Bioethics and cara sui.
Cara sui (care of the self) is a guiding thread in Foucault's later writings on ethics. Following Foucault in that inquiry, we are urged beyond our fairly superficial conceptions of consequences, harms, benefits, and the rights of persons, and led to examine ourselves and try to articulate the sense of life that animates ethical reasoning. The result is a nuanced understanding with links to virtue ethics and post-modern approaches to ethics and subjectivity. The approach I have articulated draws on the phenomenology of Levinas and Heidegger, the Virtue ethics of Baier, and the post-structuralist writing of Michel Foucault. The subject is seen as negotiable, embodied, provisional and able to be transformed in a way that denies essentialism about human beings, their moral status, and the idea of the good. The human being emerges as responsible because, properly, responsive to the context of discourse in which morality becomes articulated. When we import this style of thinking into bioethics we find that it reaches beyond issues of policy or right conduct and allows us to use the biomedical sciences and the clinical world to revise and interrogate our understanding of ourselves and the theoretical foundations of health care ethics.


No previews are good news: using preview search to probe categorical grouping for orientation.
We used the preview search procedure (Watson, D. G., & Humphreys G. W. (1997). Prioritising selection for new objects by top-down attentional inhibition of old objects. Psychological Review, 104, 90-122.) to examine distractor grouping in visual search for categorically-defined targets in the orientation dimension (Wolfe, J. M., Friedman-Hill, S. R., Stewart, M. I., & O'Connell, K. M. (1992). The role of categorization in visual search for orientation. Journal of Experimental Psychology: Human Perception and Performance, 18, 34-49). Participants searched for a relatively steep target presented amongst distractors of two shallow orientations. In a preview condition, the different distractors were presented in different time steps and search was found to be worse than a full-set baseline (Experiment 1). Further experiments determined this was not due to attentional capture by new distractors that were steeper than old items, nor to participants using different search strategies in the preview and full-set baselines. However, there were costs to performance when the old distractor group differed in orientation from the new distractors. We attribute the results to the preview condition disrupting grouping between distractors, with the different distractor groups then competing for selection with the target. An examination of the time-course of the preview effect suggested that grouping and segmentation was fast-acting, and separate from a process such as visual marking, involving the slow suppression of distractors over time. Under asynchronous presentation conditions, preview and new distractors that differ from the target orientation category, can compete rather than cooperate in grouping.


Effect of sensor systems for cow management on milk production, somatic cell count, and reproduction.
To improve management on dairy herds, sensor systems have been developed that can measure physiological, behavioral, and production indicators on individual cows. It is not known whether using sensor systems also improves measures of health and production in dairy herds. The objective of this study was to investigate the effect of using sensor systems on measures of health and production in dairy herds. Data of 414 Dutch dairy farms with (n=152) and without (n=262) sensor systems were available. For these herds, information on milk production per cow, days to first service, first calving age, and somatic cell count (SCC) was provided for the years 2003 to 2013. Moreover, year of investment in sensor systems was available. For every farm year, we determined whether that year was before or after the year of investment in sensor systems on farms with an automatic milking system (AMS) or a conventional milking system (CMS), or whether it was a year on a farm that never invested in sensor systems. Separate statistical analyses were performed to determine the effect of sensor systems for mastitis detection (color, SCC, electrical conductivity, and lactate dehydrogenase sensors), estrus detection for dairy cows, estrus detection for young stock, and other sensor systems (weighing platform, rumination time sensor, fat and protein sensor, temperature sensor, milk temperature sensor, urea sensor, β-hydroxybutyrate sensor, and other sensor systems). The AMS farms had a higher average SCC (by 12,000 cells/mL) after sensor investment, and CMS farms with a mastitis detection system had a lower average SCC (by 10,000 cells/mL) in the years after sensor investment. Having sensor systems was associated with a higher average production per cow on AMS farms, and with a lower average production per cow on CMS farms in the years after investment. The most likely reason for this lower milk production after investment was that on 96% of CMS farms, the sensor system investment occurred together with another major change at the farm, such as a new barn or a new milking system. Most likely, these other changes had led to a decrease in milk production that could not be compensated for by the use of sensor systems. Having estrus detection sensor systems did not improve reproduction performance. Labor reduction was an important reason for investing in sensor systems. Therefore, economic benefits from investments in sensor systems can be expected more from the reduction in labor costs than from improvements in measures of health and production in dairy herds.


Temporomandibular disorders and cutaneous allodynia are associated in individuals with migraine.
The objective of this study was to estimate and contrast the occurrence of ictal and interictal cutaneous allodynia (CA) in individuals with migraine with and without temporomandibular disorders (TMD). Both TMD and CA are common in migraine and may be associated with migraine transformation from episodic into a chronic form. Herein we hypothesize that TMD contributes to the development of CA and to more severe headaches. In a clinic-based sample of individuals with episodic migraine, the presence of TMD was assessed using the research diagnostic criteria for myofascial or mixed (myofascial and arthralgic) TMD. Ictal CA was quantified using the validated Allodynia Symptom Checklist (ASC-12). The ASC-12 measures CA over the preceding month by asking 12 questions about the frequency of allodynia symptoms during headaches. Interictal CA was assessed in the domains of heat, cold and mechanical static allodynia using quantitative sensory testing. Our sample consists of 55 individuals; 40 (73%) had TMD (23 with myofascial TMD and 17 with the mixed type). CA of any severity (as assessed by ASC-12) occurred in 40% of those without TMD (reference group), 86.9% of those with myofascial TMD (P = 0.041, RR = 3.2, 95% CI = 1.5-7.0) and in 82.3% of those with mixed TMD (P = 0.02, RR = 2.5, 95% CI = 1.2-5.3). Individuals with TMD were more likely to have moderate or severe CA associated with their headaches. Interictally (quantitative sensory testing), thresholds for heat and mechanical nociception were significantly lower in individuals with TMD. Cold nociceptive thresholds were not significantly different in migraine patients with and without TMD. TMDs were also associated with change in extra-cephalic pain thresholds. In logistical regression, TMD remained associated with CA after adjusting for aura, gender and age. TMD and CA are associated in individuals with migraine.


Optimization methods for the imputation of missing values in Educational Institutions Data.
The imputation of missing values in the detail data of Educational Institutions is a difficult task. These data contain multivariate time series, which cannot be satisfactory imputed by many existing imputation techniques. Moreover, almost all the data of an Institution are interconnected: the number of graduates is not independent from the number of students, the expenditure is not independent from the staff, etc. In other words, each imputed value has an impact on the whole set of data of the institution. Therefore, imputation techniques for this specific case should be designed very carefully. We describe here the methods and the codes of the imputation methodology developed to impute the various patterns of missing values which appear in similar interconnected data. In particular, a first part of the proposed methodology, called ``trend smoothing imputation'', is designed to impute missing values in time series by respecting the trend and the other features of an Institution. The second part of the proposed methodology, called ``donor imputation'', is designed to impute larger chunks of missing data by using values taken form similar Institutions in order to respect again their size and trend.•Trend smoothing imputation can handle missing subsequences in time series, and is given by a weighted combination of: (a) weighed average of the other available values of the sequence, and (b) linear regression.•Donor imputation can handle full sequence missing in time series. It imputes the Recipient Institution using the values taken from a similar institution, called Donor, selected using optimization criteria.•The values imputed by our techniques should respect the trend, the size and the ratios of each Institution.


Formal and informal care in relation to activities of daily living and self-perceived health among older care-dependent individuals in Norway.
Background. Research about formal care of older home-dwelling people in the Nordic countries is comprehensive, while research on informal care has been less inclusive. Aim. To describe self-reported activities of daily living and perceived health, and to relate them to amount and types of formal and informal care received by a group of care-dependent, home-dwelling older individuals in Norway. Design and methods. A sample consisting of 242 persons aged 75+ years receiving home nursing services. Data were collected by means of structured interviews with questions about activities of daily living (ADL), amount and types of formal and informal care and demographic variables. Descriptive statistics, chi-square test, Mann-Whitney U-test and multiple stepwise regression were used in the analyses. Results. ADL dependency was the only predictor for explaining quantity of home nursing received. Those who received a generous amount of formal care also received a lot of care and support from informal networks. The type of care from the two sources differed. The home nurses performed PADL tasks. While the informal caregivers offered help with IADL tasks. Conclusion. This study of receiving help in this group of older people in Norway shows that formal and informal care resources complement one another.


Tensile properties of the murine ventral vertical midline incision.
In clinical surgery, the vertical midline abdominal incision is popular but associated with healing failures. A murine model of the ventral vertical midline incision was developed in order to study the healing of this incision type. The strength of the wild type murine ventral abdominal wall in the midline was contained within the dermis; the linea alba made a negligible contribution. Unwounded abdominal wall had a downward trend (nonsignificant) in maximal tension between 12 and 29 weeks of age. The incision attained 50% of its final strength by postoperative day 40. The maximal tension of the ventral vertical midline incision was nearly that of unwounded abdominal wall by postwounding day 60; there was no difference in unwounded vs. wounded maximal tension at postwounding day 120. After 120 days of healing, the ventral vertical midline incision in the wild type mouse was not significantly different from age-matched nonwounded controls. About half of the final incisional strength was attained after 6 weeks of healing. The significance of this work was to establish the kinetics of wild type incisional healing in a model for which numerous genotypes and genetic tools would be available for subsequent study.


Infection prevention and control insights from a decade of pathogen whole-genome sequencing.
Pathogen whole-genome sequencing has become an important tool for understanding the transmission and epidemiology of infectious diseases. It has improved our understanding of sources of infection and transmission routes for important healthcare-associated pathogens, including Clostridioides difficile and Staphylococcus aureus. Transmission from known infected or colonized patients in hospitals may explain fewer cases than previously thought and multiple introductions of these pathogens from the community may play a greater a role. The findings have had important implications for infection prevention and control. Sequencing has identified heterogeneity within pathogen species, with some subtypes transmitting and persisting in hospitals better than others. It has identified sources of infection in healthcare-associated outbreaks of food-borne pathogens, Candida auris and Mycobacterium chimera, as well as individuals or groups involved in transmission and historical sources of infection. SARS-CoV-2 sequencing has been central to tracking variants during the COVID-19 pandemic and has helped understand transmission to and from patients and healthcare workers despite prevention efforts. Metagenomic sequencing is an emerging technology for culture-independent diagnosis of infection and antimicrobial resistance. In future, sequencing is likely to become more accessible and widely available. Real-time use in hospitals may allow infection prevention and control teams to identify transmission and to target interventions. It may also provide surveillance and infection control benchmarking. Attention to ethical and wellbeing issues arising from sequencing identifying individuals involved in transmission is important. Pathogen whole-genome sequencing has provided an incredible new lens to understand the epidemiology of healthcare-associated infection and to better control and prevent these infections.


