Serum pepsinogens as a gastric cancer and gastritis biomarker in South and Southeast Asian populations.
Serum pepsinogens have been widely acknowledged as gastric mucosal biomarkers; however, a multicountry report on the benefits of pepsinogens as biomarkers has not yet been published. We analyzed 1,206 sera and gastric mucosal samples collected from Bangladesh, Bhutan, Indonesia, Myanmar, Nepal and Thailand then assessed the association between gastric mucosal changes and Helicobacter pylori infection. The new cutoff values for serum pepsinogen values were evaluated using a receiver operating characteristic analysis. The participants with H. pylori infection had significantly lower pepsinogen I and higher pepsinogen II values, but a lower pepsinogen I/II ratio than participants without the infection (all P < .001). The pepsinogen I and pepsinogen I/II values were significantly higher and lower, respectively, in individuals with atrophic gastritis than in those without (both P < .001). Among uninfected individuals, only the pepsinogen I/II ratio was significantly lower in atrophic individuals. Pepsinogen I/II ratio also were significantly different between disease among H. pylori-positive and H. pylori-negative individuals, suggesting the pepsinogen I/II ratio is a robust biomarker for determining both chronic and atrophic gastritis. The cutoffs for detecting chronic and atrophic gastritis for the pepsinogen I/II ratio were 4.65 and 4.95, respectively. In conclusion, pepsinogen levels are useful biomarker for both chronic gastritis and atrophic gastritis, but they should be used with caution. Population-based validation is necessary to determine the best cutoff values. Among all pepsinogen values, the pepsinogen I/II ratio was the most reliable gastric mucosal-change biomarker.


Flexible structure multiple modeling using irregular self-organizing maps neural network.
The MMSOM identification method, which had been presented by the authors, is improved to the multiple modeling by the irregular self-organizing map (MMISOM) using the irregular SOM (ISOM). Inputs to the neural networks are parameters of the instantaneous model computed adaptively at every instant. The neural network learns these models. The reference vectors of its output nodes are estimation of the parameters of the local models. At every instant, the model with closest output to the plant output is selected as the model of the plant. ISOM used in this paper is a graph of all the nodes and some of the weighted links between them to make a minimum spanning tree graph. It is shown in this paper that it is possible to add new models if the number of models is initially less than the appropriate one. The MMISOM shows more flexibility to cover the linear model space of the plant when the space is concave.


Haemodynamic stress-induced breaches of the arterial intima trigger inflammation and drive atherogenesis.
Inflammatory mediators, including blood cells and their products, contribute critically to atherogenesis, but the igniting triggers of inflammation remain elusive. Atherosclerosis develops at sites of flow perturbation, where the enhanced haemodynamic stress could initiate the atherogenic inflammatory process due to the occurrence of mechanic injury. We investigated the role of haemodynamic stress-induced breaches, allowing the entry of blood cells in the arterial intima, in triggering inflammation-driven atherogenesis. Human coronary samples isolated from explanted hearts, (n = 47) displayed signs of blood entry (detected by the presence of iron, ferritin, and glycophorin A) in the subintimal space (54%) as assessed by histology, immunofluorescence, high resolution episcopic microscopy, and scanning electron microscopy. Computational flow dynamic analysis showed that intimal haemorrhagic events occurred at sites of flow disturbance. Experimental carotid arteries from Apoe deficient mice showed discrete endothelial breaches and intimal haemorrhagic events specifically occurring at the site of flow perturbation, within 3 days after the exacerbation of the local haemodynamic stress. Endothelial tearing was associated with increased VCAM-1 expression and, within 7 days, substantial Ly6G+ leucocytes accumulated at the sites of erythrocyte-derived iron and lipids droplets accumulation, pathological intimal thickening and positive oil red O staining. The formation of fatty streaks at the sites of intimal breaches was prevented by the depletion of Ly6G+ leucocytes, suggesting that the local injury driven by haemodynamic stress-induced breaches triggers atherogenic inflammation. Haemodynamic-driven breaches of the arterial intima drive atherogenic inflammation by triggering the recruitment of leucocyte at sites of disturbed arterial flow.


Imaging the Zigzag Wigner Crystal in Confinement-Tunable Quantum Wires.
The existence of Wigner crystallization, one of the most significant hallmarks of strong electron correlations, has to date only been definitively observed in two-dimensional systems. In one-dimensional (1D) quantum wires Wigner crystals correspond to regularly spaced electrons; however, weakening the confinement and allowing the electrons to relax in a second dimension is predicted to lead to the formation of a new ground state constituting a zigzag chain with nontrivial spin phases and properties. Here we report the observation of such zigzag Wigner crystals by use of on-chip charge and spin detectors employing electron focusing to image the charge density distribution and probe their spin properties. This experiment demonstrates both the structural and spin phase diagrams of the 1D Wigner crystallization. The existence of zigzag spin chains and phases which can be electrically controlled in semiconductor systems may open avenues for experimental studies of Wigner crystals and their technological applications in spintronics and quantum information.


Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide.
Interactions between fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) regulate microglial activation in the CNS. Recent findings indicate that age-associated impairments in CX3CL1 and CX3CR1 are directly associated with exaggerated microglial activation and an impaired recovery from sickness behavior after peripheral injection of lipopolysaccharide (LPS). Therefore, the purpose of this study was to determine the extent to which an acute LPS injection causes amplified and prolonged microglial activation and behavioral deficits in CX3CR1-deficient mice (CX3CR1-/-). CX3CR1-/- mice or control heterozygote mice (CX3CR1+/-) were injected with LPS (0.5 mg/kg i.p.) or saline and behavior (i.e., sickness and depression-like behavior), microglial activation, and markers of tryptophan metabolism were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions. LPS injection caused a prolonged duration of social withdrawal in CX3CR1-/- mice compared to control mice. This extended social withdrawal was associated with enhanced mRNA expression of IL-1β, indolamine 2,3-dioxygenase (IDO) and kynurenine monooxygenase (KMO) in microglia 4 h after LPS. Moreover, elevated expression of IL-1β and CD14 was still detected in microglia of CX3CR1-/- mice 24 h after LPS. There was also increased turnover of tryptophan, serotonin, and dopamine in the brain 24 h after LPS, but these increases were independent of CX3CR1 expression. When submitted to the tail suspension test 48 and 72 h after LPS, an increased duration of immobility was evident only in CX3CR1-/- mice. This depression-like behavior in CX3CR1-/- mice was associated with a persistent activated microglial phenotype in the hippocampus and prefrontal cortex. Taken together, these data indicate that a deficiency of CX3CR1 is permissive to protracted microglial activation and prolonged behavioral alterations in response to transient activation of the innate immune system.


