransmitter-selective, age-related reduction of GABA in the CIC. These findings support the hypothesis that impairment of inhibitory GABAergic neurotransmission in the CIC may contribute to abnormal auditory perception and processing seen in neural presbycusis.


Enhancing the Relationship Between Regulators and Their Profession.
Regulators face unique pressures to balance competing priorities related to patient safety, public accountability, and practitioners' expectations. Historically, the collegial model of self-regulation has been used as a tool for risk management, to recognize the importance of profession- and context-specific judgment in complex, ambiguous clinical situations. Increasingly, as public accountability concerns have grown dominant within regulatory bodies, this collegial model has shifted toward a more antagonistic relationship between the regulators and the regulated. Wilkie and Tzountzouris (2017) highlight one profession's journey toward embedding professionalism within regulatory practices and policies through application of a right-touch regulatory philosophy. Given the complexity of regulatory work, this shift required significant strategic and deliberative thinking. The challenges of facilitating this sort of cultural shift in the role of a regulator are significant, but so too are the potential gains associated with a more engaged relationship between regulators and their practitioners.


Young investigator challenge: MicroRNA-21/MicroRNA-126 profiling as a novel tool for the diagnosis of malignant mesothelioma in pleural effusion cytology.
In pleural effusion cytology, the distinction of malignant mesothelioma (MM) from reactive mesothelial cells (RMCs) may be challenging, even with the aid of immunocytochemistry or fluorescence in situ hybridization. It has been demonstrated that several microRNAs (miRNAs) are useful for this purpose in cell lines and histologic samples. In the current study, the authors evaluated the utility of an miRNA-based classifier as a complement to cytology. Quantitative reverse transcriptase-polymerase chain reaction analysis of 15 miRNAs was performed in mesothelial (MET-5A) and MM (H28 and H2052) cell lines. Significant miRNAs were validated in 51 MM and 40 nonneoplastic pleural histologic samples and then were tested in 29 MM and 24 RMC cytologic specimens. The performance of individual and combined miRNAs was assessed for their ability to differentiate between MM and RMCs. MiRNA-19a (MiR-19a), miR-19b, miR-21, miR-25, and miR-126 were differentially expressed in cell lines and histologic samples. MiR-126 was down-regulated in MM surgical specimens compared with nonneoplastic specimens, whereas all of the other miRNAs were overexpressed. In cytologic specimens, all miRNAs except miR-25 were confirmed, exhibiting a sensitivity or a specificity higher than the threshold of 0.80, as recommended by the International Mesothelioma Interest Group. The best classifier resulted from the combination of miR-21 and miR-126, which achieved 0.86 sensitivity and 0.87 specificity. Subject to validation of the current results in further larger studies, miR-21 and miR-126 profiling could be an effective and reliable tool for the diagnosis of MM in pleural effusions complementary to cytology evaluation.


Risk based urban watershed management under conflicting objectives.
Ecological impairment and flooding caused by urbanization can be expressed numerically by calculating the risks throughout the watershed (floodplain) and along the main stems of the streams. The risks can be evaluated in terms of the present and/or future. This article describes the methodologies for ascertaining the risks in the Geographical Information Systems (GIS) environment. The objectives of urban flood controls and ecological preservation/restoration of urban waters are often conflicting and, in the past, the sole emphasis on flood control led to destruction of habitat and deterioration of water quality. An optimal solution to these two problems may be achieved by linking the risks to the concepts of risk communication, risk perception, and public willingness to pay for projects leading to ecological restoration and ecologically sustainable flood control. This method is appropriate because, in each case, public funds are used and the projects require approval and backing of policy makers and stakeholders. This article briefly describes a research project that attempts to resolve the conflict between the flood protection and stream ecological preservation and restoration and suggests alternative ways of expressing benefits of urban stream flood control and restoration projects.