Comparison of Quick Sequential Organ Failure Assessment and Modified Systemic Inflammatory Response Syndrome Criteria in a Lower Middle Income Setting.
Quick Sequential Organ Failure Assessment (qSOFA) is potentially feasible tool to identify risk of deteriorating in the context of infection for to use in resource limited settings. To compare the discriminative ability of qSOFA and a simplified systemic inflammatory response syndrome (SIRS) score to detect deterioration in patients admitted with infection. Observational study conducted at District General Hospital Monaragala, Sri Lanka, utilising bedside available observations extracted from healthcare records. Discrimination was evaluated using area under the receiver operating curve (AUROC). 15,577 consecutive adult ( ≥ 18 years) admissions were considered. Patients classifi ed as having infection per ICD-10 diagnostic coding were included. Both scores were evaluated for their ability to discriminate patients at risk of death or a composite adverse outcome (death, cardiac arrest, intensive care unit [ICU], admission or critical care transfer). 1844 admissions (11.8%) were due to infections with 20 deaths (1.1%), 29 ICU admissions (1.6%), 30 cardiac arrests and 9 clinical transfers to a tertiary hospital (0.5%). Sixty-seven (3.6%) patients experienced at least one event. Complete datasets were available for qSOFA in 1238 (67.14%) and for simplified SIRS (mSIRS) in 1628 (88.29%) admissions. Mean (SD) qSOFA score and mSIRS score at admission were 0.58 (0.69) and 0.66 (0.79) respectively. Both demonstrated poor discrimination for predicting adverse outcome AUROC = 0.625; 95% CI, 0.56-0.69 and AUROC = 0.615; 95% CI, 0.55-0.69 respectively) with no significant difference (p value = 0.74). Similarly, both systems had poor discrimination for predicting deaths (AUROC = 0.685; 95% CI, 0.55-0.82 and AUROC = 0.629; 95% CI, 0.50-0.76 respectively) with no statistically signifi cant difference (p value = 0.31). qSOFA at admission had poor discrimination and was not superior to the bedside observations featured in SIRS. Availability of observations, especially for mentation, is poor in these settings and requires strategies to improve reporting.


Muller's muscle-conjunctival resection for correction of upper eyelid ptosis: relationship between phenylephrine testing and the amount of tissue resected with final eyelid position.
To evaluate the outcome of Müller's muscle-conjunctival resection (MMCR) for correction of upper eyelid ptosis and to explore the relationship between phenylephrine testing, muscle resection, and surgical outcome. Medical records were reviewed for all patients who underwent MMCR at the Jules Stein Eye Institute, Los Angeles, California, from January 1, 1999, through June 30, 2005. Outcome measures were margin reflex distance-1, ptosis correction after instillation of phenylephrine drops, extent of MMCR, ptosis correction, and eyelid symmetry. In 80 patients who underwent 131 MMCR procedures for correction of upper eyelid ptosis, margin reflex distance-1 increased on average by 1.6 mm (P < .001). In 106 patients (81%), eyelid symmetry equal to or less than 1 mm was achieved (P = .02). Phenylephrine testing underestimated the extent of ptosis correction achieved with MMCR. A weak correlation was found between the extent of MMCR and ptosis correction (r = 0.2; P = .04). Müller's muscle-conjunctival resection is effective for ptosis correction in patients with good levator muscle function; good eyelid symmetry is achieved in most patients. Phenylephrine testing underestimated the ptosis correction achieved with MMCR by 40%. The relationship between MMCR and ptosis correction is complex.


Effect of fluoxetine on a neuronal, voltage-dependent potassium channel (Kv1.1).
1. Fluoxetine (Prozac) is widely used as an antidepressant drug and is assumed to be a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI). Claims that its beneficial psychotropic effects extend beyond those in treatment of depression have drawn clinical and popular attention to this compound, raising the question of whether there is anything exceptional about the supposed selective actions. 2. We have used the voltage clamp technique to study the effect of fluoxetine on a neuronal, voltage-dependent potassium (K+) channel (RCK1; Kv1.1), expressed in p6nopus laevis oocytes. This channel subunit is abundantly expressed in the central nervous system and K+ channels containing this subunit are involved in the repolarization process of many types of neurones. 3. Blockade of the K+ currents by fluoxetine was found to be use- and dose-dependent. Wash-out of this compound could not be achieved. Fluoxetine did not affect the ion selectivity of this K+ channel, as the reversal potential was unaltered. 4. Slowing of both activation and deactivation kinetics of the channel by fluoxetine was observed, including tail current crossover upon repolarization. 5. Hodgkin-Huxley type of models and more generalized Markov chain models were used to fit the kinetics of the data. Based upon a Markov kinetic scheme, our data can be interpreted to mean that blockade of fluoxetine consists of two components: a voltage-independent occurring in the last closed, but available state of the channel, and a voltage-dependent occurring in the open state. 6. This study describes the first biophysical working model for the mechanism of action of fluoxetine on a neuronal, voltage-dependent K+ channel, RCK1. Although this channel is not very potently blocked by fluoxetine when expressed in oocytes, this study may help us to understand some of the clinical symptoms seen with elevated serum concentrations of this SSRI.


Cr(OH)3(s) oxidation induced by surface catalyzed Mn(II) oxidation.
We examined the feasibility of Cr(OH)3(s) oxidation mediated by surface catalyzed Mn(II) oxidation under common groundwater pH conditions as a potential pathway of natural Cr(VI) contaminations. Dissolved Mn(II) (50 μM) was reacted with or without synthesized Cr(OH)3(s) (1.0 g/L) at pH 7.0-9.0 under oxic or anoxic conditions. Homogeneous Mn(II) oxidation by dissolved O2 was not observed at pH ≤ 8.0 for 50 days. At pH 9.0, by contrast, dissolved Mn(II) was completely removed within 8 days and precipitated as hausmannite. When Cr(OH)3(s) was present, this solid was oxidized and released substantial amounts of Cr(VI) as dissolved Mn(II) was added into the suspension at pH ≥ 8.0 under oxic conditions. Production of Cr(VI) was attributed to Cr(OH)3(s) oxidation by a newly formed Mn oxide via Mn(II) oxidation catalyzed on Cr(OH)3(s) surface. XANES results indicated that this surface-catalyzed Mn(II) oxidation produced a mixed valence Mn(III/IV) solid phase. Our results suggest that toxic Cr(VI) can be naturally produced via Cr(OH)3(s) oxidation coupled with the oxidation of dissolved Mn(II). In addition, this study evokes the potential environmental hazard of sparingly soluble Cr(OH)3(s), which has been considered the most common and a stable remediation product of Cr(VI) contamination.


Coating of meso-porous metallic membranes with oriented channel-like fine pores by pulsed laser deposition.
There is increasing demand to functionalize meso- and nanoporous materials by coating and make the porous substrate biocompatible or environmentally friendly. However, coating on a meso-porous substrate poses great challenges, especially if the pore aspect ratio is high. We adopted the pulsed laser deposition (PLD) method to coat Ni(3)Al-based meso-porous membranes, which were fabricated from a single-crystal Ni-based superalloy by a unique selective phase dissolution technique. These membranes were about 250 µm thick and had channel-like pores (∼200 nm wide) with very high aspect ratio. Two different coating materials, i.e. diamond-like carbon (DLC) and titanium, were used to coat these membranes. High energy C or Ti ions, produced in the plasma plume by the PLD process, penetrated the channel-like pores and deposited coatings on the pore walls deep inside the membrane. The thickness and the quality of coatings on the pore walls were examined using the dual-beam system. The coating thickness, of the order of 50 nm, was adherent to the pore walls and was quite uniform at different depths. The carbon and the Ti deposition behaved quite similarly. The preliminary experiments showed that the PLD is an adequate method for coating fine open cavities of complex geometry. Simulations based on stopping and the range of ions in matter (SRIM) calculations helped in understanding the deposition processes on pore walls at great depths.


Protein self-entanglement modulates successful folding to the native state: A multi-scale modeling study.
The computer-aided investigation of protein folding has greatly benefited from coarse-grained models, that is, simplified representations at a resolution level lower than atomistic, providing access to qualitative and quantitative details of the folding process that would be hardly attainable, via all-atom descriptions, for medium to long molecules. Nonetheless, the effectiveness of low-resolution models is itself hampered by the presence, in a small but significant number of proteins, of nontrivial topological self-entanglements. Features such as native state knots or slipknots introduce conformational bottlenecks, affecting the probability to fold into the correct conformation; this limitation is particularly severe in the context of coarse-grained models. In this work, we tackle the relationship between folding probability, protein folding pathway, and protein topology in a set of proteins with a nontrivial degree of topological complexity. To avoid or mitigate the risk of incurring in kinetic traps, we make use of the elastic folder model, a coarse-grained model based on angular potentials optimized toward successful folding via a genetic procedure. This light-weight representation allows us to estimate in silico folding probabilities, which we find to anti-correlate with a measure of topological complexity as well as to correlate remarkably well with experimental measurements of the folding rate. These results strengthen the hypothesis that the topological complexity of the native state decreases the folding probability and that the force-field optimization mimics the evolutionary process these proteins have undergone to avoid kinetic traps.