[Multi-dimensional study of the voice in the teaching professionals of La Rioja].
The vocal pathology is very frequent among the teaching professionals. We have selected 140 teachers, 70 normals, and 70 with dysphonia. To all of them we have realised a complete voice exploration: aerodyinamic tests, tone and extension of the voice, perceptual evaluation of the voice with the GRBAS scale and also a videolaringostroboscopy to diagnose the teachers. Among the dysphonic teachers there is a poor neumophonologic coordination, a major use or an inadequate use of the respiratory and/or laryngeal musculature. The dysphonic teachers present a more pathological voice in the GRBAS scale than the normal teachers.


SseK1 and SseK2 are novel translocated proteins of Salmonella enterica serovar typhimurium.
Salmonella enterica is a gram-negative, facultative intracellular pathogen that causes disease symptoms ranging from gastroenteritis to typhoid fever. A key virulence strategy is the translocation of bacterial effector proteins into the host cell, mediated by the type III secretion systems (TTSSs) encoded in Salmonella pathogenicity island 1 (SPI-1) and SPI-2. In S. enterica serovar Typhimurium LT2, we identified the protein products of STM4157 and STM2137 as novel candidate secreted proteins by comparison to known secreted proteins from enterohemorrhagic Escherichia coli and Citrobacter rodentium. The STM4157 and STM2137 proteins, which we have designated SseK1 and SseK2, respectively, are 61% identical at the amino acid level and differ mainly in their N termini. Western analysis showed that in vitro accumulation and secretion of these proteins in serovar Typhimurium were affected by mutations in the two-component systems SsrA/B and PhoP/Q, which are key mediators of intracellular growth and survival. SPI-2 TTSS-dependent translocation of recombinant SseK1::Cya was evident at 9 h postinfection of epithelial cells, while translocation of SseK2::Cya was not detected until 21 h. Remarkably, the translocation signal for SseK1 was contained within the N-terminal 32 amino acids. Fractionation of infected epithelial cells revealed that following translocation SseK1 localizes to the host cytosol, which is unusual among the currently known Salmonella effectors. Phenotypic analysis of DeltasseK1, DeltasseK2, and DeltasseK1/DeltasseK2 mutants provided evidence for a role that was not critical during systemic infection. In summary, this work demonstrates that SseK1 and SseK2 are novel translocated proteins of serovar Typhimurium.


Antiatherogenic, hepatoprotective, and hypolipidemic effects of coenzyme Q10 in alloxan-induced type 1 diabetic rats.
Diabetes mellitus, one of the leading metabolic syndromes, accounts for highest morbidity and mortality worldwide. In this study, we examined possible protective effect of coenzyme Q10 on lipid profile, atherogenic index, and liver enzyme markers in alloxan-induced type 1 diabetic rats. A total of 30 male rats were randomly divided into three groups; group 1 as control, group 2 diabetic untreatment, and group 3 treatments with coenzyme Q10 by 15 mg/kg i.p. daily, respectively .Diabetes was induced in the second and third groups by alloxan injection subcutaneously. After 8 weeks, the levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), very low-density lipoprotein (VLDL), high density lipoprotein (HDL), atherogenic index, atherogenic coefficient, cardiac risk ratio, and the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) of all groups were analyzed. Data were analyzed using non-parametric Mann-Whitney test (using SPSS) and P < 0.05 was considered as significant. Coenzyme Q10 inhibited significantly the activities of ALT (11.17%), AST (19.35%) and ALP (36.67%) and decreased FBG (21.19%), TG (37.24%), TC (17.15%), LDL (30.44%), VLDL (37.24%), atherogenic index (44.24%), atherogenic coefficient (49.69%), and cardiac risk ratio (37.97%), HDL level was significantly (33.38%) increased when treated with coenzyme Q10. The findings of this study suggest that coenzyme Q10 exert beneficial effects on the lipid profile, atherogenic index, and liver enzymes activity in alloxan-induced type 1 diabetic rats.


Reported occupational respiratory diseases in Catalonia.
A voluntary surveillance system was implemented in Catalonia (Spain) to ascertain the feasibility, incidence, and characteristics of occupational respiratory diseases and compare them with those of the compulsory official system. In 2002, in collaboration with the Occupational and Thoracic Societies of Catalonia, occupational and chest physicians and other specialists were invited to report, on a bimonthly basis, newly diagnosed cases of occupational respiratory diseases. Information requested on each case included diagnosis, age, sex, place of residence, occupation, suspected agent, and physician's opinion on the likelihood that the condition was work related. Compulsory official system data derived from statistics on work related diseases for possible disability benefits declared by insurance companies, which are responsible for declaring these diseases to the Autonomous Government of Catalonia. Of 142 physicians seeing patients with occupational respiratory diseases approached, 102 (74%) participated. Three hundred and fifty nine cases were reported, of which asthma (48.5%), asbestos related diseases (14.5%), and acute inhalations (12.8%) were the most common. Physicians rated 63% of suspected cases as highly likely, 28% as likely, and 8% as low likelihood. The most frequent suspected agents reported for asthma were isocyanates (15.5%), persulphates (12.1%), and cleaning products (8.6%). Mesothelioma (5.9%) was the most frequent diagnosis among asbestos related diseases. The number of acute inhalations reported was high, with metal industries (26%), cleaning services (22%), and chemical industries (13%) being the most frequently involved. The frequency of occupational respiratory diseases recorded by this voluntary surveillance system was four times higher than that reported by the compulsory official system. The compulsory scheme for reporting occupational lung diseases is seriously underreporting in Catalonia. A surveillance programme based on voluntary reporting by physicians may provide better understanding of the incidence and characteristics of these diseases. Persulphates and cleaning products, besides isocyanates, were the most reported causes of occupational asthma. Metal industries and cleaning services were the occupations most frequently involved in acute inhalations with a remarkably high incidence in our register.


