Evolution of alternative insect life histories in stochastic seasonal environments.
Deterministic seasonality can explain the evolution of alternative life history phenotypes (i.e., life history polyphenism) expressed in different generations emerging within the same year. However, the influence of stochastic variation on the expression of such life history polyphenisms in seasonal environments is insufficiently understood. Here, we use insects as a model and explore (1) the effects of stochastic variation in seasonality and (2) the life cycle on the degree of life history differentiation among the alternative developmental pathways of direct development and diapause (overwintering), and (3) the evolution of phenology. With numerical simulation, we determine the values of development (growth) time, growth rate, body size, reproductive effort, adult life span, and fecundity in both the overwintering and directly developing generations that maximize geometric mean fitness. The results suggest that natural selection favors the expression of alternative life histories in the alternative developmental pathways even when there is stochastic variation in seasonality, but that trait differentiation is affected by the developmental stage that overwinters. Increasing environmental unpredictability induced a switch to a bet-hedging type of life history strategy, which is consistent with general life history theory. Bet-hedging appeared in our study system as reduced expression of the direct development phenotype, with associated changes in life history phenotypes, because the fitness value of direct development is highly variable in uncertain environments. Our main result is that seasonality itself is a key factor promoting the evolution of seasonally polyphenic life histories but that environmental stochasticity may modulate the expression of life history phenotypes.


Design and demonstration of ultra-compact microcell concentrating photovoltaics for space.
Optical concentration can improve the efficiency and reduce the cost of photovoltaic power but has traditionally been too bulky, massive, and unreliable for use in space. Here, we explore a new ultra-compact and low-mass microcell concentrating photovoltaic (µCPV) paradigm for space based on the monolithic integration of transfer-printed microscale solar cells and molded microconcentrator optics. We derive basic bounds on the compactness as a function of geometric concentration ratio and angular acceptance, and show that a simple reflective parabolic concentrator provides the best combination of specific power, angular acceptance, and overall fabrication simplicity. This architecture is simulated in detail and validated experimentally with a µCPV prototype that is less than 1.7 mm thick and operates with six, 650 µm square triple-junction microcells at a geometric concentration ratio of 18.4×. In outdoor testing, the system achieves a terrestrial power conversion efficiency of 25.8 ± 0.2% over a ±9.5° angular range, resulting in a specific power of approximately 111 W/kg. These results lay the groundwork for future space µCPV systems and establish a realistic path to exceed 350 W/kg specific power at >33% power conversion efficiency by scaling down to even smaller microcells.


Nonrandomized comparison of local urokinase thrombolysis versus systemic heparin anticoagulation for superior sagittal sinus thrombosis.
We sought to compare the safety and efficacy of direct urokinase thrombolysis with systemic heparin anticoagulation for superior sagittal sinus thrombosis (SSST). At University at Buffalo (NY) and University of Texas (Dallas, Houston), we reviewed 40 consecutive patients with SSST, treated with local urokinase (thrombolysis group) or systemic heparin anticoagulation (heparin group). The thrombolysis group (n=20) received local urokinase into the SSS followed by systemic heparin anticoagulation. The heparin group (n=20) received systemic heparin anticoagulation only. Neurological dysfunction was rated as follows: 0, normal; 1, mild (but able to ambulate and communicate); 2, moderate (unable to ambulate, normal mentation); and 3, severe (unable to ambulate, altered mentation). Age (P=0.49), sex (P=0.20), baseline venous infarction (P=0.73), and predisposing illnesses (P=0.52) were similar between the thrombolysis and heparin groups. Pretreatment neurological function was worse in the thrombolysis group (normal, n=5; mild, n=8; moderate, n=4; severe, n=3) than in the heparin group (normal, n=8; mild, n=8; moderate, n=3; severe, n=1) (P=NS). Discharge neurological function was better in the thrombolysis group (normal, n=16; mild, n=3; moderate, n=1; severe, n=0) than in the heparin group (normal, n=9; mild, n=6; moderate, n=5; severe, n=0) (P=0.019, Mann-Whitney U test). Hemorrhagic complications were 10% (n=2) in the thrombolysis group (subdural hematoma, retroperitoneal hemorrhage) and none in the heparin group (P=0.49). Three of the heparin group patients developed complications of the underlying disease (status epilepticus, hydrocephalus, refractory papilledema). No deaths occurred. Length of hospital stay was similar between the groups (P=0.79). Local thrombolysis with urokinase is fairly well tolerated and may be more effective than systemic heparin anticoagulation alone in treating SSST. A randomized, prospective study comparing these 2 treatments for SSST is warranted.


An assessment of land conservation patterns in Maine based on spatial analysis of ecological and socioeconomic indicators.
Given the nature of modern conservation acquisitions, which often result from gifts and opportunistic purchases of full or partial property rights, there is a risk that the resulting mosaic of conserved resources may not represent a coherent set of public values and benefits. With different public and private entities engaged in land conservation, one would further expect that each organization would apply separate goals and criteria to the selection and acquisition of its conservation portfolio. This set of circumstances raises an important question: what is the aggregate outcome of this land conservation process? Retrospective assessments provide a means of reviewing cumulative historical decisions and elucidating lessons for improving future conservation strategies. This study used GIS-based spatial analysis to examine the relationships of private and public conservation lands in Maine to a variety of landscape metrics in order to determine the degree to which these lands represent core ecological and socioeconomic values that are meaningful to a wide cross-section of citizens. Results revealed that the gains of past conservation efforts in Maine are counter-balanced to some extent by apparent gaps in the existing fabric of conservation holdings. Conservation lands capture a representative sample of diverse habitat, provide a large measure of protection for multiple conservation values and indicators, and offer an unusual mix of outdoor recreational opportunities for residents and visitors alike. Yet, the majority of parcels are relatively small and isolated, and thus do not provide contiguous habitat blocks that offset ongoing processes of landscape fragmentation. Furthermore, the majority of area associated with many of the ecological metrics examined in this report is located outside the boundaries of current conservation holdings. The under-represented metrics identified in this investigation can be viewed as potential targets for new strategic conservation initiatives.


Malignant hypertension in women of childbearing age and its relation to the contraceptive pill.
Eleven of 34 women aged 15-44 with malignant phase hypertension were taking oral contraceptives at presentation. All had had normal blood pressure before starting to take the pill. In four the interval between the start of oral contraception and the diagnosis of malignant hypertension was less than four months, and in eight no other cause for the hypertension was found. Underlying renal disease and renal failure were less common among pill users than among non-users with malignant hypertension who were of similar age. No pill user became normotensive after withdrawal of the pill, but blood pressure was well controlled (diastolic less than 90 mm Hg) in three patients taking only one drug. By contrast, all 23 non-users needed two or more antihypertensive drugs to control blood pressure. Ten year survival was 90% among pill users and 50% among non-users. These results suggest that oral contraceptives may be a common cause of malignant hypertension in women of child-bearing age. If the pill is stopped and underlying renal disease excluded the long term prognosis for such patients is excellent.


Injectable dual-gelling cell-laden composite hydrogels for bone tissue engineering.
The present work investigated the osteogenic potential of injectable, dual thermally and chemically gelable composite hydrogels for mesenchymal stem cell (MSC) delivery in vitro and in vivo. Composite hydrogels comprising copolymer macromers of N-isopropylacrylamide were fabricated through the incorporation of gelatin microparticles (GMPs) as enzymatically digestible porogens and sites for cellular attachment. High and low polymer content hydrogels with and without GMP loading were shown to successfully encapsulate viable MSCs and maintain their survival over 28 days in vitro. GMP incorporation was also shown to modulate alkaline phosphatase production, but enhanced hydrogel mineralization along with higher polymer content even in the absence of cells. Moreover, the regenerative capacity of 2 mm thick hydrogels with GMPs only, MSCs only, or GMPs and MSCs was evaluated in vivo in an 8 mm rat critical size cranial defect for 4 and 12 weeks. GMP incorporation led to enhanced bony bridging and mineralization within the defect at each timepoint, and direct bone-implant contact as determined by microcomputed tomography and histological scoring, respectively. Encapsulation of both GMPs and MSCs enabled hydrogel degradation leading to significant tissue infiltration and osteoid formation. The results suggest that these injectable, dual-gelling cell-laden composite hydrogels can facilitate bone ingrowth and integration, warranting further investigation for bone tissue engineering.


Serotonin transporter and seasonal variation in blood serotonin in families with obsessive-compulsive disorder.
The serotonin transporter (HTT) is a candidate gene for obsessive-compulsive disorder (OCD) that has been associated with anxiety-related traits. The long (l) and short (s) variants of the HTT promoter have different transcriptional efficiencies. HTT promoter genotype and blood 5-HT concentration were examined in 70 subjects from 20 families ascertained through children and adolescents with a DSM-III-R diagnosis of OCD. The HTT promoter variant had a significant effect on blood 5-HT content. Subjects with the l/l and l/s genotypes had significantly higher blood 5-HT levels than did those with the s/s genotype. There was a significant interaction between HTT promoter genotype and seasonal variation in blood 5-HT content, with significant seasonal differences in 5-HT occurring only in the subjects with the l/l genotype. Further studies of the regulation of HTT gene expression are indicated.


The evaluation of altered antioxidative defense mechanism and acetylcholinesterase activity in rat brain exposed to chlorpyrifos, deltamethrin, and their combination.
ABSTRACT The present investigation was undertaken to examine the effects of chlorpyrifos (CP, an organophosphate) and deltamethrin (DM, a pyrethroid pesticide) treatments at low and high doses and their combination on lipid peroxidation and antioxidant enzyme activities such as SOD, GSH-Px, and CAT and also AChE activity in rat brain following 16 weeks of exposure. Antioxidative defense mechanisms and lipid peroxidation in rat brain tissues display different responses depending on different pesticide treatments and doses. Biochemical analysis showed that administration of chlorpyrifos and deltamethrin causes brain damage via production of MDA and inhibition of AChE. In the present study, we observed that LPO levels are higher at low doses than at high doses, but DM is more pronounced than CP in this increase. Observations show that SOD increases with the dose, CAT decreases at the higher dose, and GSH-Px again increases with the dose in both pesticide treatments, but especially in DM. Experimentally, oxidative-antioxidative balance is more affected by deltamethrin treatment than that of chlorpyrifos. The effects of combination of DM and CP on LPO may be due to functional, dispositional, or chemical antagonism, while the effect of the combination on CAT activity may be synergistic.