Preparation and characterization of an intravenous solution of IgG from human immunodeficiency virus-seropositive donors.
An intravenous solution of 99% pure globulin (hyperimmune IgG, HIVIG) was obtained from pooled plasma of selected human immunodeficiency virus (HIV-1)-seropositive asymptomatic donors with greater than 400 CD4+/microliters cells per microliter and a high titer of antibody to HIV-1 p24 protein. HIVIG had high titers of antibody to p24, glycoprotein 41 (gp41), and gp120, group-specific neutralizing activity, and binding to the gp120 hypervariable loop region. It inhibited syncytia formation. At low concentration, it enhanced viral production of HIV-1 in infected peripheral blood monocytes but was inhibitory at higher concentration. HIVIG directed group-specific antibody-dependent cellular cytotoxicity against HIV-infected targets. For a period of 6 to 28 months, plasma donors kept stable antibody titers and had a 1.0% decrease in CD4+ cells per month. One gram per kilogram HIVIG injected in two juvenile chimpanzees was well tolerated and did not transmit HIV, as measured by negative cell culture, IgM immune response to HIV proteins, and polymerase chain reaction. The mean half-life of HIV-1 p24 antibody was 15 days. These preliminary data suggest that HIVIG is a safe product suitable for clinical trial in HIV-1-infected individuals.


PI3K Pathway Effectors pAKT and FOXO1 as Novel Markers of Endometrioid Intraepithelial Neoplasia.
The diagnosis of endometrioid intraepithelial neoplasia (EIN) is challenging owing to limited sampling, hormonal status, and other confounding histologic variables. Markers such as PTEN or PAX2 can delineate EIN in some cases, but are not wholly reliable. Clearly, new markers of EIN are needed. We explored several potential markers of EIN based rationally on molecular pathways most frequently misregulated in endometrial cancer: the 3-phosphoinositide kinase (PI3K)/AKT, β-catenin, and mismatch repair pathways. We studied PTEN, PAX2, β-catenin, and MLH1, in conjunction with 2 new markers-FOXO1 and phosphorylated AKT (pAKT)-not previously investigated in EIN. Benign (n=14) and EIN (n=35) endometria were analyzed by immunohistochemistry. Staining patterns were interpreted, tabulated, and scored by "clonal distinctiveness" in neoplastic lesions; that is, pattern alterations relative to normal glands. In normal endometria, FOXO1 was cytoplasmic in proliferative phase, but nuclear in secretory phase, showing that PI3K/FOXO1 participates in endometrial cycling and that FOXO1 is a readout of PI3K status. pAKT expression was low across normal endometria. FOXO1 or pAKT expression was altered in the majority of EINs (27/35, 77%), with FOXO1 and pAKT being co-altered only in some (20/35, 57%). β-catenin or MLH1 also exhibited clonal distinctiveness in EINs, showing that these are also useful markers in some cases. This is the first study to demonstrate the potential of pAKT and FOXO1 as biomarkers in the histopathologic evaluation of EIN. However, variability in expression poses challenges in interpretation.


Engineering optical properties of a graphene oxide metamaterial assembled in microfluidic channels.
The dense packing of two dimensional flakes by van der Waals forces has enabled the creation of new metamaterials with desirable optical properties. Here we assemble graphene oxide sheets into a three dimensional metamaterial using a microfluidic technique and confirm their ordering via measurements of ellipsometric parameters, polarized optical microscopy, polarized transmission spectroscopy, infrared spectroscopy and scanning electron microscopy. We show that the produced metamaterials demonstrate strong in-plane optical anisotropy (Δn≈0.3 at n≈1.5-1.8) combined with low absorption (k<0.1) and compare them with as-synthesized samples of graphene oxide paper. Our results pave the way for engineered birefringent metamaterials on the basis of two dimensional atomic crystals including graphene and its derivatives.