Li6E5Li6: Tetrel Sandwich Complexes with 10-π-Electrons.
When six π-electrons are located in single ring, it conventionally qualifies as aromatic. According Hückel's rule, systems possessing ten π-electrons should be aromatic. Herein we report the D5h Li6E5Li6 sandwich structures, representing the first global minima featuring ten π-electrons E510- ring (E = Si-Pb). However, these π-electrons localize as five π-lone-pairs rather than delocalized orbitals. The high symmetry structure achieved is a direct consequence of σ-aromaticity, particularly favored in elements from Si to Pb, resulting in a pronounced diatropic ring current flow that contributes to the enhanced stability of these systems.


αE-catenin regulates cell-cell adhesion and membrane blebbing during zebrafish epiboly.
αE-catenin is an actin-binding protein associated with the E-cadherin-based adherens junction that regulates cell-cell adhesion. Recent studies identified additional E-cadherin-independent roles of αE-catenin in regulating plasma membrane dynamics and cell migration. However, little is known about the roles of αE-catenin in these different cellular processes in vivo during early vertebrate development. Here, we examined the functions of αE-catenin in cell-cell adhesion, cell migration and plasma membrane dynamics during morphogenetic processes that drive epiboly in early Danio rerio (zebrafish) development. We show that depletion of αE-catenin caused a defect in radial intercalation that was associated with decreased cell-cell adhesion, in a similar manner to E-cadherin depletion. Depletion of αE-catenin also caused deep cells to have protracted plasma membrane blebbing, and a defect in plasma membrane recruitment of ERM proteins that are involved in controlling membrane-to-cortex attachment and membrane blebbing. Significantly, depletion of both E-cadherin and αE-catenin suppressed plasma membrane blebbing. We suggest that during radial intercalation the activities of E-cadherin and αE-catenin in the maintenance of membrane-to-cortex attachment are balanced, resulting in stabilization of cell-cell adhesion and suppression of membrane blebbing, thereby enabling proper radial intercalation.


Premature aortic smooth muscle cell differentiation contributes to matrix dysregulation in Marfan Syndrome.
Thoracic aortic aneurysm and dissection are life-threatening complications of Marfan syndrome (MFS). Studies of human and mouse aortic samples from late stage MFS demonstrate increased TGF-β activation/signaling and diffuse matrix changes. However, the role of the aortic smooth muscle cell (SMC) phenotype in early aneurysm formation in MFS has yet to be fully elucidated. As our objective, we investigated whether an altered aortic SMC phenotype plays a role in aneurysm formation in MFS. We describe previously unrecognized concordant findings in the aortas of a murine model of MFS, mgR, during a critical and dynamic phase of early development. Using Western blot, gelatin zymography, and histological analysis, we demonstrated that at postnatal day (PD) 7, before aortic TGF-β levels are increased, there is elastic fiber fragmentation/disorganization and increased levels of MMP-2 and MMP-9. Compared to wild type (WT) littermates, aortic SMCs in mgR mice express higher levels of contractile proteins suggesting a switch to a more mature contractile phenotype. In addition, tropoelastin levels are decreased in mgR mice, a finding consistent with a premature switch to a contractile phenotype. Proliferation assays indicate a decrease in the proliferation rate of mgR cultured SMCs compared to WT SMCs. KLF4, a regulator of smooth muscle cell phenotype, was decreased in aortic tissue of mgR mice. Finally, overexpression of KLF4 partially reversed this phenotypic change in the Marfan SMCs. This study indicates that an early phenotypic switch appears to be associated with initiation of important metabolic changes in SMCs that contribute to subsequent pathology in MFS.


Infrequent Provision of Palliative Care to Patients with Dialysis-Requiring AKI.
The use of palliative care in AKI is not well described. We sought to better understand palliative care practice patterns for hospitalized patients with AKI requiring dialysis in the United States. Using the 2012 National Inpatient Sample, we identified patients with AKI and palliative care encounters using validated International Classification of Diseases, Ninth Revision, Clinical Modification codes. We compared palliative care encounters in patients with AKI requiring dialysis, patients with AKI not requiring dialysis, and patients without AKI. We described the provision of palliative care in patients with AKI requiring dialysis and compared the frequency of palliative care encounters for patients with AKI requiring dialysis with that for patients with other illnesses with similarly poor prognoses. We used logistic regression to determine factors associated with the provision of palliative care, adjusting for demographics, hospital-level variables, and patient comorbidities. We identified 3,031,036 patients with AKI, of whom 91,850 (3%) received dialysis. We observed significant patient- and hospital-level differences in the provision of palliative care for patients with AKI requiring dialysis; adjusted odds were 26% (95% confidence interval, 12% to 38%) lower in blacks and 23% (95% confidence interval, 3% to 39%) lower in Hispanics relative to whites. Lower provision of palliative care was observed for rural and urban nonteaching hospitals relative to urban teaching hospitals, small and medium hospitals relative to large hospitals, and hospitals in the Northeast compared with the South. After adjusting for age and sex, there was low utilization of palliative care services for patients with AKI requiring dialysis (8%)-comparable with rates of utilization by patients with other illnesses with poor prognosis, including cardiogenic shock (9%), intracranial hemorrhage (10%), and acute respiratory distress syndrome (10%). The provision of palliative care varied widely by patient and facility characteristics. Palliative care was infrequently used in hospitalized patients with AKI requiring dialysis, despite its poor prognosis and the regular application of life-sustaining therapy.