Predictions of phase separation in three-component lipid membranes by the MARTINI force field.
The phase behavior of the coarse-grained MARTINI model for three-component lipid bilayers composed of dipalmytoyl-phosphatidylcholine (DPPC), cholesterol (Chol), and an unsaturated phosphatidylcholine (PC) was systematically investigated by molecular dynamics simulations. The aim of this study is to understand which types of unsaturated PC induce the formation of thermodynamically stable coexisting phases when added to mixtures of DPPC and Chol and to unravel the mechanisms that drive phase separation in such three-component mixtures. Our simulations indicate that the currently used MARTINI force field does not induce such phase separation in mixtures of DPPC, Chol, and unsaturated PCs with a low unsaturation level, such as palmitoyl-oleoyl-phosphatidylcholine (POPC) or dioleoyl-phosphatidylcholine (DOPC). Also, we found that phase separation does occur in mixtures of DPPC, Chol, and polyunsaturated PCs, such as dilinoleyl-phosphatidylcholine (DUPC) and diarachidonoyl-phosphatidylcholine (DAPC). Through systematic tweaking of the interactions between the hydrophobic groups of the PC molecules, we show that the appearance of phase separation in three-component lipid bilayers, as modeled through the MARTINI force field, is primarily due to the interactions between the coarse-grained molecules, i.e., the beads, rather than due to the differences between the conformations of saturated and unsaturated lipid acyl chains, namely entropy driven.


Epitaxial cubic gadolinium oxide as a dielectric for gallium arsenide passivation
Epitaxial growth of single-crystal gadolinium oxide dielectric thin films on gallium arsenide is reported. The gadolinium oxide film has a cubic structure isomorphic to manganese oxide and is (110)-oriented in single domain on the (100) gallium arsenide surface. The gadolinium oxide film has a dielectric constant of approximately 10, with low leakage current densities of about 10(-9) to 10(-10) amperes per square centimeter at zero bias. Typical breakdown field is 4 megavolts per centimeter for an oxide film 185 angstroms thick and 10 megavolts per centimeter for an oxide 45 angstroms thick. Both accumulation and inversion layers were observed in the gadolinium oxide-gallium arsenide metal oxide semiconductor diodes, using capacitance-voltage measurements. The ability to grow thin single-crystal oxide films on gallium arsenide with a low interfacial density of states has great potential impact on the electronic industry of compound semiconductors.


An internalization-competent influenza hemagglutinin mutant causes the redistribution of AP-2 to existing coated pits and is colocalized with AP-2 in clathrin free clusters.
Image correlation spectroscopy and cross correlation spectroscopy were used to demonstrate that approximately 25% of the internalization-competent influenza virus hemagglutinin mutant, HA+8, is colocalized with clathrin and AP-2 at the plasma membrane of intact cells, while wild-type HA (which is excluded from coated pits) does not colocalize with either protein. Clathrin and AP-2 clusters were saturated when HA+8 was overexpressed, and this was accompanied by a redistribution of AP-2 into existing coated pits. However, de novo coated pit formation was not observed. In nontreated cells, the number of clusters of clathrin or AP-2 colocalized with HA+8 was always comparable. Hypertonic treatment which disperses the clathrin lattices resulted in more clusters containing AP-2 and HA+8 than clathrin and HA+8. Less colocalization of HA+8 with clathrin was also observed after cytosol acidification, which causes the formation of deeply invaginated pits, where the HA+8 may be inaccessible to extracellular labeling by antibodies, and blocks coated vesicle budding. However, cytosol acidification elevated the number of clusters containing both HA+8 and AP-2, suggesting an increase in their level of association outside of the deep invaginations. Our results imply that AP-2 and HA+8 can colocalize in clusters devoid of clathrin, at least in cells treated to alter the clathrin lattice structure. Although we cannot ascertain whether this also occurs in untreated cells, we propose that AP-2 binding to membrane proteins carrying internalization signals can occur prior to the binding of AP-2 to clathrin. While such complexes can in principle serve to recruit clathrin for the formation of new coated pits, the higher affinity of the internalization signals for clathrin-associated AP-2 [Rapoport, I., et al. (1997) EMBO J. 16, 2240-2250] makes it more likely that once the AP-2-membrane protein complexes form, they are quickly recruited into existing coated pits.


Olig2/Plp-positive progenitor cells give rise to Bergmann glia in the cerebellum.
NG2 (nerve/glial antigen2)-expressing cells represent the largest population of postnatal progenitors in the central nervous system and have been classified as oligodendroglial progenitor cells, but the fate and function of these cells remain incompletely characterized. Previous studies have focused on characterizing these progenitors in the postnatal and adult subventricular zone and on analyzing the cellular and physiological properties of these cells in white and gray matter regions in the forebrain. In the present study, we examine the types of neural progeny generated by NG2 progenitors in the cerebellum by employing genetic fate mapping techniques using inducible Cre-Lox systems in vivo with two different mouse lines, the Plp-Cre-ER(T2)/Rosa26-EYFP and Olig2-Cre-ER(T2)/Rosa26-EYFP double-transgenic mice. Our data indicate that Olig2/Plp-positive NG2 cells display multipotential properties, primarily give rise to oligodendroglia but, surprisingly, also generate Bergmann glia, which are specialized glial cells in the cerebellum. The NG2+ cells also give rise to astrocytes, but not neurons. In addition, we show that glutamate signaling is involved in distinct NG2+ cell-fate/differentiation pathways and plays a role in the normal development of Bergmann glia. We also show an increase of cerebellar oligodendroglial lineage cells in response to hypoxic-ischemic injury, but the ability of NG2+ cells to give rise to Bergmann glia and astrocytes remains unchanged. Overall, our study reveals a novel Bergmann glia fate of Olig2/Plp-positive NG2 progenitors, demonstrates the differentiation of these progenitors into various functional glial cell types, and provides significant insights into the fate and function of Olig2/Plp-positive progenitor cells in health and disease.


Clinical Development of Mepolizumab for the Treatment of Severe Eosinophilic Asthma: On the Path to Personalized Medicine.
The development of mepolizumab, an anti-IL-5 monoclonal antibody for the treatment of severe eosinophilic asthma, is an example of a clinical development program that evolved over time based on sound, basic scientific principles. Initial clinical data on the effects of mepolizumab on lung function in a general asthmatic population were disappointing. However, it became clear that mepolizumab may be more effective against other clinical endpoints, particularly asthma exacerbations, in patients with more severe disease. Furthermore, a developing understanding of asthma disease pathobiology led to the identification of an appropriate target population and predictive biomarker for mepolizumab treatment: patients with severe eosinophilic asthma and blood eosinophil count. Mepolizumab use provides clinically meaningful benefits in this target population, fulfilling an unmet need. This Clinical Commentary Review describes the clinical development of mepolizumab and details of how this program informed the development of other biologic therapies in patients with severe asthma. This account highlights how a personalized approach toward treatment of patients with severe eosinophilic asthma, supported by a large body of scientific evidence, ultimately led to new and effective treatments and improved patient outcomes.


Analysis of gene expression array in TSC2-deficient AML cells reveals IRF7 as a pivotal factor in the Rheb/mTOR pathway.
Mutations in tuberous sclerosis (TSC) genes cause the genetic disorder TSC, as well as other neoplasms, including lymphangioleiomyomatosis (LAM) and angiomyolipomas (AMLs). AMLs are benign renal tumors occur both in sporadic LAM and in TSC. As they carry the same mutations, AML cell lines serve as a model for TSC and LAM. Rheb/mammalian target of rapamycin complex 1 (mTORC1) pathway is chronically activated in TSC-deficient cells, and this activation can be diminished using the appropriate inhibitors. Rapamycin (sirolimus) is a known specific inhibitor of mTORC1, whereas S-trans,trans-farnesylthiosalicylic acid (FTS; salirasib) has been shown to inhibit Rheb. To examine the effect of the Rheb/mTOR inhibition pathway, we used human TSC2-deficient AML cells, derived from a LAM patient. FTS indeed inhibited Rheb in these cells and attenuated their proliferation. After comparative treatments with FTS or rapamycin or by re-expression of TSC2, we carried out a gene array analysis. This yielded a substantial number of commonly altered genes, many of which we identified as downstream targets of the interferon (IFN) regulatory factor 7 (IRF7) transcription factor, a central activator of the IFN type 1 immune response. Furthermore, nuclear localization of IRF7 was impaired by each of the three treatments. Interestingly, the phenomena seen on FTS or rapamycin treatment were selective for TSC2-deficient cells. Moreover, knockdown of IRF7 by siRNA mimicked the decrease in number of the abovementioned genes and also inhibited AML cell proliferation. Altogether, these findings support FTS as a potential treatment for TSC and its related pathologies and IRF7 as a novel target for treatment.