The cost-effectiveness of typhoid Vi vaccination programs: calculations for four urban sites in four Asian countries.
The burden of typhoid fever remains high in impoverished settings, and increasing antibiotic resistance is making treatment costly. One strategy for reducing the typhoid morbidity and mortality is vaccination with the Vi polysaccharide vaccine. We use a wealth of new economic and epidemiological data to evaluate the cost-effectiveness of Vi vaccination against typhoid in sites in four Asian cities: Kolkata (India), Karachi (Pakistan), North Jakarta (Indonesia), and Hue (Vietnam). We report results from both a societal as well as a public sector financial perspective. Baseline disease burden estimates in the four areas are: 750 cases per year in two Kolkata neighborhoods (pop 185,000); 84 cases per year in the city of Hue (pop 280,000); 298 cases per year in two sub-districts in North Jakarta (pop 161,000), and 538 cases per year in three squatter settlements in Karachi (pop 102,000). We estimate that a vaccination program targeting all children (2-14.9) would prevent 456, 158, and 258 typhoid cases (and 4.6, 1.6, and 2.6 deaths), and avert 126, 44, and 72 disability-adjusted life years (DALYs) over 3 years in Kolkata, North Jakarta and Karachi, respectively. The net social costs would be US$160 and US$549, per DALY averted in Kolkata and North Jakarta, respectively. These programs, along with a similar program in Karachi, would be considered "very cost-effective" (e.g. costs per DALY averted less than per capita gross national income (GNI)) under a wide range of assumptions. Community-based vaccination programs that also target adults in Kolkata and Jakarta are less cost-effective because incidence is lower in adults than children, but are also likely to be "very cost-effective". A program targeting school-aged children in Hue, Vietnam would prevent 21 cases, avert 6 DALYs, and not be cost-effective (US$3779 per DALY averted) because of the low typhoid incidence there.


Selective export of human GPI-anchored proteins from the endoplasmic reticulum.
Selective export of transmembrane proteins from the endoplasmic reticulum (ER) relies on recognition of cytosolic-domain-localized transport signals by the Sec24 subunit of the COPII vesicle coat. Human cells express four Sec24 isoforms, termed Sec24A, Sec24B, Sec24C and Sec24D that are differentially required for selective, signal-mediated ER export of transmembrane proteins. By contrast, luminally exposed glycosylphosphatidylinositol (GPI)-anchored membrane proteins cannot bind directly to Sec24 and must either use membrane-spanning cargo receptors or alternative mechanisms for ER export. Little is known about the mechanism underlying export of GPI-anchored proteins from the ER in higher eukaryotes. Using siRNA-based silencing, we identified that ER-to-Golgi transport of the human GPI-anchored protein CD59 requires Sec24, with preference for the Sec24C and Sec24D isoforms, and the recycling transmembrane protein complex p24-p23 that exhibited the same Sec24C-Sec24D isoform preference for ER export. Co-immunoprecipitation indicated unprecedented physical interaction of CD59 as well as a GFP-folate-receptor-GPI-anchor hybrid with a p24-p23 complex. Density gradient centrifugation revealed co-partitioning of CD59 and p24-p23 into biosynthetically early lipid raft fractions, and CD59 transport to the Golgi was cholesterol dependent. The results suggest that the 24p-23p complex acts as a cargo receptor for GPI-anchored proteins by facilitating their export from the ER in a Sec24-isoform-selective manner involving lipid rafts as early sorting platforms.


Repair of residual aortic dissections with frozen elephant trunk technique.
In this study, we present our mid-term results of reoperation with the frozen elephant trunk procedure due to patent false lumen-related complications in patients previously undergoing supracoronary aortic repair for acute type A aortic dissection. Between January 2013 and September 2018, a total of 23 patients (17 males, 6 females; mean age 51.5±9.7 years; range, 30 to 67 years) who underwent ascending aortic replacement due to type A aortic dissection and, later, frozen elephant trunk procedure for residual distal dissection were included. For diagnostic purposes and follow-up, computed tomography angiography was performed in all patients, and both re-entry and aortic diameters were evaluated. Echocardiography was used to evaluate cardiac function and valve pathologies. The Ishimaru zone 0 (n=11, 47.8%), Ishimaru zone 1 (n=1, 4.3%), Ishimaru zone 2 (n=4, 17.4%), and Ishimaru zone 3 (n=7, 30.4%) were used for frozen elephant trunk stent graft fixation. The mean duration of cardiopulmonary bypass and antegrade selective cerebral perfusion was 223.9±71.2 min and 88.9±60.3 min, respectively. In-hospital mortality was 13%, while there was one (4.3%) aortic-related death and four (17.4%) re-interventions during follow-up. Early repair should be considered in the presence of persistent dissections due to alarmingly high mortality rates of reoperations. Reoperation with the frozen elephant trunk procedure has acceptable results and the decision of the procedure to be performed should be based on preoperative risk factors of the patient.


A critical SiOx layer on Si porous structures to construct highly-reversible anode materials for lithium-ion batteries.
A novel Si/SiOx porous structure with a SiOx coating layer of varying thicknesses was prepared via a simple annealing and acid washing process. When used as an anode material for lithium-ion batteries, the Si/SiOx porous structure with an ∼9 nm SiOx coating layer demonstrates significantly improved electrochemical performance with a high reversible discharge capacity of over 915 mA h g-1 after 500 long cycles at 1 A g-1. The lithiation mechanism of a SiOx layer of different thicknesses has also been investigated.


Indications for Detection, Completion, and Retention Rates of Small Bowel Capsule Endoscopy Based on the 10-Year Data from the Korean Capsule Endoscopy Registry.
Capsule endoscopy (CE) is widely used. However, CE has limitations including incomplete examination, inadequate bowel preparation, and retention. The aim of this study was to estimate the indications for and detection, completion, and retention rates of small intestine CE based on the 10-year data from the Korean Capsule Endoscopy Registry. Twenty-four hospitals participated in this study. Clinical information, such as reasons for CE, method and quality of bowel preparation, and incomplete examination and capsule retention rates, was collected and analyzed. A total of 2,914 CEs were registered. The most common reason for CE was obscure gastrointestinal bleeding (59%). Significant lesions were detected in 66% of cases. Positive CE diagnosis occurred in 63% of cases. The preparation method did not significantly affect the quality of bowel preparation for CE. The overall incomplete rate was 33%, and was high in the elderly and those with poor bowel preparation. Capsule retention was 3% and high in patients with small bowel tumors and Crohn's disease and in children under 10 years of age. CE is a valuable technique; while the overall detection rate is high, incompletion and retention rates are also relatively high. CE should be carefully considered in the elderly and children less than 10 years of age, as well as in patients with small bowel tumors and Crohn's disease.


Shear ordering in thin films of spherical block copolymer.
We have investigated shear-induced alignment of a bilayer of spherical diblock copolymer micelles within thin films using molecular dynamics simulations at two different levels of coarse-graining. At the microscopic level, the copolymers are modeled as bead and spring chains with specific interaction potentials which produce strongly segregated spherical micelles. The simulations qualitatively reveal that long-range shear-induced ordering of hexagonally arranged micelles arises because of the tendency of micelles to pursue trajectories of minimum frictional resistance against micelles in the opposing layer. This influences their alignment in the direction of shear without them breaking apart and reforming within the time scale of the simulations. As observed in experiments, the ordering is shown to be very sensitive to the film thickness and shearing rates. To access larger lengths and longer time scales, we further coarse-grain our system to a mesoscopic level where an individual micelle is represented by a spherical particle, which interacts with other micelles through an effective potential obtained from the microscopic simulations. This approach enables us to follow the time evolution of global order from locally ordered domains. An exponentially fast growth of the orientational correlation length of the hexagonal pattern at early times, followed by a crossover to linear growth, is found in the presence of shear, in contrast to the much slower power-law scalings observed in experiments without shear.


Prolactin receptor gene expression in lymphoid cells.
To understand the role of pituitary prolactin (PRL) and its receptor (PRL-R) in the growth and differentiation of lymphoid cells, PRL-R gene expression was analyzed in various lymphoid tissues and in a rat T lymphoma cell line, Nb2, which requires PRL for growth. The technique of reverse transcription coupled to polymerase chain reaction (RT-PCR) was used to detect the low abundance PRL-R transcripts. Within 30 min to 1 h, PRL stimulates a rapid but transient increase in PRL-R mRNA levels in Nb2 T cells. By 4 h, PRL-R mRNA returned to near basal levels and then gradually declined to a new steady-state level by 12 h. Significant increases in receptor RNA levels were observed in the presence of protein synthesis inhibitors, which suggests that PRL-R mRNA levels are under negative regulation. PRL-R gene expression was also demonstrated in normal mouse thymocytes, splenocytes, and in several lymphoid cell lines. The expression of the PRL-R gene in stimulated lymphoid cells provides additional evidence for the role of PRL as an immunomodulatory molecule.


Surgical reduction of adipose tissue in the male Sprague-Dawley rat.
The lipostatic theory of regulation of adipose tissue mass was tested by a method for surgical reduction (adipectomy) of 24% of the total body fat of nonobese adult Sprague-Dawley rats, as judged from carcass analyses. The reduction persisted during an observation period of 12 wk without any evidence of altered food intake, weight gain, or compensatory hypertrophy or hyperplasia of adipose tissue compared with sham-operated controls. No changes were found in serum free fatty acids, glycerol, triglycerides, cholesterol, or insulin between adipectomized and control animals, implying an intact quantitative function of the remaining adipose tissue. It is concluded that the size of the adipocytes rather than the number is important for a presumed lipostatic regulation of adipose tissue mass in the adult male Sprague-Dawley rat.


Integrating population, health, and environment programs with contraceptive distribution in rural Ethiopia: a qualitative case study.
In rural Ethiopia, environmental degradation and a shortage of arable land impose a major toll on the population. Population, health, and environment (PHE) programs, such as that of the Ethio-Wetlands and Natural Resources Association (EWNRA), have evolved to address these issues. This article examines the community-based distribution (CBD) of family planning commodities in rural Ethiopia through EWNRA's large, multisectoral PHE program. Participants indicated that the integrated program encouraged acceptance of family planning and reduced geographic barriers to access. Through peer education and collaboration across government ministries, EWNRA leveraged integrated population-environment messages to garner support for its network of CBD providers. These integration strategies are a model for PHE programs worldwide, especially amid the global response to climate change. Because of the complex nature of PHE organizations, researchers often find it difficult to effectively document and evaluate their programs. With this in mind, we propose a framework to assess PHE integration.