Effect of sodium bicarbonate on rate of passage and degradation of soybean meal in postpartum dairy cows.
Effects of sodium bicarbonate on rate of passage and disappearance of soybean meal from the rumen were determined in a change-over experiment with eight cows. Experimental diets containing 50 or 60% roughage were fed over five 21-day periods with four cows per diet. Sodium bicarbonate at 1.0 and 2.5% (diet dry matter) were changed over in periods 2 and 4, whereas periods 1, 3, and 5 served as control. Rate of passage of soybean meal was measured with chromium-mordanted soybean meal and rate of disappearance by nylon bag technique. Effects of diet were similar for all responses. Response to the two percents of buffer was similar for dry matter intake, milk yield, milk fat, and protein. Percent buffer fed was associated positively with ruminal pH and with disappearance of nitrogen from nylon bags. The 0, 1, and 2.5% of buffer resulted in turnover rates of mordanted soybean meal of 8.22, 9.80, and 10.52%/h, but degradation of protein remained relatively constant at 36.0, 38.4, and 38.2%. The influence of rate of passage on ruminal degradability is discussed.


Reading without spaces: The role of precise letter order.
Prior research points to efficient identification of embedded words as a key factor in facilitating the reading of text printed without spacing between words. Here we further tested the primary role of bottom-up word identification by altering this process with a letter transposition manipulation. In two experiments, we examined silent reading and reading aloud of normal sentences and sentences containing words with letter transpositions, in both normally spaced and unspaced conditions. We predicted that letter transpositions should be particularly harmful for reading unspaced text. In line with our prediction, the majority of our measures of reading fluency showed that unspaced text with letter transpositions was disproportionately difficult to read. These findings provide further support for the claim that reading text without between-word spacing relies principally on efficient bottom-up processing, enabling accurate word identification in the absence of visual cues to identify word boundaries.


Does an Interactive, Teleconference-Delivered, Palliative Care Lecture Series Improve Nursing Home Staff Confidence?
Background: Project ECHO™ (Extension for Community Healthcare Outcomes) is a form of online interactive teaching, which has gained international traction. This project evaluates the effectiveness of an ECHO-delivered palliative care education program for the South Dublin region of Ireland. Our aim was to measure project success by quantifying gains in staff confidence. Methods: The educational program consisted of 10 interactive sessions over a five-month period on palliative care topics ranging from pain management to advance care planning. Twenty nursing homes took part in the education program. Of these, a subgroup of six nursing homes were randomly selected for assessment. Likert scale-based questionnaires assessed staff confidence before and after each lecture and assessment was repeated at least six weeks postlecture. Five of the 10 sessions were assessed in this way. Other characteristics such as staff role and years of experience were also collected. Results: Twenty nursing homes and 353 staff participated in the education sessions. Of the 6 nursing homes chosen for assessment, an average of 42 questionnaires were returned per session (n = 211), representing 83% of attendees at these 6 selected nursing homes. Seventy-seven percent of questionnaires were successfully followed up for six weeks. Average confidence increased by 27% pre- to postlecture (6.4 [SD = 1.4] to 8.1 [SD = 2.1], p < 0.005). Confidence gains persisted at six weeks; 8.1 of 10 (SD = 1.4), with no significant drop-off (-0.01/10, p = 0.95). All staff groups (nursing vs. non-nursing) exhibited equal confidence gains (nursing gain of 27%, non-nursing gain 22%, p = 0.16), and all confidence gains persisted at six weeks. Conclusion: This interactive, novel, training program significantly improved nursing home staff confidence in managing palliative care situations, and this confidence was sustained at least six weeks after the sessions.


Endophytic fungi of Lycium barbarum: isolation, determination, bioactivity and separation of compounds.
Lycium barbarum is widely distributed in China and used as a traditional Chinese medicine herb to treat dizziness, abdominal pain, dry cough, headache and fatigue. Several studies have examined the endophytes of L. barbarum from northwest China; however, few have focused on that from eastern China. The objective of this study was to isolate and determine the endophytic fungi of L. barbarum from Shandong province, as well as to obtain and identify active secondary metabolites from the endophytes. In this study, 17 endophytic fungi were isolated from L. barbarum and denoted as GQ-1 to GQ-17, respectively. These fungi were further classified into ten genera based on the morphological and ITS identification. The crude extracts of these fungi were obtained by using liquid fermentation and EtOAc extraction, and their antibacterial, cytotoxic, and antioxidant activities were evaluated. The results showed that GQ-6 and GQ-16 exhibited high inhibitory activity; GQ-6 and GQ-9 showed high cytotoxic activity and GQ-5 exhibited high scavenging capability for DPPH free radicals. Additionally, Cladosporium sp. GQ-6 was used to investigate the secondary metabolites. The crude extracts were purified by using column chromatography, reverse column, and liquid chromatography, and four monomeric compounds were identified, including two known compounds (α-acetylorcinol (1) and cladosporester B (2)) and two new compounds (cladosporacid F (3) and cladosporester D (4)). The anti-fungal and antibacterial activities of these compounds were confirmed, but no cytotoxic activity was observed. In conclusion, endophytic fungi of L. barbarum from eastern China can serve as a potential source of active natural products with antibacterial and antioxidant properties.


When endocrinology and democracy collide: emotions, cortisol and voting at national elections.
Faced with stressful experiences, such as uncertainty or novelty, the adrenal glands secrete glucocorticoid hormones to help us cope with stress. Since many decision-making situations are stressful, there is reason to believe that voting is a stressful event. In this study, we asked voters in Israel's national election (N=113) to report on their general affective state immediately before entering the polling place using the Positive Affect Negative Affect Schedule (PANAS) and to provide us with a saliva sample through which we could evaluate their cortisol levels. Compared to a second sample of voters who reported their affective state on election night (N=70), we found that voters at the ballot box had higher positive and negative affect. Moreover, our voters at the polling place exhibited cortisol levels that were significantly higher than their own normal levels obtained on a similar day, and significantly higher than those of a second control group sampled the day after the elections (N=6). Our data demonstrate that elections are exciting, yet stressful events, and it is this stress, among other factors, that elevates the cortisol levels of voters. Since elevated cortisol has been found to affect memory consolidation, impair memory retrieval and lead to risk-seeking behavior, we discuss how these outcomes of elevated cortisol levels may affect voting in general and the field of electoral studies in particular.