Liver blood dynamics after bariatric surgery: the effects of mixed-meal test and incretin infusions.
The mechanisms for improved glycemic control after bariatric surgery in subjects with type 2 diabetes (T2D) are not fully known. We hypothesized that dynamic hepatic blood responses to a mixed-meal are changed after bariatric surgery in parallel with an improvement in glucose tolerance. A total of ten morbidly obese subjects with T2D were recruited to receive a mixed-meal and a glucose-dependent insulinotropic polypeptide (GIP) infusion before and early after (within a median of less than three months) bariatric surgery, and hepatic blood flow and volume (HBV) were measured repeatedly with combined positron emission tomography/MRI. Ten lean non-diabetic individuals served as controls. Bariatric surgery leads to a significant decrease in weight, accompanied with an improved β-cell function and glucagon-like peptide 1 (GLP-1) secretion, and a reduction in liver volume. Blood flow in portal vein (PV) was increased by 1.65-fold (P = 0.026) in response to a mixed-meal in subjects after surgery, while HBV decreased in all groups (P < 0.001). When the effect of GIP infusion was tested separately, no change in hepatic arterial and PV flow was observed, but HBV decreased as seen during the mixed-meal test. Early after bariatric surgery, PV flow response to a mixed-meal is augmented, improving digestion and nutrient absorption. GIP influences the post-prandial reduction in HBV thereby diverting blood to the extrahepatic sites.


MagT1: a highly specific magnesium channel with important roles beyond cellular magnesium homeostasis.
Over recent years, the study of magnesium homeostasis has greatly benefited from molecular genetic approaches that identified several new classes of magnesium transporters. These proteins demonstrate a diversity of structural properties and biophysical functions that often translate into a wide range of tissue-specific cellular activities. Among these novel channels, MagT1 has gained most of the attention, given its high selectivity for Mg(2+) and its possible involvement in cellular functions reaching far beyond magnesium homeostasis, as the latest findings seem to imply. Indeed, a signaling role for MagT1 has been proven in T lymphocytes, where Mg(2+) functions as a second messenger, coupling TCR activation to intracellular effectors. We herein review these intriguing results and discuss their potential implications for magnesium research, and ultimately for therapeutic opportunities. As our knowledge of magnesium advances, it becomes increasingly clear that a deeper understanding of magnesium homeostasis is the key for a deeper insight into relevant pathophysiological conditions, and their treatment.


Development of a novel FePt-based multifunctional ferroptosis agent for high-efficiency anticancer therapy.
Ferroptosis as an emerging mechanism has become a research hotspot for killing cancer cells. In this work, a novel ferroptosis agent, FePt-PTTA-Eu3+-FA (FPEF), was rationally designed by harnessing the luminescent lanthanide complexes PTTA-Eu3+ and folic acid (FA) in FePt nanoparticles. FePt-Based nanomaterials have potential applications in magnetic resonance imaging/computed tomography (MRI/CT) in clinical diagnosis and have excellent capacity to induce cancer cell death. Mechanistic studies of FPEP showed that the FePt induced cancer cell death was affirmed as the ferroptosis mechanism. To the best of our knowledge, it will be the first report that proves the existence of the ferroptosis process in FePt NPs. The in vitro tests of FPEF demonstrated that the as-prepared NPs exhibit a satisfactory anticancer effect towards FA-positive tumor cells including 4T1, MCF-7 and HeLa cells. The in vivo studies using tumor-bearing balb/c mice revealed that the FPEF NPs could significantly inhibit tumor progression. Such all-in-one therapeutic strategies have great potential in early diagnosis, prognosis and treatment of cancer.


Comparative efficacy and safety of Crocus sativus L. for treating mild to moderate major depressive disorder in adults: a meta-analysis of randomized controlled trials.
To investigate the efficacy and safety of saffron in the treatment of major depressive disorder (MDD) in comparison to placebo and synthetic antidepressants. We conducted a systematic search in several electronic databases as well as manual search in bibliographies of relevant studies. We included randomized controlled trials that investigated the efficacy and safety of saffron for treating MDD in adults in comparison to either placebo or synthetic antidepressants. Primary outcome was change in scores on depressive symptoms from baseline. Secondary outcomes included remission rate, response rate, and drop-out rate for all reasons. We chose a random-effects model in order to obtain more conservative results. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated as the overall effect index by inverse variance models. Seven studies were included in this meta-analysis. Overall quality of these included studies was moderate. As for the primary outcome, saffron showed more improvements in depression symptoms when compared with placebo, with an SMD of -1.22 (95% CI -1.94, -0.49, P=0.001). Meanwhile, saffron was as effective as synthetic antidepressants, with an SMD of 0.16 (95% CI -0.25, 0.57, P=0.44). Moderate heterogeneity existed in our analysis. Through subgroup analyses, we found that treatment dosage and duration, types of synthetic antidepressants administered in the comparison group, and outcome measures could explain most of the variance. No differences were found in remission rate, response rate, or drop-out rate. Saffron was effective in the treatment of MDD and had comparable efficacy to synthetic antidepressants. Saffron was also a safe drug without serious adverse events reported.


Clinical significance of post-procedural TIMI flow in patients with cardiogenic shock undergoing primary percutaneous coronary intervention.
We sought to evaluate the impact of post-primary percutaneous coronary intervention (PCI) Thrombolysis In Myocardial Infarction (TIMI) flow grades in the infarct-related artery (IRA) in patients with ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock. The clinical implications and correlates of post-procedural TIMI flow grades in patients with STEMI and cardiogenic shock treated with primary PCI have not been elucidated. We evaluated 4,731 STEMI patients with cardiogenic shock undergoing primary PCI at 567 hospitals participating in the American College of Cardiology-National Cardiovascular Database CathPCI Registry to determine the association of post-procedural TIMI flow grades 0 to 2 with in-hospital outcomes. Post-PCI TIMI flow grades 0 to 2 in the IRA were present in 14.7% of patients. Compared with patients with TIMI flow grade 3, those with TIMI flow grades 0 to 2 were more likely to undergo coronary artery bypass graft surgery after PCI (20% vs. 5.4%), and develop renal failure (10.1% vs. 5.1%), cardiac tamponade (1.0% vs. 0.5%), and bleeding requiring blood transfusion (35.2% vs. 21.6%). Unadjusted mortality was more than 2-fold higher with TIMI flow grades 0 to 2 versus TIMI flow grade 3 (63% vs. 27%). There was a graded inverse relationship with TIMI flow in the IRA and the adjusted mortality (odds ratio [OR] for TIMI flow grades 0/1: 5.47 [95% confidence interval (CI): 4.13 to 7.24] and for TIMI flow grade 2: 2.63 [95% CI: 2.02 to 3.42] compared with TIMI flow grade 3). Our study also identified factors associated with post-PCI TIMI flow grades 0 to 2. Lack of procedural success (post-PCI TIMI flow grades 0 to 2 in the IRA) after primary PCI for STEMI among patients with cardiogenic shock is associated with a much higher risk of mortality compared with the risk for patients with normal post-PCI TIMI flow grade 3.


Using existing population-based data sets to measure the American Academy of Pediatrics definition of medical home for all children and children with special health care needs.
National health goals include ensuring that all children have a medical home. Historically, medical home has been determined by the presence of a usual or primary source of care, such as a pediatrician or a family physician. More recent definitions expand on this simplistic notion of medical home. A definition of medical home set forth by the American Academy of Pediatrics (AAP) includes 7 dimensions and 37 discrete concepts for determining the presence of a medical home for a child. Standardized methods to operationalize these definitions for purposes of national, state, health plan, or medical practice level reporting on the presence of medical homes for children are essential to assessing and improving health care system performance in this area. The objective of this study was to identify methods to measure the presence of medical homes for all children and for children with special health care needs (CSHCN) using existing population-based data sets. Methods were developed for using existing population-based data sets to assess the presence of medical homes, as defined by the AAP, for children with and without special health care needs. Data sets evaluated included the National Survey of Children With Special Health Care Needs, the National Medical Expenditures Panel Survey, the Consumer Assessment of Health Plans Study Child Survey (CAHPS), and the Consumer Assessment of Health Plans Study Child Survey--Children With Chronic Conditions (CAHPS-CCC2.0H). Alternative methods for constructing measures using existing data were compared and results used to inform the design of a new method for use in the upcoming National Survey of Children's Health. Data from CAHPS-CCC2.0H are used to illustrate measurement options and variations in the overall presence of medical homes for children across managed health care plans as well as to evaluate in which areas of the AAP definition of medical home improvements may be most needed for all CSHCN. Existing surveys vary in their coverage of concepts included in the AAP definition of medical home and, therefore, in their capacity to evaluate medical home for children with and without special health care needs. Using data from CAHPS-CCC2.0H, the overall proportion of children who were enrolled in managed care health plans and met criteria for having a medical home varied from 43.9% to 74% depending on the specific scoring method selected for these items. Wide variations across health plans were observed and were most prominent in the areas of "accessible care" and "comprehensive care." Performance was uniformly poorest in the area of "coordinated care" and for CSHCN. Although children with a personal doctor or nurse were more likely to meet the AAP criteria for having a medical home, simply having a personal doctor or nurse was not highly predictive of whether a child experienced the other core qualities of a medical home (positive predictive value: .50; negative predictive value: .59). Despite differences across existing surveys and gaps in concepts represented, we believe that the AAP definition of medical home can be well represented by the small subset of concepts represented in the National Survey of Children With Special Health Care Needs and the CAHPS-CCC2.0H. A less comprehensive yet still worthwhile measure is possible using the Medical Expenditures Panel Survey. The varying degrees of empirical evidence and consensus for each of the AAP definition domains for medical home suggest the need for constructing measures that also vary in terms of criteria for determining that a child does or does not have a medical home. In addition to a simple "yes or no," or rate-based, measure, a continuous medical "homeness" score that places a child or group of children on a continuum of medical "homeness" is also valuable. Findings indicate that health plans have an important role to play in ensuring medical homes for children in addition to medical practices and those who set policies that guide the design and delivery of health care for children. Oven. Overall, using existing population-based data, a measure of medical home that is aligned with the AAP definition is feasible to include in the annual National Healthcare Quality Report, in state reports on the quality of Medicaid, State Children's Health Insurance Program, and Title V programs as well as to evaluate performance on the Healthy People 2010 objectives and the President's New Freedom Initiative.