Immunizations in children with inflammatory bowel disease treated with immunosuppressive therapy.
The vast majority of patients with inflammatory bowel disease (IBD) will receive immunosuppressive therapy at some point for their disease, whether for the short term (such as a course of corticosteroids) or long term (such as maintenance therapy with immunomodulators or biologics). The systemic immunosuppression places patients at increased risk for infections. Therefore, it is important that patients are up-to-date with immunizations to minimize vaccine-preventable infections. However, the literature shows that the rate of immunization in patients with IBD is low. Ideally, the vaccination status is checked at diagnosis, and patients are immunized with the vaccines they need. Drawing titers is helpful in cases in which vaccination history is unclear or to confirm that titers are at an adequate level in cases in which patients have been vaccinated. Current guidelines recommend that patients with IBD follow the same routine immunization schedule as healthy children, but patients should not be administered live vaccines if they are receiving immunosuppressive therapy. Therefore, it is ideal to administer any necessary vaccinations as early as possible, prior to starting immunosuppressive therapy. Patients may receive inactivated vaccines regardless of immunosuppressive status. The IBD literature suggests that inactivated vaccines are safe and do not worsen disease activity. In general, patients with IBD mount an immune response to vaccines, but the response may be lower if patients are receiving immunosuppressive therapy, especially tumor necrosis factor inhibitors.


The association between surgeon case volume and hospitalization costs in free flap oral cancer reconstruction operations.
Although inverse volume-cost relationships have been reported for many major surgical procedures, such relationships remain unexplored in the field of microsurgery for oral cancer reconstruction. This study therefore was conducted to confirm, or refute, the hypothesis that higher surgeon volume is associated with better economic outcomes in free-flap operations for oral cancer reconstruction. From a population-based data set covering the years 2002 to 2003, the authors selected a total of 2325 oral cancer patients who had undergone free-flap operations. These were then divided into four roughly equivalent surgeon volume groups consisting of less than or equal to 12 cases (low volume), 13 to 29 cases (medium volume), 30 to 65 cases (high volume), and greater than or equal to 66 cases (very high volume). Hierarchical linear regression analysis was subsequently performed to examine the relationship between surgeon case volume and hospitalization costs. The mean hospitalization costs among the 2325 patients were $9879 (all costs are given in U.S. dollars); however, after adjusting for physician, hospital, and patient characteristics, the costs per patient for low-volume surgeons were found to be $995 (p = 0.001) higher than those for high-volume surgeons, and $2138 (p < 0.001) higher than those for very-high-volume surgeons. The difference between medium- and low-volume surgeons was not significant. The authors conclude that after adjusting for physician, hospital, and patient characteristics, low-volume surgeons performing free-flap operations for oral cancer reconstruction incurred significantly higher costs per patient than high-volume or very-high-volume surgeons.


Implementation of the Community Health Assistant (CHA) Cadre in Zambia: A Process Evaluation to Guide Future Scale-Up Decisions.
Universal health coverage requires an adequate health workforce, including community health workers (CHWs) to reach rural communities. To improve healthcare access in rural areas, in 2010 the Government of Zambia implemented a national CHW strategy that introduced a new cadre of healthcare workers called community health assistants (CHAs). After 1 year of training the pilot class of 307 CHAs deployed in September 2012. This paper presents findings from a process evaluation of the barriers and facilitators of implementation of the CHA pilot, along with how evidence was used to guide ongoing implementation and scale-up decisions. Qualitative inquiry was used to assess implementation during the first 6 months of the program rollout, with 43 in-depth individual and 32 small group interviews across five respondent types: CHAs, supervisors, volunteer CHWs, community members, and district leadership. Potential 'implementation moderators' were explored using deductive coding and thematic analysis of participant perspectives on community acceptance of CHAs, supervision support mechanisms, and coordination with volunteer CHWs, and health system integration of a new cadre. Community acceptance of CHAs was generally high, but coordination between CHAs and existing volunteer CHWs presented some challenges. The supervision support system was found to be inconsistent, limiting assurance of consistent quality care delivered by CHAs. Underlying health system weaknesses regarding drug supply and salary payments furthermore hindered incorporation of a new cadre within the national health system. Recommendations for implementation and future scale based on the process evaluation findings are discussed.


Effects of Motility and Adsorption Rate Coefficient on Transport of Bacteria through Saturated Porous Media.
Three strains of Pseudomonas fluorescens with different motility rates and adsorption rate coefficients were injected into porous-medium reactors packed with l-mm-diameter glass spheres. Cell breakthrough, time to peak concentration, tailing, and cell recovery were measured at three interstitial pore velocities (higher than, lower than, and much lower than the maximal bacterial motility rate). All experiments were done with distilled water to reduce the effects of growth and chemotaxis. Contrary to expectations, motility did not result in either early breakthrough or early time to peak concentration at flow velocities below the motility rate. Bacterial size exclusion effects were shown to affect breakthrough curve shape at the very low flow velocity, but no such effect was seen at the higher flow velocity. The tendency of bacteria to adsorb to porous-medium surfaces, as measured by adsorption rate coefficients, profoundly influenced transport characteristics. Cell recoveries were shown to be correlated with the ratio of advective to adsorptive transport in the reactors. Adsorption rate coefficients were found to be better predictors of microbial transport phenomena than individual characteristics, such as size, motility, or porous-medium hydrodynamics.


Analysis of first-pass and delayed contrast-enhancement patterns of dysfunctional myocardium on MR imaging: use in the prediction of myocardial viability.
The purpose of the study was to analyze first-pass and delayed contrast-enhancement patterns of dysfunctional myocardial regions on MR imaging after injection of gadopentetate dimeglumine to predict myocardial viability in patients with coronary artery disease. Twelve patients with wall motion abnormalities and related coronary artery disease revealed by conventional coronary angiography underwent MR imaging at 1.5-T before and 3 months after revascularization therapy. Short-axis images were acquired using a cine gradient-echo sequence. Each slice was divided into eight segments. Overall, 73 segments with impaired contractility were imaged during the first-pass and 14 +/- 2 min after injection of 0.05-mmol/kg gadopentetate dimeglumine at a flow of 3 ml/sec using a T1-weighted turbo fast low-angle shot sequence. Improved systolic wall thickening 3 months after revascularization served as the criterion of viability. At study entry, 26 dysfunctional segments showed delayed hyperenhancement compared with the adjacent functional segments within the same slice, and 47 did not reveal hyperenhancement. After revascularization, 25 (96%) of the 26 hyperenhanced segments did not recover function, whereas 39 (83%) of the 47 segments without hyperenhancement showed mechanical improvement. Segment-related sensitivity and specificity for the correlation of lack of delayed hyperenhancement with myocardial viability were 39 (98%) of 40 and 25 (76%) of 33, respectively. Hypoenhancement during first-pass did not serve as a reliable criterion of viability. Evidence of delayed hyperenhancement of dysfunctional myocardium may be used to predict lack of mechanical improvement or nonviability, whereas the lack of hyperenhancement can be correlated with improvement of regional contractility or viability after revascularization.


Muscle power and function two years after unicompartmental knee replacement.
Unicompartmental knee replacement (UKR) is a commonly performed procedure, suitable for one in four patients requiring knee replacement for end-stage osteoarthritis. Recovery and return of function is quicker than with total knee replacement (TKR), but little information is known about the recovery of muscle power. We prospectively studied a cohort of forty four patients undergoing medial UKR to document their functional recovery and leg extensor power. Muscle power was measured using a Leg Extensor Power rig preoperatively and at 1 and 2 years after surgery. Function was self reported using the Oxford Knee Score (OKS) and Tegner Activity Scale (TAS). At 1 year all patients had made significant improvements on all functional measures, with a mean gain in OKS of 15.9 and TAS of 0.84. There were also significant increases in leg extensor power (LEP) of both legs. The mean change in LEP of the operated leg at 1 year was 0.50 W/kg and the non-operated leg was 0.10 W/kg. Between 1 and 2 years there were very slight improvements in strength in both legs, but these were not significant. Compared with healthy age matched normative values, the UKR LEP values at 2 years after surgery were decreased. The recovery of strength and function following UKR had stabilised by 1 year and during the following year further improvements were minimal.


Comparative Genomics of Early-Diverging Mushroom-Forming Fungi Provides Insights into the Origins of Lignocellulose Decay Capabilities.
Evolution of lignocellulose decomposition was one of the most ecologically important innovations in fungi. White-rot fungi in the Agaricomycetes (mushrooms and relatives) are the most effective microorganisms in degrading both cellulose and lignin components of woody plant cell walls (PCW). However, the precise evolutionary origins of lignocellulose decomposition are poorly understood, largely because certain early-diverging clades of Agaricomycetes and its sister group, the Dacrymycetes, have yet to be sampled, or have been undersampled, in comparative genomic studies. Here, we present new genome sequences of ten saprotrophic fungi, including members of the Dacrymycetes and early-diverging clades of Agaricomycetes (Cantharellales, Sebacinales, Auriculariales, and Trechisporales), which we use to refine the origins and evolutionary history of the enzymatic toolkit of lignocellulose decomposition. We reconstructed the origin of ligninolytic enzymes, focusing on class II peroxidases (AA2), as well as enzymes that attack crystalline cellulose. Despite previous reports of white rot appearing as early as the Dacrymycetes, our results suggest that white-rot fungi evolved later in the Agaricomycetes, with the first class II peroxidases reconstructed in the ancestor of the Auriculariales and residual Agaricomycetes. The exemplars of the most ancient clades of Agaricomycetes that we sampled all lack class II peroxidases, and are thus concluded to use a combination of plesiomorphic and derived PCW degrading enzymes that predate the evolution of white rot.


On perfect cloaking.
We show in principle how to cloak a region of space to make its contents classically invisible or transparent to waves. The method uses sensors and active sources near the surface of the region, and could operate over broad bandwidths. A general expression is given for calculating the necessary sources, and explicit, fully causal simulations are shown for scalar waves. Vulnerability to broad-band probing is discussed, and any active scheme should detectable by a quantum probe, regardless of bandwidth.


Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations.
Germline aryl hydrocarbon receptor interacting protein (AIP) gene mutations confer a predisposition to pituitary adenoma (PA), predominantly GH-secreting (GH-PA). As recent data suggest a role for AIP in the pathogenesis of sporadic GH-PA and their response to somatostatin analogues (SSA), the expression of AIP and its partner, aryl hydrocarbon receptor (AHR), was determined by semiquantitative immunohistochemistry scoring in 62 sporadic GH-PA (37 treated with SSA preoperatively). The influence of Gsp status was studied in a subset of tumours (n=39, 14 Gsp(+)) and six GH-PA were available for primary cultures. AIP and AHR were detected in most cases, with a positive correlation between AIP and cytoplasmic AHR (P=0.012). Low AIP expression was significantly more frequent in untreated vs SSA-treated tumours (44.0 vs 20.5%, P=0.016). AHR expression or localisation did not differ between the two groups. Similarly, in vitro octreotide induced a median twofold increase in AIP expression (range 1.2-13.9, P=0.027) in GH-PA. In SSA-treated tumours, the AIP score was significantly higher in the presence of preoperative IGF1 decrease or tumour shrinkage (P=0.008 and P=0.014 respectively). In untreated tumours, low AIP expression was significantly associated with invasiveness (P=0.028) and suprasellar extension (P=0.019). The only effect of Gsp status was a significantly lower nuclear AHR score in Gsp(+) vs Gsp(-) tumours (P=0.025), irrespective of SSA. In conclusion, AIP is involved in the aggressiveness of sporadic GH-PA, regardless of Gsp status, and AIP up-regulation in SSA-treated tumours is associated with a better preoperative response, with no clear role for AHR.


Prognostic value of nonangiogenic and angiogenic growth patterns in non-small-cell lung cancer.
An essential prerequisite of nonangiogenic growth appears to be the ability of the tumour to preserve the parenchymal structures of the host tissue. This morphological feature is visible on a routine tissue section. Based on this feature, we classified haematoxylin and eosin-stained tissue sections from 279 patients with non-small-cell lung cancer into three growth patterns: destructive (angiogenic; n=196), papillary (intermediate; n=38) and alveolar (nonangiogenic; n=45). A Cox multiple regression model was used to test the prognostic value of growth patterns together with other relevant clinicopathological factors. For overall survival, growth pattern (P=0.007), N-status (P=0.001), age (P=0.020) and type of operation (P=0.056) were independent prognostic factors. For disease-free survival, only growth pattern (P=0.007) and N-status (P<0.001) had an independent prognostic value. Alveolar (hazard ratio=1.825, 95% confidence interval=1.117-2.980, P=0.016) and papillary (hazard ratio=1.977, 95% confidence interval=1.169-3.345, P=0.011) growth patterns were independent predictors of poor prognosis. The proposed classification has an independent prognostic value for overall survival as well as for disease-free survival, providing a possible explanation for survival differences of patients in the same disease stage.


First Report of Crown Gall, Caused by Agrobacterium tumefaciens on Soapberry (Sapindus delavayi) in China.
Soapberry (Sapindus delavayi (Franch.) Radlk.,) plants are widely grown as shade trees in the subtropical to tropical regions of China. In July 2011, large, aerial galls were observed on the above-ground trunks of 5-year-old soapberry plants in two commercial nursery gardens located in Zhejiang Province. Disease incidence was estimated to be 75%. The galls varied in weight from 2 to 24 g and in texture from soft and spongy to hard, and in some cases, the galls completely girdled the trunk. The trees with galls exhibited poor growth compared with healthy trees. Isolations from the grinded and macerated galls yielded nearly pure white, circular, and glistening bacterial colonies on Roy Sauer medium (2). Six random colonies from different galls were selected for bacterial identification, and showed the same morphological, physiological, and biochemical characters and 16S rDNA sequences. All six isolates (isolate SD01 to SD06) were gram negative, rod-shaped bacteria. Carbon source utilization testing with the Biolog GN Bacterial Identification System (version 3.50) confirmed the bacteria as Agrobacterium tumefaciens with a similarity of 0.90. The most-parsimonious tree from the maximum parsimony analysis (PHYLIP package, version 3.68, 500 replicates) of bacterial 16S rDNA gene sequences showed that A. tumefaciens SD01 (GenBank Accession No. JX997939) clustered phylogenetically most closely (99.5% similarity) with A. tumefaciens C58 (AE007870.2). Pathogenicity was confirmed by injecting 3- to 5-week old tomato and sunflower plants and 2-year-old soapberry with approximately 5 μl of the bacterial suspension (108 CFU/ml) in sterile, distilled water. Sterile distilled water was used as a negative control. Ten plants of each treatment were inoculated. Inoculated plants were then transferred to a greenhouse at 25°C. Typical tumors developed at the inoculation sites on tomatoes and sunflower plants 3 weeks after inoculation and on soapberry 6 weeks after inoculation. No symptoms were observed on the control plants. The bacteria that were readily reisolated from the inoculated plants exhibited the same morphological, physiological characters and 16S rDNA sequence as the original culture and were confirmed as A. tumefaciens, fulfilling Koch's postulates. A. tumefaciens is endemic to China and has a very wide host range (1). However, crown gall of soapberry has never been found in China and other countries. To our knowledge, this is the first report of A. tumefaciens on soapberry plants in China. References: (1) M. A. Escobar and A. M. Dandekar. Trends Plant Sci. 8:380, 2003. (2) L. W. Moore et al. Page 17 in: Laboratory Guide for Identification of Plant Pathogenic Bacteria. 3rd ed. N. W. Schaad et al., eds. The American Phytopathological Society, St. Paul, MN, 2001.


Epidemiological and clinical characteristics of community-acquired severe sepsis and septic shock: a prospective observational study in 12 university hospitals in Korea.
A prospective multicenter observational study was performed to investigate the epidemiology and outcomes of community-acquired severe sepsis and septic shock. Subjects included 1,192 adult patients admitted to the 22 participating intensive care units (ICUs) of 12 university hospitals in the Korean Sepsis Registry System from April, 2005 through February, 2009. Male accounted for 656 (55%) patients. Mean age was 65.0 ± 14.2 yr. Septic shock developed in 740 (62.1%) patients. Bacteremia was present in 422 (35.4%) patients. The 28-day and in-hospital mortality rates were 23.0% and 28.0%, respectively. Men were more likely to have comorbid illnesses and acute organ dysfunctions, and had higher mortality and clinical severity compared to women. While respiratory sources of sepsis were common in men, urinary sources were predominant in women. In the multivariate logistic regression analysis, cancer (odds ratio 1.89; 95% confidence interval 1.13-3.17), urinary tract infection (0.25; 0.13-0.46), APACHE II score (1.05; 1.02-1.09), SOFA score on day 1 (1.13; 1.06-1.21) and metabolic dysfunction (2.24, 1.45-3.45) were independent clinical factors for gender-related in-hospital mortality. This study provided epidemiological and clinical characteristics of community-acquired severe sepsis and septic shock in ICUs in Korea, and demonstrated the impact of clinical factors on gender difference in mortality.


Dietary fish oil reduces systemic inflammation and ameliorates sepsis-induced liver injury by up-regulating the peroxisome proliferator-activated receptor gamma-mediated pathway in septic mice.
This study investigated the effect of dietary fish oil on systemic inflammation and hepatic injury in mice with polymicrobial sepsis. Male ICR mice were assigned to a control group (C, n=30) and a fish oil group (FO, n=30). Mice in the C group were fed a semi-purified diet with 10% soybean oil, and those in the FO group were fed a fish oil diet (2.5% fish oil+7.5% soybean oil; w/w). Three weeks later, sepsis was induced by cecal ligation and puncture (CLP), and mice were sacrificed at 0, 6 and 24 h after CLP, respectively. Results showed that compared with C group, the FO group had lower plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and nitrite at 6 and 24 h after CLP. Also, peritoneal lavage fluid concentrations of TNF-α and prostaglandin (PG) E2 were significantly lower at 24 h in the FO than in the C group. The FO group had lower myeloperoxidase activities at 6 h after CLP in various organs. Plasma aminotransferase and alanine aminotransferase activities revealed significantly decreased in the FO group. The DNA-binding activity of peroxisome proliferators-activated receptor gamma (PPARγ) and mRNA expression of I kappaB alpha (IκBα) were up-regulated while nuclear factor (NF)-κB p65 DNA-binding activity, inducible nitric oxide synthase protein expression and the concentration of nitrotyrosine were significantly decreased in the FO group in liver after CLP. These results indicate that dietary fish oil administration may attenuate systemic inflammation and up-regulate hepatic PPARγ DNA-binding activity, which may consequently have ameliorated liver injury in these septic mice.


A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response.
The Hippo pathway is an evolutionarily conserved regulator of organ size and tumorigenesis that negatively regulates cell growth and survival. Here we report that Yes-associated protein (YAP), the terminal effector of the Hippo pathway, interacts with FoxO1 in the nucleus of cardiomyocytes, thereby promoting survival. YAP and FoxO1 form a functional complex on the promoters of the catalase and manganese superoxide dismutase (MnSOD) antioxidant genes and stimulate their transcription. Inactivation of YAP, induced by Hippo activation, suppresses FoxO1 activity and decreases antioxidant gene expression, suggesting that Hippo signalling modulates the FoxO1-mediated antioxidant response. In the setting of ischaemia/reperfusion (I/R) in the heart, activation of Hippo antagonizes YAP-FoxO1, leading to enhanced oxidative stress-induced cell death through downregulation of catalase and MnSOD. Conversely, restoration of YAP activity protects against I/R injury. These results suggest that YAP is a nuclear co-factor of FoxO1 and that the Hippo pathway negatively affects cardiomyocyte survival by inhibiting the function of YAP-FoxO1.