Improving Regional Blood Pressure Control: a Positive Deviance Tiered Intensity Approach.
Accelerated translation of real-world interventions for hypertension management is critical to improving cardiovascular outcomes and reducing disparities. To determine whether a positive deviance approach would improve blood pressure (BP) control across diverse health systems. Quality improvement study using 1-year cross sections of electronic health record data over 5 years (2013-2017). Adults ≥ 18 with hypertension with two visits in 2 years with at least one primary care visit in the last year (N = 114,950 at baseline) to a primary care practice in Better Health Partnership, a regional health improvement collaborative. Identification of a "positive deviant" and dissemination of this system's best practices for control of hypertension (i.e., accurate/repeat BP measurement; timely follow-up; outreach; standard treatment algorithm; and communication curriculum) using 3 different intensities (low: Learning Collaborative events describing the best practices; moderate: Learning Collaborative events plus consultation when requested; and high: Learning Collaborative events plus practice coaching). We used a weighted linear model to estimate the pre- to post-intervention average change in BP control (< 140/90 mmHg) for 35 continuously participating clinics. BP control post-intervention improved by 7.6% [95% confidence interval (CI) 6.0-9.1], from 67% in 2013 to 74% in 2017. Subgroups with the greatest absolute improvement in BP control included Medicaid (12.0%, CI 10.5-13.5), Hispanic (10.5%, 95% CI 8.4-12.5), and African American (9.0%, 95% CI 7.7-10.4). Implementation intensity was associated with improvement in BP control (high: 14.9%, 95% CI 0.2-19.5; moderate: 5.2%, 95% CI 0.8-9.5; low: 0.2%, 95% CI-3.9 to 4.3). Employing a positive deviance approach can accelerate translation of real-world best practices into care across diverse health systems in the context of a regional health improvement collaborative (RHIC). Using this approach within RHICs nationwide could translate to meaningful improvements in cardiovascular morbidity and mortality.


Food Matrix Effects of Polyphenol Bioaccessibility from Almond Skin during Simulated Human Digestion.
The goal of the present study was to quantify the rate and extent of polyphenols released in the gastrointestinal tract (GIT) from natural (NS) and blanched (BS) almond skins. A dynamic gastric model of digestion which provides a realistic simulation of the human stomach was used. In order to establish the effect of a food matrix on polyphenols bioaccessibility, NS and BS were either digested in water (WT) or incorporated into home-made biscuits (HB), crisp-bread (CB) and full-fat milk (FM). Phenolic acids were the most bioaccessible class (68.5% release from NS and 64.7% from BS). WT increased the release of flavan-3-ols (p < 0.05) and flavonols (p < 0.05) from NS after gastric plus duodenal digestion, whereas CB and HB were better vehicles for BS. FM lowered the % recovery of polyphenols, the free total phenols and the antioxidant status in the digestion medium, indicating that phenolic compounds could bind protein present in the food matrix. The release of bioactives from almond skins could explain the beneficial effects associated with almond consumption.


Advanced imaging of gout.
Gout is a metabolic disorder in which there is either an increase in production or a decrease in excretion of uric acid leading to hyperuricemia. Long-lasting hyperuricemia causes the deposition of monosodium urate crystals in the joints and soft tissues triggering gouty arthritis and, if not properly treated, the formation of gouty tophi. Characteristic of gout are well-defined, punched-out erosion with overhanging edges, with preservation of the joint space, lack of periarticular osteopenia, asymmetrical involvement, soft tissue nodules, and intraosseous calcifications. On magnetic resonance imaging, tophi usually have low signal intensity on both TI- and T2-weighted images and a variable enhancement pattern.


Schoolchildren's consumption of competitive foods and beverages, excluding à la carte.
Competitive foods/beverages are those in school vending machines, school stores, snack bars, special sales, and items sold à la carte in the school cafeteria that compete with United States Department of Agriculture (USDA) meal program offerings. Grouping à la carte items with less nutritious items allowed in less regulated venues may obfuscate analysis of the school competitive food environment. Excluding à la carte items from competitive foods, the objectives were to: (1) assess competitive food use by gender, ethnicity, eligibility for free or reduced-price meals, and participation in school meals programs, (2) determine differences between grade levels in energy intakes obtained from food sources, (3) determine the nutrient intake derived from competitive foods for students who consumed them, and (4) determine energy-adjusted differences in 24-hour nutrient intakes of protein, calcium, iron, and other selected nutrients between competitive food consumer and nonconsumers. Competitive foods/beverages use, excluding à la carte items, was examined using the third School Nutrition Dietary Assessment Study (SNDA III), a nationally representative sample of 2309 schoolchildren in grades 1 to 12. Mean nutrient intakes were adjusted for energy intake and other covariates, and differences between consumers and nonconsumers of competitive items were determined using analysis of variance and sudaan. Excluding à la carte items, 22% of schoolchildren consumed competitive items in a representative school day and use was highest in high school. Consumers of competitive items other than à la carte had significantly higher mean energy, sugar intakes, and lower sodium, dietary fiber, B vitamins, and iron intakes than nonconsumers. Use of competitive foods/beverages, excluding à la carte, was detrimental to children's diet quality.


Oral shelling within an adaptive radiation of pupfishes: Testing the adaptive function of a novel nasal protrusion and behavioural preference.
Dietary specialization on hard prey items, such as mollusks and crustaceans, is commonly observed in a diverse array of fish species. Many fish consume these types of prey by crushing the shell to consume the soft tissue within, but a few fishes extricate the soft tissue without breaking the shell using a method known as oral shelling. Oral shelling involves pulling a mollusc from its shell and it may be a way to subvert an otherwise insurmountable shell defence. However, the biomechanical requirements and potential adaptations for oral shelling are unknown. Here, we test the hypothesis that a novel nasal protrusion is an adaptation for oral shelling in the durophagous pupfish (Cyprinodon brontotheroides). We first demonstrate oral shelling in this species and then predict that a larger nasal protrusion would allow pupfish to consume larger snails. Durophagous pupfish are found within an endemic radiation of pupfish on San Salvador Island, Bahamas. We took advantage of closely related sympatric species and outgroups to test: (a) whether durophagous pupfish shell and consume more snails than other species, (b) if F1 and F2 durophagous hybrids consume similar amounts of snails as purebred durophagous pupfish, and (c) if nasal protrusion size in parental and hybrid populations increases the maximum size of consumed snails. We found that durophagous pupfish and their hybrids consumed the most snails, but did not find a strong association between nasal protrusion size and maximum snail size consumed within the parental or F2 hybrid population, suggesting that the size of their novel nasal protrusion does not provide a major benefit in oral shelling. Instead, we suggest that the nasal protrusion may increase feeding efficiency, act as a sensory organ, or is a sexually selected trait, and that a strong feeding preference may be most important for oral shelling.