Spatial risk distribution and determinants of E. coli contamination in household drinking water: a case study of Bangladesh.
The Escherichia coli (E. coli) contamination in the household (HH) drinking water is often a public health concern. Very few studies explore the associated factors and spatial risk modeling together for E. coli contamination in Bangladesh, this research gap motivates to explore this fact further by utilizing Bangladesh Multiple Indicator Cluster Survey (MICS) 2012-13 data. A Bayesian spatial ordered logit model was used to examine the associated factors and spatial risks of the E. coli contamination. The results show that 62% of HH water samples were contaminated with E. coli. After controlling for different factors, a high level of E. coli contamination was observed among HHs who had access to non-improved water sources. Moreover, no significant rural-urban difference was observed. The spatial prediction of the high-risk contamination was prominent in districts like Dhaka and Bandarban. The study findings can provide insights into the planning of policy activities in Bangladesh.


Recurrent sampling models for the Helmholtz machine.
Many recent analysis-by-synthesis density estimation models of cortical learning and processing have made the crucial simplifying assumption that units within a single layer are mutually independent given the states of units in the layer below or the layer above. In this article, we suggest using either a Markov random field or an alternative stochastic sampling architecture to capture explicitly particular forms of dependence within each layer. We develop the architectures in the context of real and binary Helmholtz machines. Recurrent sampling can be used to capture correlations within layers in the generative or the recognition models, and we also show how these can be combined.


A mutated HLA-A*0101 allele in the colorectal cell line HCA-7.
The colorectal cell line HCA-7 expresses surface human leucocyte antigen-A*0201 (HLA-A*0201), but lacks expression of HLA-A*0101 whilst the normal B-cell line (EVA-1224), derived from the same individual, expresses both surface HLA-A1 and HLA-A2. Amplification refractory mutation system-polymerase chain reaction analysis, using sequence-specific primers, suggested that HCA-7 has a mutation in a 7 base pair (bp) cytosine repeat sequence located at the beginning of Exon 4 (bp 621-627). Cloning and sequencing revealed HCA-7 to have eight cytosine residues in this repeat sequence. In contrast, EVA-1224 contained only 7 cytosines. Analysis of the mRNA for HLA-A*010 using reverse trancriptase-polymerase chain reaction (RT-PCR), with an allele-specific 5' primer in exon 2 (bp 253-271) and a series of 3' primers in exons 3, 4 and 7 and in the 3'untranslated region, revealed that HCA-7 contained a shortened message terminating in the region of the exon 3/4 boundary. The insertion of an extra cytosine in this region, which is only two bases from the exon 3/4 splice site, is presumed to lead to a splicing defect between exons 3 and 4 resulting in the lack of expression of a functional HLA-A*0101 product. HCA-7 is mismatch repair (MMR) defective due to lack of expression of hMLH1 resulting from hypermethylation of the promoter region. The consequential increase in errors in single-nucleotide repeat stretches of DNA can account for the HLA-A*0101 mutation. This has probably then been selected for in the tumour to enable escape from immune attack against an HLA-A*0101-restricted tumour-specific determinant that has also arisen as a result of the tumour being MMR defective.


HIV and dyadic intervention: an interdependence and communal coping analysis.
The most common form of HIV transmission in sub-Saharan Africa is heterosexual sex between two partners. While most HIV prevention interventions are aimed at the individual, there is mounting evidence of the feasibility, acceptability, and efficacy of dyadic interventions. However, the mechanisms through which dyadic-level interventions achieve success remain little explored. We address this gap by using Lewis et al's interdependence model of couple communal coping and behaviour change to analyse data from partners participating in an HIV prevention trial in Uganda and Zambia. We conducted a comparative qualitative study using in-depth interviews. Thirty-three interviews were conducted in total; ten with couples and twenty-three with staff members at the two sites. The Ugandan site recruited a sero-discordant couple cohort and the Zambian site recruited women alone. Spouses' transformation of motivation is strong where couples are recruited and both partners stand to gain considerably by participating in the research; it is weaker where this is not the case. As such, coping mechanisms differ in the two sites; among sero-discordant couples in Uganda, communal coping is evidenced through joint consent to participate, regular couple counselling and workshops, sharing of HIV test results, and strong spousal support for adherence and retention. By contrast, coping at the Zambian site is predominantly left to the individual woman and occurs against a backdrop of mutual mistrust and male disenfranchisement. We discuss these findings in light of practical and ethical considerations of recruiting couples to HIV research. We argue for the need to consider the broader context within which behaviour change occurs and propose that future dyadic research be situated within the framework of the 'risk environment'.


Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions.
Alcohol consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Diosmin (DIO) is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features that underlay its protection against cardiac, hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus, the current study aimed to investigate the potential protective effects of DIO against ethanol-induced gastric injury in rats. Pretreatment with DIO (100 mg/kg p.o.) attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of ulcer index (UI) scores, area of gastric lesions, histopathologic aberrations and leukocyte invasion. These actions were analogous to those exerted by the reference antiulcer sucralfate. DIO suppressed gastric inflammation by curbing of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels along with nuclear factor kappa B (NF-κB) p65 expression. It also augmented the anti-inflammatory interleukin-10 (IL-10) levels. Meanwhile, DIO halted gastric oxidative stress via inhibition of lipid peroxides with concomitant enhancement of glutathione (GSH), glutathione peroxidase (GPx) and the total antioxidant capacity (TAC). With respect to gastric mucosal apoptosis, DIO suppressed caspase-3 activity and cytochrome C (Cyt C) with enhancement of the anti-apoptotic B cell lymphoma-2 (Bcl-2) in favor of cell survival. These favorable actions were associated with upregulation of the gastric cytoprotective prostaglandin E2 (PGE2) and nitric oxide (NO). Together, these findings accentuate the gastroprotective actions of DIO in ethanol gastric injury which were mediated via concerted multi-pronged actions, including suppression of gastric inflammation, oxidative stress and apoptosis besides boosting of the antioxidant and the cytoprotective defenses.


In-depth analysis of hyaline fibromatosis syndrome frameshift mutations at the same site reveal the necessity of personalized therapy.
Hyaline fibromatosis syndrome is an autosomal recessive disease caused by mutations in ANTXR2, a gene involved in extracellular matrix homeostasis. Sixty percent of patients carry frameshift mutations at a mutational hotspot in exon 13. We show in patient cells that these mutations lead to low ANTXR2 mRNA and undetectable protein levels. Ectopic expression of the proteins encoded by the mutated genes reveals that a two base insertion leads to the synthesis of a protein that is rapidly targeted to the ER-associated degradation pathway due to the modified structure of the cytosolic tail, which instead of being hydrophilic and highly disordered as in wild type ANTXR2, is folded and exposes hydrophobic patches. In contrast, one base insertion leads to a truncated protein that properly localizes to the plasma membrane and retains partial function. We next show that targeting the nonsense mediated mRNA decay pathway in patient cells leads to a rescue of ANTXR2 protein in patients carrying one base insertion but not in those carrying two base insertions. This study highlights the importance of in-depth analysis of the molecular consequences of specific patient mutations, which even when they occur at the same site can have drastically different consequences.


Cost-effectiveness of universal serologic screening to prevent nontraumatic hip and vertebral fractures in patients with celiac disease.
Patients with asymptomatic or poorly managed celiac disease can experience bone loss, placing them at risk for hip and vertebral fractures. We analyzed the cost-effectiveness of universal serologic screening (USS) vs symptomatic at-risk screening (SAS) strategies for celiac disease because of the risk of nontraumatic hip and vertebral fractures if untreated or undiagnosed. We developed a lifetime Markov model of the screening strategies, each with male or female cohorts of 1000 patients who were 12 years old when screening began. We screened serum samples for levels of immunoglobulin A, compared with tissue transglutaminase and total immunoglobulin A, and findings were confirmed by mucosal biopsy. Transition probabilities and quality of life estimates were obtained from the literature. We used generalizable cost estimates and Medicare reimbursement rates and ran deterministic and probabilistic sensitivity analyses. For men, the average lifetime costs were $8532 and $8472 for USS and SAS strategies, respectively, corresponding to average quality-adjusted life year gains of 25.511 and 25.515. Similarly for women, costs were $11,383 and $11,328 for USS and SAS strategies, respectively, corresponding to quality-adjusted life year gains of 25.74 and 25.75. Compared with the current standard of care (SAS), USS produced higher average lifetime costs and lower quality of life for each sex. Deterministic and probabilistic sensitivity analyses showed that the model was robust to realistic changes in all the variables, making USS cost-ineffective on the basis of these outcomes. USS and SAS are similar in lifetime costs and quality of life, although the current SAS strategy was overall more cost-effective in preventing bone loss and fractures among patients with undiagnosed or subclinical disease. On the basis of best available supportive evidence, it is more cost-effective to maintain the standard celiac screening practices, although future robust population-based evidence in other health outcomes could be leveraged to reevaluate current screening guidelines.


An analysis of patients in palliative care with pressure injuries.
The aim of this study was to evaluate the factors that are effective for the treatment, recovery of pressure injury (PI) and costs in palliative care (PC) patients. From a retrospective review of patient records, the PI localization, the presence of infection, PI stage on admission, discharge and treatment costs were recorded. Patients were grouped according to diagnoses, and PI localizations (sacrum, trochanter, ischium, and heel). The comparison was made of changes in wound stage in the groups. PI was present in all 154 patients during hospitalization and in 94 (61%) on discharge. Full recovery was determined in 52/129 (40.3%) patients with PI in the sacrum, in 23/46 (50%) in the trochanter, in 22/40 (55.0%) in the heel, and in 10/12 (83.3%) in the ischium. Worsening PI stage was observed in 5 (3.9%) in the sacrum, in 1 in the trochanter and in 4 in the heel. Improvement in PI stage was seen in 96 (74.4%) in the sacrum, in 35 (3.9%) in the trochanter, in 27 (50.5%) in the heel, and in 10 (83.3%) in the ischium. Regardless of wound localization, the improvement was observed in 168 (74%) of 227 PI and worsening in 10 (4.4%). The group with no change in the PI stage had prolonged hospital stay and higher costs. The Karnovsky Performance Score and Glasgow Coma Score of fully recovered patients were determined to be higher, and no statistically significant difference was seen in respect of age. PC patients are prone to PI due to many chronic diseases. The localization of PI and infection are effective factors in the healing of ulcers. The treatment costs for PC patients is higher if they have a pressure ulcer. More comprehensive studies will be useful to clarify the economic and social dimensions of this issue.