A longitudinal investigation of maternal influences on the development of child hostile attributions and aggression.
Aggression in children is associated with an enhanced tendency to attribute hostile intentions to others. However, limited information is available regarding the factors that contribute to the development of such hostile attribution tendencies. We examined factors that contribute to individual differences in child hostile attributions and aggression, focusing on potential pathways from maternal hostile attributions via negative parenting behavior. We conducted a longitudinal study of 98 mothers and children (47 male, 51 female), recruited from groups experiencing high and low levels of psychosocial adversity. Maternal hostile attributions, observed parenting, and child behaviour were assessed at 18 months and 5 years child age, and child hostile attributions were also examined at 5 years. Independent assessments of maternal and child processes were utilized where possible. Analyses provided support for a direct influence of maternal hostile attributions on the development of child hostile attributions and aggressive behaviour. Maternal hostile attributions were also associated with negative parenting behaviour, which in turn influenced child adjustment. Even taking account of possible parenting influences and preexisting child difficulties, hostile attributions in the mother showed a direct link with child aggression at 5 years. Maternal hostile attributions were themselves related to psychosocial adversity. We conclude that maternal hostile attributions are prevalent in high-risk samples and are related to less optimal parenting behaviour, child hostile attributions, and child aggression. Targeting hostile maternal cognitions may be a useful adjunct to parenting programs.


Quantitative social science. A network framework of cultural history.
The emergent processes driving cultural history are a product of complex interactions among large numbers of individuals, determined by difficult-to-quantify historical conditions. To characterize these processes, we have reconstructed aggregate intellectual mobility over two millennia through the birth and death locations of more than 150,000 notable individuals. The tools of network and complexity theory were then used to identify characteristic statistical patterns and determine the cultural and historical relevance of deviations. The resulting network of locations provides a macroscopic perspective of cultural history, which helps us to retrace cultural narratives of Europe and North America using large-scale visualization and quantitative dynamical tools and to derive historical trends of cultural centers beyond the scope of specific events or narrow time intervals.


Familial colorectal cancer.
Identifying individuals with a genetic predisposition to developing familial colorectal cancer (CRC) is crucial to the management of the affected individual and their family. In order to do so, the physician requires an understanding of the different gene mutations and clinical manifestations of familial CRC. This review summarises the genetics, clinical manifestations and management of the known familial CRC syndromes, specifically Lynch syndrome, familial adenomatous polyposis, MUTYH-associated neoplasia, juvenile polyposis syndrome and Peutz-Jeghers syndrome. An individual suspected of having a familial CRC with an underlying genetic predisposition should be referred to a familial cancer centre to enable pre-test counselling and appropriate follow up.


Effective scoring function for protein sequence design.
We have developed an effective scoring function for protein design. The atomic solvation parameters, together with the weights of energy terms, were optimized so that residues corresponding to the native sequence were predicted with low energy in the training set of 28 protein structures. The solvation energy of non-hydrogen-bonded hydrophilic atoms was considered separately and expressed in a nonlinear way. As a result, our scoring function predicted native residues as the most favorable in 59% of the total positions in 28 proteins. We then tested the scoring function by comparing the predicted stability changes for 103 T4 lysozyme mutants with the experimental values. The correlation coefficients were 0.77 for surface mutations and 0.71 for all mutations. Finally, the scoring function combined with Monte Carlo simulation was used to predict favorable sequences on a fixed backbone. The designed sequences were similar to the natural sequences of the family to which the template structure belonged. The profile of the designed sequences was helpful for identification of remote homologues of the native sequence.


NAD(P)H quinone oxidoreductase (NQO1): an enzyme which needs just enough mobility, in just the right places.
NAD(P)H quinone oxidoreductase 1 (NQO1) catalyses the two electron reduction of quinones and a wide range of other organic compounds. Its physiological role is believed to be partly the reduction of free radical load in cells and the detoxification of xenobiotics. It also has non-enzymatic functions stabilising a number of cellular regulators including p53. Functionally, NQO1 is a homodimer with two active sites formed from residues from both polypeptide chains. Catalysis proceeds via a substituted enzyme mechanism involving a tightly bound FAD cofactor. Dicoumarol and some structurally related compounds act as competitive inhibitors of NQO1. There is some evidence for negative cooperativity in quinine oxidoreductases which is most likely to be mediated at least in part by alterations to the mobility of the protein. Human NQO1 is implicated in cancer. It is often over-expressed in cancer cells and as such is considered as a possible drug target. Interestingly, a common polymorphic form of human NQO1, p.P187S, is associated with an increased risk of several forms of cancer. This variant has much lower activity than the wild-type, primarily due to its substantially reduced affinity for FAD which results from lower stability. This lower stability results from inappropriate mobility of key parts of the protein. Thus, NQO1 relies on correct mobility for normal function, but inappropriate mobility results in dysfunction and may cause disease.


Establishment success of introduced amphibians increases in the presence of congeneric species.
Darwin's naturalization hypothesis predicts that the success of alien invaders will decrease with increasing taxonomic similarity to the native community. Alternatively, shared traits between aliens and the native assemblage may preadapt aliens to their novel surroundings, thereby facilitating establishment (the preadaptation hypothesis). Here we examine successful and failed introductions of amphibian species across the globe and find that the probability of successful establishment is higher when congeneric species are present at introduction locations and increases with increasing congener species richness. After accounting for positive effects of congeners, residence time, and propagule pressure, we also find that invader establishment success is higher on islands than on mainland areas and is higher in areas with abiotic conditions similar to the native range. These findings represent the first example in which the preadaptation hypothesis is supported in organisms other than plants and suggest that preadaptation has played a critical role in enabling introduced species to succeed in novel environments.


Effect of morphine on breathing and behavior in fetal sheep.
To define the dose response of apnea and breathing to morphine we studied 12 fetuses at 116-141 days of gestation using our window technique. We instrumented the fetus to record electrocortical activity (ECoG), eye movements (EOG), diaphragmatic activity (integral of EMGdi), heart rate, carotid blood pressure, and amniotic pressure. Saline and morphine in doses of 0.03, 0.1, 0.5, 1, and 3 mg/kg were injected in random order in the jugular vein of the fetus during low-voltage ECoG. Fetuses were videotaped for evaluation of fetal behavior. We found 1) that saline did not elicit a response; 2) apnea, associated with a change from low- to high-voltage ECoG, increased from 2.2 +/- 1.5 (SE) min in two fetuses at a dose of 0.03 mg to 20 +/- 6.3 min in seven fetuses at 3 mg/kg (P less than 0.005); 3) the length of the breathing responses, associated with a change from high- to low-voltage ECoG, were 15 +/- 1.8 and 135.9 +/- 18.1 min (P less than 0.0005); 4) integral of EMGdi X frequency, an index equivalent to minute ventilation, increased from 1,763 +/- 317 arbitrary units to 10,658 +/- 1,843 at 1.0 mg/kg and then decreased to 7,997 +/- 1,335 at 3.0 mg/kg. These changes were related to a steady increase in integral of EMGdi, whereas frequency decreased at 3 mg/kg. There was an increase in breathing response to morphine plasma concentrations or morphine doses.(ABSTRACT TRUNCATED AT 250 WORDS)


The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies.
SARS-CoV-2 infection fatality rate (IFR) doubles with every five years of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ~20% of deceased patients across age groups. In the general population, they are found in ~1% of individuals aged 20-70 years and in >4% of those >70 years old. With a sample of 1,261 deceased patients and 34,159 uninfected individuals, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to non-carriers. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRD was 17.0[95% CI:11.7-24.7] for individuals under 70 years old and 5.8[4.5-7.4] for individuals aged 70 and over, whereas, for autoantibodies neutralizing both molecules, the RRD was 188.3[44.8-774.4] and 7.2[5.0-10.3], respectively. IFRs increased with age, from 0.17%[0.12-0.31] for individuals <40 years old to 26.7%[20.3-35.2] for those ≥80 years old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84%[0.31-8.28] to 40.5%[27.82-61.20] for the same two age groups, for autoantibodies neutralizing both molecules. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, particularly those neutralizing both IFN-α2 and -ω. Remarkably, IFR increases with age, whereas RRD decreases with age. Autoimmunity to type I IFNs appears to be second only to age among common predictors of COVID-19 death.


Seizures and status epilepticus may be risk factor for cardiac arrhythmia or cardiac arrest across multiple time frames.
To determine if Emergency Department (ED) or inpatient encounters for epilepsy or status epilepticus are associated with increased odds of cardiac arrhythmia or cardiac arrest over successively longer time frames. The State Inpatient and ED Databases (from New York, Florida, and California) are statewide datasets containing data on 97% of hospitalizations and ED encounters from these states. In this retrospective, case-crossover study, we used International Classification of Diseases, Ninth Revision, Clinical Modification codes to identify index cardiac arrhythmia encounters. Exposures were inpatient or ED encounters for epilepsy or status epilepticus. The case-crossover analysis tested whether an epilepsy or status epilepticus encounter within various case periods (1, 3, 7, 30, 60, 90, and 180 days prior to index encounter) was associated with subsequent ED or inpatient encounter for cardiac arrhythmia, as compared to control periods of equal length one year prior. The odds ratio (OR) for cardiac arrhythmia after an epilepsy encounter was significant at all time intervals (OR range 2.37-3.36), and highest at 1 day after epilepsy encounter (OR 3.63, 95% confidence interval [CI] 1.66-7.93, p = 0.0013). The OR after status epilepticus was significant at 7- to 180-day intervals (OR range 2.25-2.74), and highest at 60 days (OR 2.74, CI 2.09-3.61, p < 0.0001). Epilepsy and status epilepticus events are associated with increased odds of subsequent cardiac arrhythmia or cardiac arrest over multiple chronic timeframes. Increased cardiac surveillance may be warranted to minimize morbidity and mortality in patients with epilepsy.