Coagglutination reactions between Candida albicans and oral bacteria.
An agglutination assay for detecting intermicrobial adherence between the cells of Candida albicans and various oral bacteria is described. Strains of Streptococcus sanguis, S. salivarius, S. mutans, S. mitis, Fusobacterium nucleatum and Actinomyces viscosus all coagglutinated with C. albicans. No interaction could be demonstrated between the cells of Bacteroides melaninogenicus and those of C. albicans. Preliminary investigations of these interactions suggest that binding of F. nucleatum and A. viscosus to C. albicans is mediated by bacterial proteins, possibly lectins. Other mechanisms must account for the binding of oral streptococci to C. albicans. The possible implications of these findings in relation to oral mucosal colonisation and oral candidal clearance are discussed.


Implications of counterfactual structure for creative generation and analytical problem solving.
In the present research, the authors hypothesized that additive counterfactual thinking mind-sets, activated by adding new antecedent elements to reconstruct reality, promote an expansive processing style that broadens conceptual attention and facilitates performance on creative generation tasks, whereas subtractive counter-factual thinking mind-sets, activated by removing antecedent elements to reconstruct reality, promote a relational processing style that enhances tendencies to consider relationships and associations and facilitates performance on analytical problem-solving tasks. A reanalysis of a published data set suggested that the counterfactual mind-set primes previously used in the literature tend to evoke subtractive counterfactuals. Studies 1 and 2 then demonstrated that subtractive counterfactual mind-sets enhanced performance on analytical problem-solving tasks relative to additive counterfactual mind-sets, whereas Studies 3 and 4 found that additive counterfactual mind-sets enhanced performance on creative generation tasks relative to subtractive counterfactual mind-sets.


Dietary patterns and semen quality: a systematic review and meta-analysis of observational studies.
A number of studies have examined the association between dietary patterns and semen quality, but the findings have been inconclusive. Herein, we conducted a systematic review and meta-analysis of observational studies to assess the association between dietary patterns and semen quality. PubMed, Cochrane library, Science direct, Scopus, Google Scholar, and ISI web of science databases were searched up to August 2016 for observational studies assessing the association between common dietary patterns and sperm quality markers. Data were pooled by the generic inverse variance method with random effects and expressed as mean differences with 95% confidence intervals (CIs). Heterogeneity was assessed (Cochrane Q-statistic) and quantified (I2 -statistic). The Newcastle-Ottawa Scale assessed study quality. Six eligible studies, involving 8207 participants, were included in our systematic review and meta-analysis. The pooled mean difference of sperm concentration for the healthy dietary pattern versus unhealthy dietary pattern intake was mean difference: 0.66; 95% CI, 0.305-1.016; p < 0.001. In comparison with those who had the highest adherence to healthy dietary pattern, individuals in the lowest adherence had significantly lower level of sperm concentration. However, no significant association was seen between eating patterns and other semen quality. Healthy dietary pattern seems to be associated with elevated sperm concentration level. Further longitudinal studies are needed to clarify this relationship.


A novel method for the remote measurement of trismus in clinical trials using mobile phone cameras.
To evaluate the reliability and validity of a novel method for remotely measuring trismus. We recruited 60 volunteers who took three types of photographs at a fixed restricted jaw position mimicking limited mouth opening, including one selfie and one portrait with or without a reference frame. Additionally, the interincisal distance and the width of the upper central incisors were measured with a ruler, as per common practice. Measurements of trismus were made using image analysis software comparing different types of photos and calibration methods. Intraclass correlation coefficient (ICC) and 95% limits of agreement (LoA) with 95% confidence interval were calculated to evaluate reliability and validity. The proposed method demonstrated high reliability (ICC 0.998; 95% CI 0.997, 0.999). Calibration of photographs using at least a baseline photograph with an external reference frame yielded unbiased measurements and minimised variability. The use of selfies compared to portrait photos also increased variability. The measurement of trismus can be performed using images taken remotely by patients using their mobile phone cameras. The proposed method is highly accurate, with best results obtained by using a reference frame for calibration of portrait photographs. We propose an easy, cheap, and accurate method that allows for remote and frequent monitoring of trismus in clinical studies using patients' mobile phones.


Tag jumps illuminated--reducing sequence-to-sample misidentifications in metabarcoding studies.
Metabarcoding of environmental samples on second-generation sequencing platforms has rapidly become a valuable tool for ecological studies. A fundamental assumption of this approach is the reliance on being able to track tagged amplicons back to the samples from which they originated. In this study, we address the problem of sequences in metabarcoding sequencing outputs with false combinations of used tags (tag jumps). Unless these sequences can be identified and excluded from downstream analyses, tag jumps creating sequences with false, but already used tag combinations, can cause incorrect assignment of sequences to samples and artificially inflate diversity. In this study, we document and investigate tag jumping in metabarcoding studies on Illumina sequencing platforms by amplifying mixed-template extracts obtained from bat droppings and leech gut contents with tagged generic arthropod and mammal primers, respectively. We found that an average of 2.6% and 2.1% of sequences had tag combinations, which could be explained by tag jumping in the leech and bat diet study, respectively. We suggest that tag jumping can happen during blunt-ending of pools of tagged amplicons during library build and as a consequence of chimera formation during bulk amplification of tagged amplicons during library index PCR. We argue that tag jumping and contamination between libraries represents a considerable challenge for Illumina-based metabarcoding studies, and suggest measures to avoid false assignment of tag jumping-derived sequences to samples.