Use of Piggyback Electrolytes for Patients Receiving Individually Prescribed vs Premixed Parenteral Nutrition.
Parenteral nutrition (PN) is available as individualized prescriptions frequently prepared with an automated compounding device or as commercially prepared premixed solutions. Our institution exclusively used individualized PN until an amino acid shortage forced a temporary switch to premixed solutions. In general, premixed solutions contain lower electrolyte levels than individualized formulations prescribed for patients with normal organ function. We aimed to quantify supplemental intravenous piggyback (IVPB) electrolyte use in adult patients receiving individualized and premixed PN and to quantify any effect on difference in the cost of therapy. We compared use of supplemental IVPB electrolytes administered to patients receiving PN during consecutive periods prior to and during the amino acid shortage. Electrolyte IVPBs tabulated were potassium chloride, 10 and 20 mEq; magnesium sulfate, 2 g and 4 g; potassium phosphate, 7.5 and 15 mmol; and sodium phosphate, 7.5 and 15 mmol IVPB. There was no statistical difference in the number of PN formulations administered per day during each period (14.7 ± 3.9 vs 14.0 ± 2.6, individualized vs premixed, respectively). Total IVPB electrolytes prescribed per day increased significantly from the individualized PN period to the premixed PN period (7.03 ± 3.8 vs 13.8 ± 6.8; P < .0001). The additional IVPB electrolyte supplementation required in patients receiving premixed PN was associated with an additional $11,855.74 cost per 30 days of therapy compared with those who received individualized PN. Inpatient use of premixed PN results in a significant increase in IVPB electrolyte supplementation and cost compared with individualized PN use.


Oral administration of nasturtium affects peptide YY secretion in male subjects.
Nasturtium plants contain the glucosinolate glucotropaeolin and its corresponding breakdown product benzyl isothiocyanate (BITC), the latter being intensively studied with regard to cancer chemoprevention and anti-inflammatory properties. In addition, recent research has shown that isothiocyanates are able to activate the release of several gut hormones in vitro and in rodent studies. Here, we tested the effects of a dietary nasturtium administration on circulating levels of gut hormones in humans. Metabolically healthy males (n = 15) received a single oral dose of 10 g freeze-dried nasturtium leaf material suspended in water or only water (control). Blood samples were taken every hour and serum concentrations of insulin, C-peptide, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide (PYY) were analyzed. Oral nasturtium intake resulted in an increased release of PYY over a time period of 6 h whereas circulating levels of other hormones were not changed. Given the finding that nasturtium consumption enhances secretion of PYY, a key hormone involved in energy regulation, special diets containing nasturtium, or supplementation with nasturtium or BITC might be considered in the treatment of obesity.


Analysis of periodontal risk profiles in adults with or without a history of myocardial infarction.
An association between periodontitis and cardiovascular diseases has been suggested. To study whether a combination of clinical variables in a functional risk diagram enhanced the ability to differentiate between subjects with or without an immediate history of acute myocardial infarction (AMI). A functional periodontal pentagon risk diagram (PPRD) with five periodontal risk vectors was created. The surface of individual PPRDs was calculated using data from 88 subjects with recent AMI and 80 matched control subjects with no history of AMI. Age, gender, number of remaining teeth (mean value: 21.1 versus 21.6 teeth), smoking status, and pocket probing depth (PPD) distribution did not differ by group. Gingival recession was greater in control subjects (mean difference: 5.7, SD: +/- 1.9, p<0.01, 95% CI: 1.8-9.6). Bone loss > or = 4.0 mm was at all levels studied was significantly greater in subjects with AMI and bone loss > or = 50% (> or = 4 mm) was the best individual predictor of AMI (beta = 2.99, p < 0.000, 95% CI: 7.5-53.4). Only PPRD scores were associated with AMI status when factors not included in the PPRD were studied (beta = 22.1, SE: 5.9, p < 0.0001, 95% CI: 10.3-33.7). The best association between AMI status and study variables was the combination of > or = 4 mm of bone loss > or = 50%, proportion of bleeding on probing (%BOP), %PPDs > or = 6 mm, and tooth loss (Nagelkirke r2 = 0.46). The combination of five periodontal parameters in a PPRD added predictive value, suggesting that comprehensive data should be used in studies of associations between periodontitis and heart diseases. Radiographic evidence of bone loss was the best individual parameter.