Outcomes of secondary self-expandable metal stents versus surgery after delayed initial palliative stent failure in malignant colorectal obstruction.
When re-intervention is required due to an occluded first colorectal self-expanding metal stent for malignant colorectal obstruction, serious controversies exist regarding whether to use endoscopic re-stenting or surgery. To compare the clinical outcomes in patients who underwent stent re-insertion versus palliative surgery as a second intervention. A total of 115 patients who received either self-expandable metal stent (SEMS) insertion or palliative surgery for treatment of a second occurrence of malignant colorectal obstruction after the first SEMS placement were retrospectively studied between July 2005 and December 2009. The median overall survival (8.2 vs. 15.5 months) and progression-free survival (4.0 vs. 2.7 months) were not significantly different between the stent and surgery groups (p = 0.895 and 0.650, respectively). The median lumen patency in the stent group was 3.4 months and that in the surgery group was 7.9 months (p = 0.003). The immediate complication rate after second stent insertion was 13.9% and late complication rate was observed in 12 of 79 (15.2%) patients. There was no mortality related to the SEMS procedure. The complication and mortality rates associated with palliative surgery were 3.5% (2/57) and 12.3% (7/57), respectively. Although there is no significant difference in the overall survival between stenting and surgery, a secondary stent insertion had a lower mortality rate despite a shorter duration of temporary colorectal decompression compared to that of palliative surgery.


Learning on 3D Meshes With Laplacian Encoding and Pooling.
3D models are commonly used in computer vision and graphics. With the wider availability of mesh data, an efficient and intrinsic deep learning approach to processing 3D meshes is in great need. Unlike images, 3D meshes have irregular connectivity, requiring careful design to capture relations in the data. To utilize the topology information while staying robust under different triangulations, we propose to encode mesh connectivity using Laplacian spectral analysis, along with mesh feature aggregation blocks (MFABs) that can split the surface domain into local pooling patches and aggregate global information amongst them. We build a mesh hierarchy from fine to coarse using Laplacian spectral clustering, which is flexible under isometric transformations. Inside the MFABs there are pooling layers to collect local information and multi-layer perceptrons to compute vertex features of increasing complexity. To obtain the relationships among different clusters, we introduce a Correlation Net to compute a correlation matrix, which can aggregate the features globally by matrix multiplication with cluster features. Our network architecture is flexible enough to be used on meshes with different numbers of vertices. We conduct several experiments including shape segmentation and classification, and our method outperforms state-of-the-art algorithms for these tasks on the ShapeNet and COSEG datasets.


Structure of the novel C-terminal domain of vacuolar protein sorting 30/autophagy-related protein 6 and its specific role in autophagy.
Vacuolar protein sorting 30 (Vps30)/autophagy-related protein 6 (Atg6) is a common component of two distinct phosphatidylinositol 3-kinase complexes. In complex I, Atg14 links Vps30 to Vps34 lipid kinase and exerts its specific role in autophagy, whereas in complex II, Vps38 links Vps30 to Vps34 and plays a crucial role in vacuolar protein sorting. However, the molecular role of Vps30 in each pathway remains unclear. Here, we report the crystal structure of the carboxyl-terminal domain of Vps30. The structure is a novel globular fold comprised of three β-sheet-α-helix repeats. Truncation analyses showed that the domain is dispensable for the construction of both complexes, but is specifically required for autophagy through the targeting of complex I to the pre-autophagosomal structure. Thus, the domain is named the β-α repeated, autophagy-specific (BARA) domain. On the other hand, the N-terminal region of Vps30 was shown to be specifically required for vacuolar protein sorting. These structural and functional investigations of Vps30 domains, which are also conserved in the mammalian ortholog, Beclin 1, will form the basis for studying the molecular functions of this protein family in various biological processes.


Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats.
Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers.


The Micro-Shear Bond Strength of Various Resinous Restorative Materials to Aged Biodentine.
The type of materials and application time of veneering restorations on calcium silicate cements are important factors which influence the interfacial properties. The aim of this study was to measure the micro-shear bond strength of a resin composite (RC) using several adhesive systems and a resin-modified glass ionomer cement (RM-GIC) to different aged Biodentine specimens. A total of 15 Biodentine blocks were prepared and assigned to three aging periods: 12 min, one week and one month. Then they were subdivided into five sub-groups to receive cylinders of resinous materials. RC was applied using different adhesive systems: A) no adhesive B) etch and rinse C) two-step self-etch and D) universal adhesive in self-etch mode and E) RM-GIC applied directly over Biodentine. Micro-shear bond strength was measured and the data were analyzed using one-way and two-way ANOVA. The level of significance was set at 0.05. There was significant interaction between Biodentine aging periods and resinous materials (P<0.05). The highest value was obtained in group D bonded to the recently set Biodentine. Increasing the aging period to one week resulted in increased micro-shear bond strength in all groups expect for group D. One-month incubation time led to reduced shear bond strength in group A, C and D. Micro-shear bond strength values of group E increased to the longer aged Biodentine. Group D showed the highest bond strength to freshly mixed Biodentine.


Acute effects of cannabinoids on addiction endophenotypes are moderated by genes encoding the CB1 receptor and FAAH enzyme.
Understanding genetic factors that contribute to cannabis use disorder (CUD) is important, but to date, findings have been equivocal. Single-nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 gene (CNR1; rs1049353 and rs806378) and fatty acid amide hydrolase (FAAH) gene (rs324420) have been implicated in CUD. Their relationship to addiction endophenotypes such as cannabis-related state satiety, the salience of appetitive cues, and craving after acute cannabinoid administration has not been investigated. Forty-eight cannabis users participated in a double-blind, placebo-controlled, four-way crossover experiment where they were administered treatments in a randomized order via vaporization: placebo, Δ9 -tetrahydrocannabinol (THC) (8 mg), THC + cannabidiol (THC + CBD) (8 + 16 mg), and CBD (16 mg). Cannabis-related state satiety, appetitive cue salience (cannabis and food), and cannabis craving were assessed each day. Participants were genotyped for rs1049353, rs806378, and rs324420. Results indicated that CNR1 rs1049353 GG carriers showed increased state satiety after THC/THC + CBD administration in comparison with placebo and reduced the salience of appetitive cues after THC in comparison with CBD administration; A carriers did not vary on either of these measures indicative of a vulnerability to CUD. CNR1 rs806378 CC carriers showed greater salience to appetitive cues in comparison with T carriers, but there was no evidence for changes in state satiety. FAAH rs324420 A carriers showed greater bias to appetitive cues after THC, in comparison with CC carriers. FAAH CC carriers showed reduced bias after THC in comparison with CBD. No SNPs modulated craving. These findings identify candidate neurocognitive mechanisms through which endocannabinoid system genetics may influence vulnerability to CUD.


Effect of Door-Locking Policy on Inpatient Treatment of Substance Use and Dual Disorders.
Substance use treatment is often performed inside locked wards. We investigate the effects of adopting a policy of open-door treatment for a substance use treatment and dual diagnosis ward. This is a prospective open-label study investigating 3-month study periods before opening (P1), immediately after (P2), and 1 year after the first period (P3). Data on committed patients, coercion (seclusion, forced medication, absconding events with subsequent police search), violence, and substance use was collected daily. We applied generalised estimating equation models. The mean daily number of patients with ongoing commitment changed from 2.64 (P1) to 2.12 (P2) to 0.96 (P3), corresponding to a reduction of relative risk (RR) for having an ongoing commitment by 20% in P2 (RR 0.80; 95% CI 0.66-0.98) and 67% in P3 (RR 0.33; 95% CI 0.25-0.42). The mean daily number of coercive events was 0.29, 0.13, and 0.05, corresponding to a risk for undergoing coercive measures reduced by 56% (RR 0.44; 95% CI 0.22-0.90) and 85% (RR 0.15; 95% CI 0.05-0.45). Substance use, violence or ward atmosphere did not differ significantly. Our results support findings from general psychiatric wards of reduced coercion after adopting a primarily open-door policy. However, coercive events were rare during all periods. The widespread practice of restricting the freedom of inpatients with substance use disorders by locking ward doors is highly questionable.


Mini review on tricyclic compounds as an inhibitor of trypanothione reductase.
Trypanosomiasis and leishmaniasis are two most ruinous parasitic infectious diseases caused by Trypanosoma and Leishmania species. The disease affects millions of people all over the world and associated with high morbidity and mortality rates. The review discuss briefly on current treatment of these parasitic diseases and trypanothione reductase (TryR) as potential targets for rational drug design. The enzyme trypanothione reductase (TryR) has been identified as unique among these parasites and has been proposed to be an effective target against for developing new drugs. The researchers have selected this enzyme as target is due to its substrate specificity in contrast to human analogous glutathione reductase and its absence from the host cell which makes this enzyme an ideal target for drug discovery. In this review we have tried to present an overview of the different tricyclic compounds which are potent inhibitors of TryR with their inhibitory activities against the parasites are briefly discussed.


A cancer-related fatigue clinic: opportunities and challenges.
Cancer-related fatigue (CRF) is the most prevalent symptom of cancer, occurring in 60% to 90% of patients and surpassing pain in frequency. CRF may increase patients' anxieties and hamper their quality of life. We developed a CRF clinic in 1998 because we believed there needed to be a more focused effort on the education, evaluation, and treatment of CRF for our patients. Since then, we have gained clinical insights into the planning, development, and evolution of this endeavor. Our objective is to share our experiences and provide preliminary analysis of the first 123 patients evaluated in this clinic.