The timing of surgery for congenital diaphragmatic hernia in infants, on or after weaning from extracorporeal membrane oxygenation: A meta-analysis.
We conducted a meta-analysis of trials to determine the optimal time to conduct surgery for congenital diaphragmatic hernia (CDH) in infants, on or after weaning from extracorporeal membrane oxygenation (ECMO). We searched the PubMed, Embase, Scopus and Cochrane Library databases to identify relevant articles published prior to May 2023 in which surgery was performed to treat congenital diaphragmatic hernia in infants. Data were collected, and continuous data were represented by the mean difference (MD) and 95% confidence interval (CI). Dichotomous data were represented by the odds ratio (OR) and 95% Cl. Review Manager V.5.4 and Stata were used to synthesize results and to assess publication bias. The results showed that infants undergoing surgery after being weaned from ECMO had reduced mortality (OR, 2.40; 95% Cl, 1.23-4.69; P=0.01) and postoperative bleeding rates (OR, 16.20; 95% Cl, 5.73-45.76; P<0.00001) and reduced ECMO duration (MD, 3.47; 95% Cl, 1.89-5.05; P<0.0001) compared to those who underwent surgery while on ECMO. There was no statistically significant difference in hospital duration (MD, 5.48; 95% Cl, -8.66-19.62; P=0.45) or ventilator duration (MD, -1.93; 95% Cl, -8.55-4.68; P=0.57). We recommend weaning patients with CDH from ECMO before performing surgery.


Current differential diagnoses and treatment options of vascular occlusions presenting as bilateral thalamic infarcts: a review of the literature.
bilateral thalamic infarctions are rare and usually caused by vascular occlusions. When symptomatic, it is important to make a distinction between different vascular etiologies in order to provide an effective and timely therapeutic response. Clinical presentations may not adequately differentiate between the vascular etiologies alone. It is therefore important to use imaging technologies to distinguish appropriately the origin of the infarct so that proper treatment can be administered. Advanced imaging techniques, such as CT angiography and MR angiography, have proved useful for distinguishing between arterial and venous causes of bithalamic infarctions. Bilateral thalamic venous infarctions can be treated with anticoagulation medication and with thrombolysis in more severe cases. Bilateral thalamic arterial infarctions may be treated with thrombolysis.


DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer.
As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties. Pancreatic tissue samples were collected from the KC(Pdx1), KPC(Pdx1), and KC(iMist1) mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses. The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphological and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression. Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell-like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention.


Surgeon Preferences Worldwide in Wound Drain Utilization in Open Lumbar Fusion Surgery for Degenerative Pathologies.
Cross-sectional survey. Although literature does not recommend routine wound drain utilization, there is a disconnect between the evidence and clinical practice. This study aims to explore into this controversy and analyze the surgeon preferences related to drain utilization, and the factors influencing drain use and criterion for removal. A survey was distributed to AO Spine members worldwide. Surgeon demographics and factors related to peri-operative drain use in 1 or 2-level open fusion surgery for lumbar degenerative pathologies were collected. Multivariate analyses by drain utilization, and criterion of removal were conducted. 231 surgeons participated, including 220 males (95.2%), orthopedics (178, 77.1%), and academic/university-affiliated (114, 49.4%). Most surgeons preferred drain use (186, 80.5%) and subfascial drains (169, 73.2%). Drains were removed based on duration by 52.87% of the surgeons, but 27.7% removed drains based on outputs. On multivariable analysis, significant predictors of drain use were surgeon's aged 35-44 (OR = 11.9, 95% CI = 1.2-117.2, P = .034), 45-54 (29.1, 3.1-269.6, P = .003), 55-64 (8.9, 1.4-56.5, .019), and wound closure using coaptive films (6.0, 1.2-29.0, P = .025). Additionally, surgeons from Asia Pacific (OR = 5.19, 95% CI = 1.65-16.38, P = .005), Europe (3.55, 1.22-10.31, P = .020), and Latin America (4.40, 1.09-17.83, .038) were more likely to remove drain based on time duration, but surgeons <5 years of experience (10.23, 1.75-59.71, P = .010) were more likely to remove drains based on outputs. Most spine surgeons worldwide prefer to place a subfascial wound drain for degenerative open lumbar surgery. The choice for drain placement is associated with the surgeon's age and use of coaptive films for wound closure, while the criterion for drain removal is associated with the surgeons' region of practice and experience.


Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features.
The clinical features of 115 patients from 90 families with Friedreich's ataxia are described. Onset of symptoms was before the age of 25 (mean 10.52) years in all the index cases. An analysis of early cases suggested that limb and truncal ataxia and absent tendon reflexes in the legs were the only consistent diagnostic criteria within five years of presentation. Dysarthria, signs of pyramidal tract dysfunction in the legs and loss of joint position and vibration sense are not necessarily present during the first five years of symptoms, but appear to develop eventually in all cases. Scoliosis and ECG evidence of cardiomyopathy were found in over two-thirds of the patients studied; pes cavus, distal amyotrophy, optic atrophy, nystagmus and deafness were all less frequent. The disorder was gradually progressive in all cases. The mean age of losing the ability to walk was 25 years; 95 per cent were chair-bound by the age of 44 years. About 10 per cent of the patients had diabetes mellitus which was controlled by oral hypoglycaemic drugs in one quarter. Diabetes appeared to be associated with a higher incidence of optic atrophy and deafness. Diabetes also clustered within sibships; the risk of an individual with Friedreich's ataxia developing diabetes if an affected sib has it is over 40 per cent. Similarly, cardiomyopathy ran true within affected members of the same sibship, but there were instances of discordance which suggest that the development of the non-neurological features of Friedreich's ataxia may be controlled by modifying genes rather than heterogeneity of the main gene. Segregation analysis and an increased consanguinity rate amongst parents of patients (5.55 per cent) confirmed that this disorder is of autosomal recessive inheritance. A study of 101 first degree relatives of the patients with Friedreich's ataxia failed to demonstrate any neurological or electrocardiographic abnormalities which could be ascribed to the heterozygous state.