Placental exosomes in normal and complicated pregnancy.
While there is considerable contemporary interest in elucidating the role of placenta-derived extracellular vesicles in normal and complicated pregnancies and their utility as biomarkers and therapeutic interventions, progress in the field is hindered by a lack of standardized extracellular vesicle taxonomy and isolation protocols. The term "extracellular vesicle" is nonspecific and refers to all membrane-bound vesicles from nanometer to micrometer diameters and of different biogenic origins. To meaningfully ascribe biological function and/or diagnostic and therapeutic utility to extracellular vesicles, and in particular exosomes, greater specificity and vesicle characterization is required. The current literature relating to exosome biology must be interpreted in this context. Exosomes are a subtype of extracellular vesicle that are specifically defined by an endosomal biogenesis and particle size (40-120 nm) and density (1.13-1.19 g/mL(-1)). Exosomes are specifically package with signaling molecules (including protein, messenger RNA, microRNA, and noncoding RNA) and are released by exocytosis into biofluid compartments. Exosomes regulate the activity of both proximal and distal target cells, including translational activity, angiogenesis, proliferation, metabolism, and apoptosis. As such, exosomal signaling represents an integral pathway mediating intercellular communication. During pregnancy, the placenta releases exosomes into the maternal circulation from as early as 6 weeks of gestation. Release is regulated by factors that include both oxygen tension and glucose concentration and correlates with placental mass and perfusion. The concentration of placenta-derived exosomes in maternal plasma increases progressively during gestation. Exosomes isolated from maternal plasma are bioactive in vitro and are incorporated into target cells by endocytosis. While the functional significance of placental exosomes in pregnancy remains to be fully elucidated, available data support a role in normal placental development and maternal immunotolerance. Similarly, the role of exosomes in the etiology and progression of complications of pregnancy remains in a formative stage. Changes in the release of placenta- and nonplacenta-derived exosomes, their concentration in maternal plasma, composition, and bioactivity have been reported in association with pregnancies complicated by gestational diabetes and preeclampsia. The data, however, are confounded by the use of different isolation methodologies and vesicle subpopulations. The application of specific and well-characterized isolation methodologies is requisite to resolving the precise role of exosomes in complications of pregnancies and their ultimate clinical utility.


The efficacy of inducibility and circumferential ablation with pulmonary vein isolation in patients with paroxysmal atrial fibrillation.
Some conflicting results of the efficacy of the inducibility test used in the catheter ablation of atrial fibrillation (AF) have been reported. The aim of this study was to investigate the inducibility and efficacy of circumferential ablation with pulmonary vein isolation (PVI) in patients with paroxysmal AF and its relationship to the atrial substrate. This study consisted of 88 patients with paroxysmal AF who underwent catheter ablation. Electroanatomic mapping using a NavX system was performed and the biatrial voltage was obtained during sinus rhythm. After successful circumferential ablation with PVI, an inducibility test was performed to determine the requirement for creating left atrial (LA) ablation line. After procedure, patients with inducible AF had a higher recurrence rate than did those with noninducibility of AF (55% vs 18%, P = 0.02). The patients with inducible AF after the PVI had a lower biatrial voltage than did those with negative inducibility. The patients with inducible AF after the final procedure who had a recurrence had a lower LA voltage (1.3 +/- 0.4 vs 1.8 +/- 0.4 mV, P = 0.02) and longer LA total activation time (99 +/- 18 vs 88 +/- 13 msec, P = 0.02) than did those with noninducible AF and no recurrence. None of the patients had occurrence of LA flutter during the follow-up. After a single procedure of circumferential ablation with PVI and noninducibility, 82% patients did not have recurrence of AF. The inducibility of AF was related to the recurrence of AF. The atrial substrate affected the outcome of the inducibility.


Generation of Adrenal Chromaffin-like Cells from Human Pluripotent Stem Cells.
Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.


Colorectal and Prostate Cancer Risk in Diabetes: Metformin, an Actor behind the Scene.
Both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide, especially in countries that are undergoing rapid industrialization changes. Apparently, lifestyle risk factors including diet, physical inactivity and obesity play pivotal, yet preventable, roles in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes. While diabetes (type 2) and cancer share many risk factors, the biological links between the two diseases are poorly characterized. In this review, we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of Metformin, a diabetes drug, to prevent and/or treat colorectal and prostate cancer. We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.