Engaging with communities, engaging with patients: amendment to the NAPCRG 1998 Policy Statement on Responsible Research With Communities.
In 1998, the North American Primary Care Research Group (NAPCRG) adopted a groundbreaking Policy Statement endorsing responsible participatory research (PR) with communities. Since that time, PR gained prominence in primary care research. To reconsider the original 1998 Policy Statement in light of increased uptake of PR, and suggest future directions and applications for PR in primary care. This work contributed to an updated Policy Statement endorsed by NAPCRG in 2015. 32 university and 30 community NAPCRG-affiliated research partners, convened a workshop to document lessons learned about implementing processes and principles of PR. This document emerged from that session and reflection and discussion regarding the original Policy Statement, the emerging PR literature, and our own experiences. The foundational principles articulated in the 1998 Policy Statement remain relevant to the current PR environment. Lessons learned since its publication include that the maturation of partnerships is facilitated by participatory processes that support increased community responsibility for research projects, and benefits generated through PR extend beyond research outcomes. Future directions that will move forward the field of PR in primary care include: (i) improve assessment of PR processes to better delineate the links between how PR teams work together and diverse PR outcomes, (ii) increase the number of models incorporating PR into translational research from project inception to dissemination, and (iii) increase application of PR approaches that support patient engagement in clinical settings to patient-provider relationship and practice change research. PR has markedly altered the manner in which primary care research is undertaken in partnership with communities and its principles and philosophies continue to offer means to assure that research results and processes improve the health of all communities.


Small area estimation of under-5 mortality in Bangladesh, Cameroon, Chad, Mozambique, Uganda, and Zambia using spatially misaligned data.
The under-5 mortality rate (U5MR) is an important metric of child health and survival. Country-level estimates of U5MR are readily available, but efforts to estimate U5MR subnationally have been limited, in part, due to spatial misalignment of available data sources (e.g., use of different administrative levels, or as a result of historical boundary changes). We analyzed all available complete and summary birth history data in surveys and censuses in six countries (Bangladesh, Cameroon, Chad, Mozambique, Uganda, and Zambia) at the finest geographic level available in each data source. We then developed small area estimation models capable of incorporating spatially misaligned data. These small area estimation models were applied to the birth history data in order to estimate trends in U5MR from 1980 to 2015 at the second administrative level in Cameroon, Chad, Mozambique, Uganda, and Zambia and at the third administrative level in Bangladesh. We found substantial variation in U5MR in all six countries: there was more than a two-fold difference in U5MR between the area with the highest rate and the area with the lowest rate in every country. All areas in all countries experienced declines in U5MR between 1980 and 2015, but the degree varied both within and between countries. In Cameroon, Chad, Mozambique, and Zambia we found areas with U5MRs in 2015 that were higher than in other parts of the same country in 1980. Comparing subnational U5MR to country-level targets for the Millennium Development Goals (MDG), we find that 12.8% of areas in Bangladesh did not meet the country-level target, although the country as whole did. A minority of areas in Chad, Mozambique, Uganda, and Zambia met the country-level MDG targets while these countries as a whole did not. Subnational estimates of U5MR reveal significant within-country variation. These estimates could be used for identifying high-need areas and positive deviants, tracking trends in geographic inequalities, and evaluating progress towards international development targets such as the Sustainable Development Goals.


Identifying the common genetic networks of ADR (adverse drug reaction) clusters and developing an ADR classification model.
Adverse drug reactions (ADRs) are one of the major concerns threatening public health and have resulted in failures in drug development. Thus, predicting ADRs and discovering the mechanisms underlying ADRs have become important tasks in pharmacovigilance. Identification of potential ADRs by computational approaches in the early stages would be advantageous in drug development. Here we propose a computational method that elucidates the action mechanisms of ADRs and predicts potential ADRs by utilizing ADR genes, drug features, and protein-protein interaction (PPI) networks. If some ADRs share similar features, there is a high possibility that they may appear together in a drug and share analogous mechanisms. Proceeding from this assumption, we clustered ADRs according to interactions of ADR genes in the PPI networks and the frequency of co-occurrence of ADRs in drugs. ADR clusters were verified based on a side effect database and literature data regarding whether ADRs have relevance to other ADRs in the same cluster. Gene networks shared by ADRs in each cluster were constructed by cumulating the shortest paths between drug target genes and ADR genes in the PPI network. We developed a classification model to predict potential ADRs using these gene networks shared by ADRs and calculated cross-validation AUC (area under the curve) values for each ADR cluster. In addition, in order to demonstrate correlations between gene networks shared by ADRs and ADRs in a cluster, we applied the Wilcoxon rank sum statistical test to the literature data and results of a Google query search. We attained statistically meaningful p-values (<0.05) for every ADR cluster. The results suggest that our approach provides insights into discovering the action mechanisms of ADRs and is a novel attempt to predict ADRs in a biological aspect.


Dramatic Change in Citrus tristeza virus Populations in the Dominican Republic.
Citrus tristeza virus (CTV) is the most destructive viral pathogen of citrus and has been an important concern for the citrus industry in the Dominican Republic. Earlier studies documented widespread distribution of mild isolates of the T30 genotype, which caused no disease in the infected trees, and a low incidence of isolates of the VT and T3 genotypes, which were associated with economically damaging decline and stem-pitting symptoms in sweet orange and Persian lime, the two major citrus varieties grown in the Dominican Republic. In light of the dramatic increase in the number of severely diseased citrus trees throughout the country over the last decade, suggesting that field populations of CTV have changed, we examined the CTV pathosystem in the Dominican Republic to assess the dynamics of virus populations. In this work, we characterized the molecular composition of 163 CTV isolates from different citrus-growing regions. Our data demonstrate a dramatic change in CTV populations, with the VT genotype now widely disseminated throughout the different regions and with the presence of two new virus genotypes, T36 and RB. Multiple infections of trees resulted in development of complex virus populations composed of different genotypes.


Role of hypothalamic monoamines in nicotine-induced anorexia in menopausal rats.
Nicotine reduces body weight by reducing appetite. Estradiol modulates food intake. Menopause or ovariectomy (Ovx) increases food intake and body weight. Nicotine and estradiol individually influence hypothalamic dopamine (DA) and serotonin (5-HT), whose interaction influences food intake and body weight. We investigated whether lower weight gain in menopausal smokers is mediated via changes in hypothalamic DA/5-HT. Ovx or sham-operated female rats had 2 microdialysis guide cannulas simultaneously implanted in ipsilateral ventromedial nucleus of hypothalamus (VMN) and contralateral lateral hypothalamic area (LHA). Rats were divided into 4 groups and received a continuous subcutaneous infusion of nicotine or saline Ovx and sham. DA and 5-HT in LHA and VMN were measured by in vivo microdialysis. Nicotine infusion decreased food intake and body weight in Ovx and sham groups. Increase in LHA-DA and VMN-5-HT in sham group occurred with nicotine, whereas an increase in VMN-DA in Ovx groups with and without nicotine and VMN-5-HT in Ovx group with nicotine was observed. In the presence of estradiol (ovary intact sham-operated rats), nicotine lowers food intake and body weight via increased LHA-DA and VMN-5-HT. In menopause (Ovx rats), nicotine lowers food intake and body weight only via increased VMN-DA and 5-HT. Data show that lower weight gain is mediated via changes in hypothalamic monoamines, primarily via ventromedial hypothalamus.


Experience with Peroral Endoscopic Myotomy for Achalasia and Spastic Esophageal Motility Disorders at a Tertiary U.S. Center.
Peroral endoscopic myotomy (POEM) is a novel procedure for the treatment of achalasia and spastic esophageal disorders. Experience with POEM is limited, but its reported outcomes are excellent. It is deemed safe even for patients with prior interventions. This retrospective review included patients who underwent POEM at a tertiary US center. POEM was performed in a multidisciplinary approach by advanced endoscopists and foregut surgeons. Clinical success was defined as a post-POEM Eckardt score ≤3. A total of 125 patients were included. Median follow-up period was 18 months (interquartile range, 10-22 months). Clinical success was achieved in 92% of patients and persisted at 12 months in 88% of patients. Mucosal barrier failure (MBF) occurred in 7 patients, 2 of whom required surgical intervention. MBF was more common in patients with prior laparoscopic Heller myotomy (19% vs. 3%, p=0.015). MBF requiring surgical intervention occurred early in the learning curve. POEM is safe and effective in the treatment of achalasia and spastic esophageal disorders even after failed prior interventions.


Discrepancies between two long-term dietary datasets in the United Kingdom (UK).
Background: Studying dietary trends can help monitor progress towards healthier and more sustainable diets but longitudinal data are often confounded by lack of standardized methods. Two main data sources are used for longitudinal analysis of diets: food balance sheets on food supply (FBS) and household budget surveys on food purchased (HBS). Methods: We used UK longitudinal dietary data on food supply, provided by the Food and Agriculture Organisation (FAO) (FAO-FBS, 1961-2018), and food purchases, provided by Defra (Defra-HBS, 1942-2018). We assessed how trends in dietary change per capita compared between FAO-FBS and Defra-HBS for calories, meat and fish, nuts and pulses, and dairy, and how disparities have changed over time. Results: FAO-FBS estimates were significantly higher (p<0.001) than Defra-HBS for calorie intake and all food types, except nuts and pulses which were significantly lower (p<0.001). These differences are partly due to inclusion of retail waste in FAO-FBS data and under-reporting in Defra- HBS data. The disparities between the two datasets increased over time for calories, meat and dairy; did not change for fish; and decreased for nuts and pulses . Between 1961 and 2018, both FAO-FBS and Defra-FBS showed an increase in meat intake (+11.5% and +1.4%, respectively) and a decrease in fish (-3.3% and -3.2%, respectively) and dairy intake (-11.2% and -22.4%). Temporal trends did not agree between the two datasets for calories, and nuts and pulses. Conclusions: Our finding raises questions over the robustness of both data sources for monitoring UK dietary change, especially when used for evidence-based decision making around health, climate change and sustainability.