Serotonin suppresses the slow afterhyperpolarization in rat intralaminar and midline thalamic neurones by activating 5-HT(7) receptors.
While the highest expression level of 5-HT(7) receptors in the brain is observed in intralaminar and midline thalamic neurones, the physiological role of these receptors in this structure is unknown. In vivo recordings have shown that stimulation of the serotonergic raphe nuclei can alter the response of these neurones to a nociceptive stimulus, suggesting that serotonin modulates their firing properties. Using the patch-clamp technique in rat thalamic brain slices, we demonstrate that activation of 5-HT(7) receptors can strongly modulate the excitability of intralaminar and midline thalamic neurones by inhibiting the calcium-activated potassium conductance that is responsible for the slow afterhyperpolarization (sAHP) following a spike discharge. This sAHP was inhibited after activation of the cAMP pathway, either by bath application of forskolin or intracellular perfusion with 8-bromo-cAMP. The inhibitory effect of 5-HT(7) receptors on sAHPs was blocked by the protein kinase A antagonist R(P)-cAMPS. Calcium-imaging experiments showed no change in intracellular calcium levels during the 5-HT(7) response, indicating that in these neurones, a global calcium signal was not necessary to activate the cAMP cascade. Finally, bath application of serotonin produced a strong increase in cytosolic cAMP concentration, as measured using the fluorescent probe FlCRhR, and an inhibition of the sAHP. Taken together, these results suggest that 5-HT(7) receptors are implicated in the effect of 5-HT on sAHP in intralaminar and midline thalamic neurones, an effect that is mediated by the cAMP second-messenger cascade.


Controlled Delivery of Vancomycin via Charged Hydrogels.
Surgical site infection (SSI) remains a significant risk for any clean orthopedic surgical procedure. Complications resulting from an SSI often require a second surgery and lengthen patient recovery time. The efficacy of antimicrobial agents delivered to combat SSI is diminished by systemic toxicity, bacterial resistance, and patient compliance to dosing schedules. We submit that development of localized, controlled release formulations for antimicrobial compounds would improve the effectiveness of prophylactic surgical wound antibiotic treatment while decreasing systemic side effects. Our research group developed and characterized oligo(poly(ethylene glycol)fumarate)/sodium methacrylate (OPF/SMA) charged copolymers as biocompatible hydrogel matrices. Here, we report the engineering of this copolymer for use as an antibiotic delivery vehicle in surgical applications. We demonstrate that these hydrogels can be efficiently loaded with vancomycin (over 500 μg drug per mg hydrogel) and this loading mechanism is both time- and charge-dependent. Vancomycin release kinetics are shown to be dependent on copolymer negative charge. In the first 6 hours, we achieved as low as 33.7% release. In the first 24 hours, under 80% of total loaded drug was released. Further, vancomycin release from this system can be extended past four days. Finally, we show that the antimicrobial activity of released vancomycin is equivalent to stock vancomycin in inhibiting the growth of colonies of a clinically derived strain of methicillin-resistant Staphylococcus aureus. In summary, our work demonstrates that OPF/SMA hydrogels are appropriate candidates to deliver local antibiotic therapy for prophylaxis of surgical site infection.


Treatment of chronic uremic patients with protein-poor diet and oral supply of essential amino acids. I. Nitrogen balance studies.
Twenty-six nitrogen balance studies were performed in 15 patients with severe uremia (Ccr mean value 5.1, range 2.3-8.5 ml/min) treated with an unselected protein-poor (16-20 g protein/day corresponding to 2.6-3.2 g N/day) diet and oral supply of the essential amino acids including histidine (2.6 g N/day). The general condition improved and the concentration of serum urea nitrogen decreased. The nitrogen balance, corrected for changes in total urea pool, was negative on the diet alone,-1.46 plus or minus 1.15 g N/day (mean plus or minus SD), but was positive when the essential amino acids were supplied, plus 0.84 plus or minus 0.68 g N/day. In four patients studied after 3 to 26 months of diet and amino acid therapy, during which time a further deterioriation of the renal function had occurred, the nitrogen balance was around zero in three and negative in one patient (-1.2 g N/day). The results show that it is possible with our new regimen to attain positive nitrogen balance or nitrogen equilibrium in severely uremic patients without excessive accumulation of urea in the body fluids.


Subsets of retinal progenitors display temporally regulated and distinct biases in the fates of their progeny.
Cell fate determination in the developing vertebrate retina is characterized by the sequential generation of seven classes of cells by multipotent progenitor cells. Despite this order of genesis, more than one cell type is generated at any time; for example, in the rat, several cell types are born during the prenatal period, while others are born postnatally. In order to examine whether there are classes of progenitor cells with distinct developmental properties contributing to this developmental progression, we examined antigen expression in progenitor cells during rat retinal development. Two markers of amacrine and horizontal cells, the VC1.1 epitope and syntaxin, were found to be expressed on a subset of progenitors in a temporally regulated manner that closely paralleled the birthdays of these cell types. In order to investigate which cell types were produced by the progenitors expressing these markers, fluorescent latex microspheres covalently coupled to VC1.1 antibodies were used to indelibly label VC1.1+ progenitor cells and their progeny. Early in retinal development, VC1.1+ progenitors generated a high percentage of amacrine and horizontal cells, but no cone photoreceptors. During this same period, a comparable number of cone photoreceptors were generated by VC1.1- progenitors. In the late embryonic and early postnatal period, VC1.1+ progenitors continued to generate predominantly amacrine cells, but also gave rise to an increasing number of rod photoreceptors. These findings demonstrate that expression of these two markers by progenitors is highly correlated with a bias towards the production of amacrine and horizontal cells. The fact that subsets of progenitors with temporally regulated and distinct biases are intermingled within the retinal neuroepithelium provides a basis for understanding how different cell types are generated both simultaneously and in a particular order by multipotent progenitors during retinal development.


Suppression mediated by anergic CD4+ T cells requires stimulation by MHC-peptide complexes and can be induced in the presence of costimulation.
In this study, we have investigated the mechanisms involved in both the induction of suppressive anergy, the stability of the anergy induced, and the possible mechanisms by which the response of immunocompetent CD4+ T cells are suppressed. We used immobilized anti-CD3 monoclonal antibody (mAb) to induce anergy in T helper (Th) 1 and Th0 cells reactive with MHC class II molecule H2 I-Ab. We observed that suppressive anergy was induced independently of costimulation in Th0 but not Th1 cells. Although the anergic and suppressive states of Th0 cells were stable in the presence of exogenous interleukin-2, this was not the case for Th1 cells. No evidence for linked epitope suppression was observed for any of the I-Ab reactive cells investigated. Neither anergy nor suppression was observed in Th0 cells upon restimulation with anti-CD3 in the presence of syngeneic antigen-presenting cells (APCs). However, anergy but not suppression was observed in co-cultures restimulated with anti-T-cell antigen receptor (TCR) mAbs/syngeneic APCs and suppression could be restored by the addition of I-Ab+ APCs. Overall, these data suggested that the MHC-peptide complex recognized by the Th0 cells was required for suppression of the response of immunocompetent cells. We propose that suppression is mediated either by down-modulation of the MHC-peptide complex recognized by the anergic T cells or that a molecule specific to the MHC-peptide/TCR interaction facilitates negative regulation by APC:T or T:T interactions.


Reinforcement learning for partially observable dynamic processes: adaptive dynamic programming using measured output data.
Approximate dynamic programming (ADP) is a class of reinforcement learning methods that have shown their importance in a variety of applications, including feedback control of dynamical systems. ADP generally requires full information about the system internal states, which is usually not available in practical situations. In this paper, we show how to implement ADP methods using only measured input/output data from the system. Linear dynamical systems with deterministic behavior are considered herein, which are systems of great interest in the control system community. In control system theory, these types of methods are referred to as output feedback (OPFB). The stochastic equivalent of the systems dealt with in this paper is a class of partially observable Markov decision processes. We develop both policy iteration and value iteration algorithms that converge to an optimal controller that requires only OPFB. It is shown that, similar to Q -learning, the new methods have the important advantage that knowledge of the system dynamics is not needed for the implementation of these learning algorithms or for the OPFB control. Only the order of the system, as well as an upper bound on its "observability index," must be known. The learned OPFB controller is in the form of a polynomial autoregressive moving-average controller that has equivalent performance with the optimal state variable feedback gain.


Cost-Effectiveness Evaluation of Etoricoxib versus Celecoxib and Nonselective NSAIDs in the Treatment of Ankylosing Spondylitis in Norway.
Objectives. To evaluate the cost-effectiveness of etoricoxib (90 mg) relative to celecoxib (200/400 mg), and the nonselective NSAIDs naproxen (1000 mg) and diclofenac (150 mg) in the initial treatment of ankylosing spondylitis in Norway. Methods. A previously developed Markov state-transition model was used to estimate costs and benefits associated with initiating treatment with the different competing NSAIDs. Efficacy, gastrointestinal and cardiovascular safety, and resource use data were obtained from the literature. Data from different studies were synthesized and translated into direct costs and quality adjusted life years by means of a Bayesian comprehensive decision modeling approach. Results. Over a 30-year time horizon, etoricoxib is associated with about 0.4 more quality adjusted life years than the other interventions. At 1 year, naproxen is the most cost-saving strategy. However, etoricoxib is cost and quality adjusted life year saving relative to celecoxib, as well as diclofenac and naproxen after 5 years of follow-up. For a willingness-to-pay ceiling ratio of 200,000 Norwegian krones per quality adjusted life year, there is a >95% probability that etoricoxib is the most-cost-effective treatment when a time horizon of 5 or more years is considered. Conclusions. Etoricoxib is the most cost-effective NSAID for initiating treatment of ankylosing spondylitis in Norway.