(-)-Epigallocatechin-3-Gallate protects SH-SY5Y cells against 6-OHDA-induced cell death through STAT3 activation.
As a natural product, (-)-Epigallocatechin-3-gallate (EGCG), has demonstrated remarkable neuronal protection by depressing oxidative stress in Parkinson's disease (PD). However, the molecular mechanisms underlying EGCG neuronal protection have not been clarified. Using 6-hydroxydopamine (6-OHDA)-treated human neuroblastoma SH-SY5Y cells as a PD cell model, we found that 6-OHDA can cause neuronal death by regulating the activity of STAT3. Pretreatment of SH-SY5Y cells with EGCG (0.1-10 microM) significantly attenuated cell death induced by 6-OHDA. In addition, STAT3 activity decline induced by 6-OHDA in SH-SY5Y cells can be completely prevented by the presence of 1 microM of EGCG, and neuronal cell proliferation can be stimulated by EGCG treatment. These results clearly demonstrate that the disruption of STAT3 signaling by 6-OHDA makes significant contribution to the neuronal death in PD, and the protection of EGCG on neurons against oxidative stress-induced cell death may result from the re-stimulation of STAT3 signaling pathway. Our study not only clarified the role of STAT3 signaling pathway in oxidative stress-induced neuronal cell death, but also identified its involvement in the protection mechanism of EGCG on neurons in PD. The data resulting from our study also suggest that STAT3 may serve as a potential therapeutic target for drug development in PD.


First Report of Colletotrichum phormii Causing Anthracnose on New Zealand Flax in the United States.
Phormium colensoi Hook.f. (syn. P. cookianum), New Zealand flax, (family Xanthorrhoeaceae) is popular in ornamental landscapes in the United States because of its sturdy blade-like foliage available in diverse colors. In February 2012, the Oregon State University Plant Clinic received three potted plants of P. colensoi 'Black Adder' from a commercial nursery in Santa Cruz County, California. The margins and midribs of several leaves had brown lesions that were variable in size, and fusiform to ellipsoidal in shape. Embedded in the lesions were black acervuli without setae that exuded salmon-colored spore masses under moist conditions. Conidia were hyaline, cylindrical to fusiform, straight to slightly curved, and 22.4 to 35.2 × 4.0 to 6.4 (average 24.7 × 4.9) μm. Based on morphology, the fungus was confirmed by USDA-APHIS National Identification Services to be Colletotrichum phormii (Henn.) D.F. Farr & Rossman (2). In March 2012, the California Department of Food and Agriculture Plant Pest Diagnostic Lab received additional samples from the same nursery lot (25% disease incidence) from which a similar fungus was recovered. rDNA sequences of the internal transcribed spacer (ITS) region from the California isolate (GenBank KC122681), amplified using primers ITS1 and ITS4 (2), were 100% identical to multiple species of Colletotrichum, including C. phormii by a BLAST query (JQ948446 through JQ948453). ITS sequence similarity alone is not sufficient to address Colletotrichum taxonomy and must be used in combination with host range and morphology (1). Pathogenicity of C. phormii (isolate CDFA986) was tested on three 'Black Adder' plants, which were inoculated with 6-mm agar plugs from a 14-day-old culture grown on half strength potato dextrose agar (PDA). Leaves were wound-inoculated along the midrib using colonized plugs (4). Five leaves per plant were inoculated with C. phormii plugs and five leaves per plant were treated with uncolonized PDA agar plugs as controls. Plants were sprayed with water and incubated in plastic bags at 22°C with a 12-h photoperiod. After 48 h, the bags and caps were removed and plants were kept under the same conditions. Two weeks later, water-soaked lesions had developed on the inoculated leaves. Lesions expanded along the midrib and became fusiform in shape after 21 to 28 days. C. phormii was isolated from lesion margins of all the inoculated leaves, but not from control leaves. This experiment was repeated once with similar results. Another Colletotrichum species, C. gloeosporiodes, also occurs on Phormium spp., but differs from C. phormii in morphology and symptom expression. Subsequent nursery and landscape surveys showed that anthracnose caused by C. phormii occurs on several P. colensoi cultivars as well as on P. tenax in five California counties including Santa Cruz, Yolo, Sacramento, San Luis Obispo, and Solano. C. phormii is also reported to infect P. colensoi and P. tenax in New Zealand, Europe, the United Kingdom, Australia, and South Africa (2,3). To our knowledge, this is the first report of C. phormii causing anthracnose on Phormium in North America. This disease could impact the American nursery trade and New Zealand flax production due to crop loss and increased production costs for pest management. References: (1) J. Crouch et al. Mycologia 101:648, 2009. (2) D. F. Farr et al. Mycol. Res. 110:1395, 2006. (3). H. Golzar and C. Wang. Australas. Plant Pathol. 5:110, 2010. (4) L. E. Yakabe et al. Plant Dis. 93:883, 2009.


Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia.
There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.


The impact and effectiveness of nurse-led care in the management of acute and chronic pain: a review of the literature.
To identify, summarise and critically appraise the current evidence regarding the impact and effectiveness of nurse-led care in acute and chronic pain. A diverse range of models of care exist within the services available for the management of acute and chronic pain. Primary studies have been conducted evaluating these models, but, review and synthesis of the findings from these studies has not been undertaken. Literature review. Searches of Pubmed (NLM) Medline, CINAHL, Web of Knowledge (Science Index, Social Science index), British Nursing Index from January 1996-March 2007 were conducted. The searches were supplemented by an extensive hand search of the literature through references identified from retrieved articles and by contact with experts in the field. Twenty-one relevant publications were identified and included findings from both primary and secondary care. The areas, in which nurses, caring for patients in pain are involved, include assessment, monitoring, evaluation of pain, interdisciplinary collaboration and medicines management. Education programmes delivered by specialist nurses can improve the assessment and documentation of acute and chronic pain. Educational interventions and the use of protocols by specialist nurses can improve patients understanding of their condition and improve pain control. Acute pain teams, led by nurses, can reduce pain intensity and are cost effective. Nurses play key roles in the diverse range of models of care that exist in acute and chronic pain. However, there are methodological weaknesses across this body of research evidence and under researched issues that point to a need for further rigorous evaluation. Nurse-led care is an integral element of the pain services offered to patients. This review highlights the effect of this care and the issues that require consideration by those responsible for the development of nurse-led models in acute and chronic pain.


Healthcare Chaplaincy as a Companion Profession: Historical Developments.
Chaplains, like professionals in a range of industries, have long sought to maintain and build occupational power by articulating their professional mandate and advocating for their work. I describe how leaders of the Association of Professional Chaplains and its predecessor organizations used multiple strategies to articulate and re-articulate their professional mandate between 1940 and the present to become a companion profession, one that comes alongside another without seeking to challenge its jurisdiction. I find chaplains seeking to develop an economic base, aligning interests across distinct segments of the profession and creating new professional associations, lobbying for legislative support, and offering their services in institutional voids. They further adopted the language of healthcare around questions of identity, charting, and accreditation and, chaplains used not just the frameworks but the methods of healthcare-evidence based research-to try to demonstrate their value. This history can help chaplains and chaplaincy leaders today to form a more comprehensive sense of their history and think more strategically regarding how to make the case for their profession going forward.


Elementary mechanics of the endothelium of blood vessels.
The endothelium lining human arteries is a continuum of endothelial cells. The flowing blood imposes a shear stress on the endothelium. To compute the internal stress in the endothelium, we use two alternative hypotheses: 1) The cell content is fluid-like so that at steady-state it has no shear stress. 2) The cell content is solid-like. Under hypothesis No. 1, the membrane tension in the upper cell membrane grows in the direction opposite to the blood flow at a rate equal to the blood shear stress. At the junction of two neighboring cells the membrane tension in the downstream cell is transmitted partly to the basal lamina, and partly to the upstream cell. The transmission depends on the osmotic or static pressure difference between the cell and blood. If the static pressure difference is zero, the tension in the upper cell membrane will accumulate upstream. At other values of static pressure, the cell membrane tension may increase, decrease, or fluctuate along the vessel depending on the inclination of the side walls of the cells at the junctions. To determine the sidewall inclinations, we propose to use the complementary energy theorem. Under hypothesis No. 2, the cell content can bear shear, which tends to reduce the cell membrane tension; but the cell membrane tension accumulation phenomenon discussed above remains valid. These results are used to analyze the interaction of the cell membrane and cell nucleus; and the effect of turbulences in the flow on causing large fluctuations in cell membrane tension and vertical oscillations of the nuclei. The implication of tensile stress on the permeability of the cell membrane is discussed. We conclude that for the study of mass transport and stress fibers in the endothelial cells, one should consider the interaction of neighboring endothelial cells as a continuum, and shift attention from the shear stress in the blood to the principal stresses in the cells.