Radiation recall dermatitis induced by sorafenib : A case study and review of the literature.
Radiation recall dermatitis (RRD) is an acute inflammatory reaction confined to previously irradiated skin, mainly subsequent to the administration of certain chemotherapeutics. Here we present a rare case of RRD induced by the oral multikinase inhibitor sorafenib. A 77-year-old male with hepatocellular carcinoma was irradiated at ten different sites for bone metastases with 20-36 Gray in 5-12 fractions from January to March 2015. Sorafenib 400 mg was administered twice daily from mid-March. One week later the patient presented with fever and erythematous lesions on the right upper arm, mandible, and trunk. All skin symptoms were confined to previously irradiated areas. After RRD was diagnosed by exclusion of other causes and skin biopsy, sorafenib was paused. With the administration of topical corticosteroids and oral antihistamines, the skin reaction subsided within several days. Sorafenib was readministered after 3 weeks, which did not lead to recurrence of RRD but did cause fluctuating fever. Only four other such cases have been reported in the literature and WHO pharmacovigilance database on individual case safety reports. The current report is the first to show a potential relationship between the severity of sorafenib-induced RRD and radiation dose, histopathological features, and simultaneous acute radiation dermatitis and mucositis. RRD induced by sorafenib is a rare phenomenon, but should be considered in patients showing erythematous skin lesions 1-2 weeks after initiation of the drug, predominantly in areas where skin has been irradiated with an equivalent dose ≥ 30 Gy. Discontinuation of sorafenib with possible readministration should be evaluated with respect to the clinical situation and severity of reaction.


Linkage disequilibrium in human ribosomal genes: implications for multigene family evolution.
Members of the rDNA multigene family within a species do not evolve independently, rather, they evolve together in a concerted fashion. Between species, however, each multigene family does evolve independently indicating that mechanisms exist which will amplify and fix new mutations both within populations and within species. In order to evaluate the possible mechanisms by which mutation, amplification and fixation occur we have determined the level of linkage disequilibrium between two polymorphic sites in human ribosomal genes in five racial groups and among individuals within two of these groups. The marked linkage disequilibrium we observe within individuals suggests that sister chromatid exchanges are much more important than homologous or nonhomologous recombination events in the concerted evolution of the rDNA family and further that recent models of molecular drive may not apply to the evolution of the rDNA multigene family.


Inhibition of cathepsin B activity attenuates extracellular matrix degradation and inflammatory breast cancer invasion.
Inflammatory breast cancer (IBC) is an aggressive, metastatic and highly angiogenic form of locally advanced breast cancer with a relatively poor three-year survival rate. Breast cancer invasion has been linked to proteolytic activity at the tumor cell surface. Here we explored a role for active cathepsin B on the cell surface in the invasiveness of IBC. We examined expression of the cysteine protease cathepsin B and the serine protease urokinase plasminogen activator (uPA), its receptor uPAR and caveolin-1 in two IBC cell lines: SUM149 and SUM190. We utilized a live cell proteolysis assay to localize in real time the degradation of type IV collagen by IBC cells. IBC patient biopsies were examined for expression of cathepsin B and caveolin-1. Both cell lines expressed comparable levels of cathepsin B and uPA. In contrast, levels of caveolin-1 and uPAR were greater in SUM149 cells. We observed that uPA, uPAR and enzymatically active cathepsin B were colocalized in caveolae fractions isolated from SUM149 cells. Using a live-cell proteolysis assay, we demonstrated that both IBC cell lines degrade type IV collagen. The SUM149 cells exhibit predominantly pericellular proteolysis, consistent with localization of proteolytic pathway constitutents to caveolar membrane microdomains. A functional role for cathepsin B was confirmed by the ability of CA074, a cell impermeable and highly selective cathepsin B inhibitor, to significantly reduce pericellular proteolysis and invasion by SUM149 cells. A statistically significant co-expression of cathepsin B and caveolin-1 was found in IBC patient biopsies, thus validating our in vitro data. Our study is the first to show that the proteolytic activity of cathepsin B and its co-expression with caveolin-1 contributes to the aggressiveness of IBC.


Modernized Classification of Cardiac Antiarrhythmic Drugs.
Among his major cardiac electrophysiological contributions, Miles Vaughan Williams (1918-2016) provided a classification of antiarrhythmic drugs that remains central to their clinical use. We survey implications of subsequent discoveries concerning sarcolemmal, sarcoplasmic reticular, and cytosolic biomolecules, developing an expanded but pragmatic classification that encompasses approved and potential antiarrhythmic drugs on this centenary of his birth. We first consider the range of pharmacological targets, tracking these through to cellular electrophysiological effects. We retain the original Vaughan Williams Classes I through IV but subcategorize these divisions in light of more recent developments, including the existence of Na+ current components (for Class I), advances in autonomic (often G protein-mediated) signaling (for Class II), K+ channel subspecies (for Class III), and novel molecular targets related to Ca2+ homeostasis (for Class IV). We introduce new classes based on additional targets, including channels involved in automaticity, mechanically sensitive ion channels, connexins controlling electrotonic cell coupling, and molecules underlying longer-term signaling processes affecting structural remodeling. Inclusion of this widened range of targets and their physiological sequelae provides a framework for a modernized classification of established antiarrhythmic drugs based on their pharmacological targets. The revised classification allows for the existence of multiple drug targets/actions and for adverse, sometimes actually proarrhythmic, effects. The new scheme also aids classification of novel drugs under investigation. We emerge with a modernized classification preserving the simplicity of the original Vaughan Williams framework while aiding our understanding and clinical management of cardiac arrhythmic events and facilitating future developments in this area.


Prognostic molecular markers for motor recovery in acute hemorrhagic stroke: A systematic review.
Molecular biomarkers are associated with poor prognosis in ischemic stroke individuals. However, it might not be generalizable to post-acute hemorrhagic stroke since the underlying mechanisms of this brain damage differ from those found in ischemic stroke. The main purpose of this review was to synthesize the potential predictive molecular biomarkers for motor recovery following acute hemorrhagic stroke. An electronic search was conducted by 2 independent reviewers in the following databases: PubMed (Medline), EMBASE, Web of Science, and CINAHL. We included studies that addressed the following: collected blood, urine, or cerebrospinal fluid samples within 72 h after hemorrhagic stroke and that reported the prognostic association with functional motor recovery for each molecular biomarker. Screening of titles, abstracts, and full texts and data extraction were undertaken independently by pairs of reviewers. Twelve thousand, five hundred and sixty-four studies were identified and 218 were considered eligible. Finally, we included 70 studies, with 96 biomarkers analyzed, of which 61 were considered as independent prognostic biomarkers, and 10 presented controversial results. This systematic review shows that motor functional recovery can be predicted by 61 independent prognostic molecular biomarkers assessed in the acute phase after a hemorrhagic stroke.


Electromechanical coupling in the membranes of Shaker-transfected HEK cells.
Membranes flex with changes in transmembrane potential as a result of changes in interfacial tension, the Lippman effect. We studied the membrane electromotility of Shaker K(+)-transfected HEK-293 cells in real time by using combined patch-clamp atomic force microscopy. In the voltage range where the channels were closed, Shaker expression had little effect on electromotility relative to wild-type cells. Depolarization between -120 and -40 mV resulted in a linear upward cantilever deflection equivalent to an increase in membrane tension. However, when depolarized sufficiently for channel opening, the electromotility saturated and only recovered over 10 s of milliseconds. This remarkable loss of motility was associated with channel opening, not ionic flux or movement of the voltage sensors. The IL mutant of Shaker, in which the voltage dependence of channel opening but not sensor movement is shifted to more positive potentials, caused the loss of electromotility saturation also to shift to more positive potentials. The temporary loss of electromotility associated with channel opening is probably caused by local buckling of the bilayer as the inner half of the channel expands as expected from X-ray structural data.


Analysis of the electron paramagnetic resonance properties of the [2Fe-2S]1+ centers in molybdenum enzymes of the xanthine oxidase family: assignment of signals I and II.
Molybdoenzymes of the xanthine oxidase family contain two [2Fe-2S](1+,2+) clusters that are bound to the protein by very different cysteine motifs. In the X-ray crystal structure of Desulfovibrio gigas aldehyde oxidoreductase, the cluster ligated by a ferredoxin-type motif is close to the protein surface, whereas that ligated by an unusual cysteine motif is in contact with the molybdopterin [Romao, M. J., Archer, M., Moura, I., Moura, J. J. G., LeGall, J., Engh, R., Schneider, M., Hof, P., and Huber, R. (1995) Science 270, 1170-1176]. These two clusters display distinct electron paramagnetic resonance (EPR) signals: the less anisotropic one, called signal I, is generally similar to the g(av) approximately 1.96-type signals given by ferredoxins, whereas signal II often exhibits anomalous properties such as very large g values, broad lines, and very fast relaxation properties. A detailed comparison of the temperature dependence of the spin-lattice relaxation time and of the intensity of these signals in D. gigas aldehyde oxidoreductase and in milk xanthine oxidase strongly suggests that the peculiar EPR properties of signal II arise from the presence of low-lying excited levels reflecting significant double exchange interactions. The issue raised by the assignment of signals I and II to the two [2Fe-2S](1+) clusters was solved by using the EPR signal of the Mo(V) center as a probe. The temperature dependence of this signal could be quantitatively reproduced by assuming that the Mo(V) center is coupled to the cluster giving signal I in xanthine oxidase as well as in D. gigas aldehyde oxidoreductase. This demonstrates unambiguously that, in both enzymes, signal I arises from the center which is closest to the molybdenum cofactor.


Multi-decadal changes in snow characteristics in sub-Arctic Sweden.
A unique long term, 49-year record (divided into three time periods 1961-1976, 1977-1992, and 1993-2009) of snow profile stratigraphy from the Swedish sub Arctic, was analyzed with a focus on changes in snow characteristics. The data set contained grain size, snow layer hardness, grain compactness, and snow layer dryness, observed every second week during the winter season. The results showed an increase in very hard snow layers, with harder snow in early winter and more moist snow during spring. There was a striking increase in the number of observations with very hard snow at ground level over time. More than twice as many occasions with hard snow at ground level were observed between 1993 and 2009 compared to previous years, which may have a significant effect on plants and animals. The changes in snow characteristics are most likely a result of the increasing temperatures during the start and the end of the snow season.


Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation.
Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC50 = 9-23 nM) were considerably weaker inhibitors of SGLT1 (IC50 = 10-19 μM). They showed no effect on the sodium independent GLUT family of glucose transporters, and the most potent ones were not acutely toxic to cultured cells. The interaction of a C-glucosyl dihydrochalcone with a POPC membrane was modeled computationally, providing evidence that it is not a pan-assay interference compound. These results point toward the discovery of structures that are potent and highly selective inhibitors of SGLT2.