An image-based algorithm for precise and accurate high throughput assessment of drug activity against the human parasite Trypanosoma cruzi.
We present a customized high content (image-based) and high throughput screening algorithm for the quantification of Trypanosoma cruzi infection in host cells. Based solely on DNA staining and single-channel images, the algorithm precisely segments and identifies the nuclei and cytoplasm of mammalian host cells as well as the intracellular parasites infecting the cells. The algorithm outputs statistical parameters including the total number of cells, number of infected cells and the total number of parasites per image, the average number of parasites per infected cell, and the infection ratio (defined as the number of infected cells divided by the total number of cells). Accurate and precise estimation of these parameters allow for both quantification of compound activity against parasites, as well as the compound cytotoxicity, thus eliminating the need for an additional toxicity-assay, hereby reducing screening costs significantly. We validate the performance of the algorithm using two known drugs against T.cruzi: Benznidazole and Nifurtimox. Also, we have checked the performance of the cell detection with manual inspection of the images. Finally, from the titration of the two compounds, we confirm that the algorithm provides the expected half maximal effective concentration (EC50) of the anti-T. cruzi activity.


Adequacy of diagnosis and treatment of chronic heart failure in primary health care in Sweden.
We performed an observational multicentre study to obtain information of the diagnostic tools and treatments currently used in patients with chronic heart failure (CHF) in primary health care (PHC) in Sweden. Data were collected from 2093 patients in 158 randomly selected PHC centres. The mean age was 79 years. The dominating aetiology of HF was hypertension and/or ischaemic heart disease. Diagnosis was based on symptoms and/or ECG and/or chest X-ray in 69% of the patients. Treatment with a renin-angiotensin system (RAS) blocker was ongoing in 74% of the patients, but only 37% had > or = 50% of the recommended target dose. In 68%, treatment with a beta-blocker (BB) was present, but only 31% had > or = 50% of the recommended target dose. Only 42% of the patients were on treatment with an RAS blocker and a BB and only 20% had > or = 50% of the recommended target dose. The diagnostic criteria for CHF according to the European Society of Cardiology were fulfilled in only approximately 30% of the patients. In addition, evidenced-based treatments to reduce morbidity and mortality were markedly underused, particularly regarding dosing. Our findings may reflect the patients' high age and the presence of important co-morbidities.


Trichinella spiralis: genome database searches for the presence and immunolocalization of protein disulphide isomerase family members.
The formation of nurse cells in host muscle cells during Trichinella spiralis infection is a key step in the infective mechanism. Collagen trimerization is set up via disulphide bond formation, catalysed by protein disulphide isomerase (PDI). In T. spiralis, some PDI family members have been identified but no localization is described and no antibodies specific for T. spiralis PDIs are available. In this work, computational approaches were used to search for non-described PDIs in the T. spiralis genome database and to check the cross-reactivity of commercial anti-human antibodies with T. spiralis orthologues. In addition to a previously described PDI (PDIA2), endoplasmic reticulum protein (ERp57/PDIA3), ERp72/PDIA4, and the molecular chaperones calreticulin (CRT), calnexin (CNX) and immunoglobulin-binding protein/glucose-regulated protein (BIP/GRP78), we identified orthologues of the human thioredoxin-related-transmembrane proteins (TMX1, TMX2 and TMX3) in the genome protein database, as well as ERp44 (PDIA10) and endoplasmic reticulum disulphide reductase (ERdj5/PDIA19). Immunocytochemical staining of paraffin sections of muscle infected by T. spiralis enabled us to localize some orthologues of the human PDIs (PDIA3 and TMX1) and the chaperone GRP78. A theoretical three-dimensional model for T. spiralis PDIA3 was constructed. The localization and characteristics of the predicted linear B-cell epitopes and amino acid sequence of the immunogens used for commercial production of anti-human PDIA3 antibodies validated the use of these antibodies for the immunolocalization of T. spiralis PDIA3 orthologues. These results suggest that further study of the role of the PDIs and chaperones during nurse cell formation is desirable.


Immune cell-derived cytokines contribute to obesity-related inflammation, fibrogenesis and metabolic deregulation in human adipose tissue.
Adipose tissue contains a variety of immune cells, which vary in abundance and phenotype with obesity. The contribution of immune cell-derived factors to inflammatory, fibrotic and metabolic alterations in adipose tissue is not well established in human obesity. Human primary adipose tissue cells, including pre-adipocytes, endothelial cells and mature adipocytes, were used to investigate deregulation of cell- and pathway-specific gene profiles. Among factors known to alter adipose tissue biology, we focus on inflammatory (IL-1β and IL-17) and pro-fibrotic (TGF-β1) factors. rIL-1β and rIL-17 induced concordant pro-inflammatory transcriptional programs in pre-adipocytes and endothelial cells, with a markedly more potent effect of IL-1β than IL-17. None of these cytokines had significant effect on fibrogenesis-related gene expression, contrasting with rTGF-β1-induced up-regulation of extracellular matrix components and pro-fibrotic factors. In mature adipocytes, all three factors promoted down-regulation of genes functionally involved in lipid storage and release. IL-1β and IL-17 impacted adipocyte metabolic genes in relation with their respective pro-inflammatory capacity, while the effect of TGF-β1 occurred in face of an anti-inflammatory signature. These data revealed that IL-1β and IL-17 had virtually no effect on pro-fibrotic alterations but promote inflammation and metabolic dysfunction in human adipose tissue, with a prominent role for IL-1β.


Metoprolol for the Prevention of Acute Exacerbations of COPD.
Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).


Early recognition of 1-year-old infants with autism spectrum disorder versus mental retardation.
Previous work based on observations of home videotapes indicates that differences can be detected between infants with autism spectrum disorder and infants with typical development at 1 year of age. The present study addresses the question of whether autism can be distinguished from mental retardation by 1 year of age. Home videotapes of first birthday parties from 20 infants later diagnosed with autism spectrum disorder, 14 infants later diagnosed with mental retardation (without autism), and 20 typically developing infants were coded by blind raters with respect to the frequencies of specific social and communicative behaviors and repetitive motor actions. Results indicated that 1-year-olds with autism spectrum disorder can be distinguished from 1-year-olds with typical development and those with mental retardation. The infants with autism spectrum disorder looked at others and oriented to their names less frequently than infants with mental retardation. The infants with autism spectrum disorder and those with mental retardation used gestures and looked to objects held by others less frequently and engaged in repetitive motor actions more frequently than typically developing infants. These results indicate that autism can be distinguished from mental retardation and typical development by 1 year of age.


The characterisation and determinants of quality of life in ANCA associated vasculitis.
To contextualise and identify the determinants of poor health related quality of life (QOL) among patients with antineutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV). A multicentre AAV case-control study was conducted using two matched groups of population and chronic disease controls. Measures of physical and mental QOL as well as putative bio-psychosocial determinants of QOL impairment were collected. Concurrently, putative clinical QOL determinants were recorded. Conditional logistic regression analyses characterised group differences while multivariable logistic regression identified within-case QOL associations which were further quantified using population attributable risks (PAR). Cases (n=410) experienced similar QOL to chronic disease controls (n=318) (physical QOL: OR 0.7, 95% CI 0.4 to 1.1; mental QOL: OR 1.1, 95% CI 0.8 to 1.6). However, they were substantially more likely to report poor QOL compared to general population controls (n=470) (physical QOL: OR 7.0, 95% CI 4.4 to 11.1; mental QOL: OR 2.5, 95% CI 1.7 to 3.6). A few clinical, but many more bio-psychosocial factors were independently associated with poor QOL. In population terms, fatigue was found to be of principal importance (physical QOL: PAR 24.6%; mental QOL: PAR 47.4%). AAV patients experienced significant QOL impairment compared to the general population, but similar to those with other chronic diseases whose considerable needs are already recognised. Potentially modifiable clinical determinants have been identified; however bio-psychosocial interventions are likely to provide the greater QOL gains in this patient population.


Quadriceps Muscle Fatigue Reduces Extension and Flexion Power During Maximal Cycling.
Purpose: To investigate how quadriceps muscle fatigue affects power production over the extension and flexion phases and muscle activation during maximal cycling. Methods: Ten participants performed 10-s maximal cycling efforts without fatigue and after 120 bilateral maximal concentric contractions of the quadriceps muscles. Extension power, flexion power and electromyographic (EMG) activity were compared between maximal cycling trials. We also investigated the associations between changes in quadriceps force during isometric maximal voluntary contractions (IMVC) and power output (flexion and extension) during maximal cycling, in addition to inter-individual variability in muscle activation and pedal force profiles. Results: Quadriceps IMVC (-52 ± 21%, P = 0.002), voluntary activation (-24 ± 14%, P < 0.001) and resting twitch amplitude (-45 ± 19%, P = 0.002) were reduced following the fatiguing task, whereas vastus lateralis (P = 0.58) and vastus medialis (P = 0.15) M-wave amplitudes were unchanged. The reductions in extension power (-15 ± 8%, P < 0.001) and flexion power (-24 ± 18%, P < 0.001) recorded during maximal cycling with fatigue of the quadriceps were dissociated from the decreases in quadriceps IMVC. Peak EMG decreased across all muscles while inter-individual variability in pedal force and EMG profiles increased during maximal cycling with quadriceps fatigue. Conclusion: Quadriceps fatigue induced by voluntary contractions led to reduced activation of all lower limb muscles, increased inter-individual variability and decreased power production during maximal cycling. Interestingly, power production was further reduced over the flexion phase (24%) than the extension phase (15%), likely due to larger levels of peripheral fatigue developed in RF muscle and/or a higher contribution of the quadriceps muscle to flexion power production compared to extension power during maximal cycling.


Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves' disease: replication using a population case control and family-based study.
Early case control studies found association of the DRB1 allele, DR3, with Graves' disease (GD). Recent reports, claim the DQA1 allele, DQA1*0501, to be the primary susceptibility determinant within the human leukocyte antigen (HLA) class II region. We typed 228 GD patients, 364 controls, and 98 families (parents, GD, and unaffected sibling) at the DRB1, DQB1, and DQA1 loci. The case control study showed an increased frequency in GD, compared to controls, of DRB1*0304 (47% vs. 24%; pc < 1.4 x 10(-5)), DQB1*02 (58% vs. 46%; pc < 0.035), DQB1*0301/4 (42% vs. 28%; pc < 3.5 x 10(-3)) and DQA1*0501 (67%, vs. 39%; pc < 7 x 10(-6)). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) vs. controls (24%; pc < 1.8 x 10(-5); odds ratio = 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to GD siblings (72%) was seen in the families (chi2 = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected siblings (53%; chi2 = 0.19; 1 d.f.; P = NS) excluded segregation distortion. These results show that linkage disequilibrium between GD and the HLA class II region is due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.


A prospective evaluation of a protocol for magnetic resonance imaging of patients with implanted cardiac devices.
Magnetic resonance imaging (MRI) is avoided in most patients with implanted cardiac devices because of safety concerns. To define the safety of a protocol for MRI at the commonly used magnetic strength of 1.5 T in patients with implanted cardiac devices. Prospective nonrandomized trial. (ClinicalTrials.gov registration number: NCT01130896) SETTING: One center in the United States (94% of examinations) and one in Israel. 438 patients with devices (54% with pacemakers and 46% with defibrillators) who underwent 555 MRI studies. Pacing mode was changed to asynchronous for pacemaker-dependent patients and to demand for others. Tachyarrhythmia functions were disabled. Blood pressure, electrocardiography, oximetry, and symptoms were monitored by a nurse with experience in cardiac life support and device programming who had immediate backup from an electrophysiologist. Activation or inhibition of pacing, symptoms, and device variables. In 3 patients (0.7% [95% CI, 0% to 1.5%]), the device reverted to a transient back-up programming mode without long-term effects. Right ventricular (RV) sensing (median change, 0 mV [interquartile range {IQR}, -0.7 to 0 V]) and atrial and right and left ventricular lead impedances (median change, -2 Ω [IQR, -13 to 0 Ω], -4 Ω [IQR, -16 to 0 Ω], and -11 Ω [IQR, -40 to 0 Ω], respectively) were reduced immediately after MRI. At long-term follow-up (61% of patients), decreased RV sensing (median, 0 mV, [IQR, -1.1 to 0.3 mV]), decreased RV lead impedance (median, -3 Ω, [IQR, -29 to 15 Ω]), increased RV capture threshold (median, 0 V, IQR, [0 to 0.2 Ω]), and decreased battery voltage (median, -0.01 V, IQR, -0.04 to 0 V) were noted. The observed changes did not require device revision or reprogramming. Not all available cardiac devices have been tested. Long-term in-person or telephone follow-up was unavailable in 43 patients (10%), and some data were missing. Those with missing long-term capture threshold data had higher baseline right atrial and right ventricular capture thresholds and were more likely to have undergone thoracic imaging. Defibrillation threshold testing and random assignment to a control group were not performed. With appropriate precautions, MRI can be done safely in patients with selected cardiac devices. Because changes in device variables and programming may occur, electrophysiologic monitoring during MRI is essential.


Estimating the selective advantage of mutant p53 tumour cells to repeated rounds of hypoxia.
The tumour suppressor gene, p53, plays an important role in tumour development. Under low levels of oxygen (hypoxia), cells expressing wild-type p53 undergo programmed cell death (apoptosis), whereas cells expressing mutations in the p53 gene may survive and express angiogenic growth factors that stimulate tumour vascularization. Given that cells expressing mutations in the p53 gene have been observed in many forms of human tumour, it is important to understand how both wild-type and mutant cells react to hypoxic conditions. In this paper a mathematical model is presented to investigate the effects of alternating periods of hypoxia and normoxia (normal oxygen levels) on a population of wild-type and mutant p53 tumour cells. The model consists of three coupled ordinary differential equations that describe the densities of the two cell types and the oxygen concentration and, as such, may describe the growth of avascular tumours in vitro and/or in vivo. Numerical and analytical techniques are used to determine how changes in the system parameters influence the time at which mutant cells become dominant within the population. A feedback mechanism, which switches off the oxygen supply when the total cell density exceeds a threshold value, is introduced into the model to investigate the impact that vessel collapse (and the associated hypoxia) has on the time at which the mutant cells become dominant within vascular tumours growing in vivo. Using the model we can predict the time it takes for a subpopulation of mutant p53 tumour cells to become the dominant population within either an avascular tumour or a localized region of a vascular tumour. Based on independent experimental results, our model suggests that the mutant population becomes dominant more quickly in vivo than in vitro (12 days vs 17 days).


Reversible Underwater Adhesion for Soft Robotic Feet by Leveraging Electrochemically Tunable Liquid Metal Interfaces.
Soft crawling robots have potential applications for surveillance, rescue, and detection in complex environments. Despite this, most existing soft crawling robots either use nonadjustable feet to passively induce asymmetry in friction to actuate or are only capable of moving on surfaces with specific designs. Thus, robots often lack the ability to move along arbitrary directions in a two-dimensional (2D) plane or in unpredictable environments such as wet surfaces. Here, leveraging the electrochemically tunable interfaces of liquid metal, we report the development of liquid metal smart feet (LMSF) that enable electrical control of friction for achieving versatile actuation of prismatic crawling robots on wet slippery surfaces. The functionality of the LMSF is examined on crawling robots with soft or rigid actuators. Parameters that affect the performance of the LMSF are investigated. The robots with the LMSF prove capable of actuating across different surfaces in various solutions. Demonstration of 2D locomotion of crawling robots along arbitrary directions validates the versatility and reliability of the LMSF, suggesting broad utility in the development of advanced soft robotic systems.


Circular stapled hemorrhoidopexy: experience of a single center with 445 cases.
This study was designed to review the results of circular stapled hemorrhoidopexy (CSH) in the management of second-, third-, and fourth-degree hemorrhoidal disease. The medical records of 483 patients who had undergone circular stapled hemorrhoidopexy for symptomatic hemorrhoidal disease from June 2001 to September 2006 were evaluated. Data regarding complications, residual symptoms, and recurrence were collected. The study included 445 patients (283 men, 162 women) between 22 and 74 years old (median age 39 years). This constituted 92% of all patients. Concomitant lateral internal sphincterotomy, skin tags' excision, and thrombus removal were done in 106 (24.0%), 83 (18.5%), and 20 (4.5%) patients, respectively. The median operating time was 24 minutes (10-45 minutes). The median hospital stay was 40 hours (11-72 hours). Complications during the first 24 hours were fecal urgency (25%), urinary retention (8%), and rectal bleeding (1%). Pruritus ani (21%), thrombosed external hemorrhoids (4%), staple line stenosis (2%), rectal bleeding (2%), anal fissure (1%), and persistent skin tags (3%) were the symptoms seen during the long-term follow-up. The median follow-up was 23 months (6-70 months). The recurrence rate was 1%. Circular stapled hemorrhoidopexy can be safely performed with low recurrence and complication rates while offering a relatively painless postoperative period for the patient.


A new instrument to measure patient satisfaction with mammography. Validity, reliability, and discriminatory power.
The benefit of mammography depends on repeated use. Therefore, surveying the mammographic quality as judged by the users addresses an important topic. The authors assess the practicality, validity, reliability, and discriminatory power of a new, brief, multidimensional questionnaire for measuring patient satisfaction with mammography. Items measuring discomfort and attitudes toward repeat adherence were included. A self-administered questionnaire was given to women from six radiology departments in Norway. Four hundred eighty-eight out of 550 women referred for screening or diagnostic mammography were included. Seventy-seven patients also completed the test/retest study, and 44 women additionally completed an Australian questionnaire. Scores for patient satisfaction on the structure, process, discomfort, and general satisfaction scales of the questionnaire were used as the main outcome measures. Response rate was 89%, and rate of completion was more than 95%. Strict psychometric criteria for construct validity and reliability were satisfied. Because lower levels of satisfaction were detectable with the new questionnaire but not with the Australian questionnaire and because an acceptable degree of variability in response was detected, support for discriminatory power was found. The discomfort dimension contributed substantially to validity and discriminatory power. Patient behavior with time may be monitored with the new questionnaire, thus representing a valuable tool for scientific and practical purposes.


A Randomized Controlled Trial to Determine the Effect of Depth of Anesthesia on Emergence Agitation in Children.
The cause of emergence agitation (EA) in children is unknown. Rapid emergence from inhaled anesthesia has been implicated because EA is more common with sevoflurane than with halothane. A dose-dependent effect of sevoflurane, which increases seizure-like electroencephalogram activity, has also been proposed. To determine whether depth of anesthesia as measured by bispectral index (BIS) affects EA, 40 ASA physical status I to II children aged 2 to 8 years undergoing ophthalmic surgery were enrolled in a blinded randomized controlled trial of low-normal (40-45, deep) versus high-normal (55-60, light) anesthesia. To distinguish transient irritability from severe EA, the primary outcome was first-stage postanesthesia care unit (PACU I) peak Pediatric Assessment of Emergence Delirium (PAED) score, with secondary outcomes of PAED and Face, Legs, Activity, Cry, and Consolability scores at emergence, postoperative fentanyl dose, emergence time, and discharge time. Subjects received a standard anesthesia protocol with oral midazolam followed by mask induction with sevoflurane 8%, fentanyl 1 to 1.5 μg/kg IV (then as needed), neuromuscular blockade, and endotracheal intubation. Providers titrated expired sevoflurane (in N2O 67%) from 0.5% to 3% to maintain BIS range. PAED, Richmond Agitation Sedation Scale, and Face, Legs, Activity, Cry, and Consolability scores were measured at emergence, at PACU I arrival, and during PACU I stay. There was little difference between the groups in the primary outcome, peak PACU I PAED score (light: 7.7 ± 4.6; deep: 8.6 ± 5.3; mean difference, 0.9; 95% confidence interval, 4.1 to -2.3; effect size, 0.18). Discharge times were similar between groups. Treatment for severe EA was rare. There was no significant effect of BIS-guided deep versus light anesthesia on severe EA.