Chemically functionalized carbon films for single molecule imaging.
Many biological complexes are naturally low in abundance and pose a significant challenge to their structural and functional studies. Here we describe a new method that utilizes strong oxidation and chemical linkage to introduce a high density of bioactive ligands onto nanometer-thick carbon films and enable selective enrichment of individual macromolecular complexes at subnanogram levels. The introduced ligands are physically separated. Ni-NTA, Protein G and DNA/RNA oligonucleotides were covalently linked to the carbon surface. They embody negligible mass and their stability makes the functionalized films able to survive long-term storage and tolerate variations in pH, temperature, salts, detergents, and solvents. We demonstrated the application of the new method to the electron microscopic imaging of the substrate-bound C3PO, an RNA-processing enzyme important for the RNA interference pathway. On the ssRNA-linked carbon surface, the formation of C3PO oligomers at subnanomolar concentrations likely mimics their assembly onto ssRNA substrates presented by their native partners. Interestingly, the 3D reconstructions by negative stain EM reveal a side port in the C3PO/ssRNA complex, and the 15Å cryoEM map showed extra density right above the side port, which probably represents the ssRNA. These results suggest a new way for ssRNAs to interact with the active sites of the complex. Together our data demonstrate that the surface-engineered carbon films are suitable for selectively enriching low-abundance biological complexes at nanomolar level and for developing novel applications on a large number of surface-presented molecules.


The role of intermediate filaments in adrenal steroidogenesis.
Cholesterol is stored in adrenal cells as ester in lipid droplets, which are transported to mitochondria to provide a substrate for steroid hormone synthesis. Using mouse adrenal tumour cells (Y-1), we show here that approximately 33% of the adrenal cell cholesterol ester is bound tightly to intermediate filaments while the rest is either loosely attached or free in the cytosol. Specific binding of droplets to intermediate filaments was demonstrated by immunofluorescence and electron microscopy. Immunofluorescence was based upon Nile Red to stain lipid and antibodies to vimentin, actin and tubulin. Electron microscopy, including immunoelectron microscopy with protein A conjugated to gold particles (5 nm), was used to examine whole mounts of cytoskeletons and intermediate filaments. Immunofluorescence reveals that bound droplets are surrounded by a capsule containing vimentin and can be removed from the filaments by extraction with ethanol or 6 M urea. Negative staining of the urea extracts revealed isolated droplets. To the extent that cholesterol ester is the storage form of steroidogenic cholesterol, the knowledge that lipid droplets containing such esters are attached to intermediate filaments may prove important in unravelling the complex process of the transport of cholesterol to mitochondria.


Administration of a synbiotic to free-living elderly and evaluation of serum cytokines. A pilot study.
Ten free-living elderly were administered with a synbiotic [fermented milk containing Lactobacillus rhamnosus Gorbach and Goldin (LGG)] and oligofructose as a prebiotic for one month. Serum cytokines were evaluated before (T(0)) and after (T(1)) synbiotic administration. At T(0), values of Interleukin (IL)-12, IL-6, IL-10, IL-1beta and Tumor Necrosis Factor (TNF)-alpha were lower than normal controls, with the exception of IL-8, thus confirming previous results on the impairment of both innate and adaptive responses in elderly. At T(1), the synbiotic was able to significantly increase, depressed values of IL-1, IL-6 and IL-8 with a trend to a modest increase for the restant cytokines. In conclusion, the synbiotic used in this study seems to be very beneficial to elderly for its capacity to maintain the immune homeostasis, even if an increase in dosage and prolongation of administration time are required for a better modulation of the aged adaptive immune response.


Prediction and prevention of intrahepatic recurrence of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) has characteristic features of the coexistence of two life-threatening conditions, cancer and cirrhosis, which makes prognostic assessment difficult. In addition, the high rate of intrahepatic recurrence is a key feature that correlates with poor prognosis and its prevention is an issue for urgent investigation. Gene expression in the tumor and adjacent liver tissue for the prediction of intrahepatic recurrence of HCC has been extensively investigated. Among them, the expression of progenitor cell feature markers in the cancer cells such as epidermal cell adhesion molecule (EpCAM), cytokeratin 19 (CK19) and CD 133 have been shown to be associated with intrahepatic recurrence of HCC. Gene expression patterns from adjacent tissues were shown to predict early and overall recurrence in patients with HCC. Insulin resistance should be included in the analysis for the prevention of recurrence. To suppress or eradicate the replication of hepatitis B and C virus must be the most important issue for prevention. Supplementation by branched chain amino acid-enrichment and administration of vitamin K, acyclic retinoid and chemotherapeutic agents have been examined. There is an urgent need to develop a predictive tool and an effective treatment for prevention. It would be extremely valuable to find a useful biomarker for prediction and to develop new molecular targeting agents for the prevention of HCC recurrence in the near future.


A registration framework for the comparison of mammogram sequences.
In this paper, we present a two-stage algorithm for mammogram registration, the geometrical alignment of mammogram sequences. The rationale behind this paper stems from the intrinsic difficulties in comparing mammogram sequences. Mammogram comparison is a valuable tool in national breast screening programs as well as in frequent monitoring and hormone replacement therapy (HRT). The method presented in this paper aims to improve mammogram comparison by estimating the underlying geometric transformation for any mammogram sequence. It takes into consideration the various temporal changes that may occur between successive scans of the same woman and is designed to overcome the inconsistencies of mammogram image formation.


The role of vocabulary and grammar in the listening text comprehension of school-age Cantonese-speaking children with developmental language disorder.
The current study examined the role of vocabulary and grammar in the listening comprehension of school-age Cantonese-speaking children with developmental language disorder in Hong Kong. Participants were 692 typically developing children (TD) and 53 children with developmental language disorder (DLD) and they were tested with a standardized test of oral Cantonese, which includes measures on listening comprehension, receptive and expressive grammar, expressive vocabulary, word definition and lexical relations. The results from multiple regression analysis revealed that listening comprehension of the TD group was explained by receptive grammar, expressive vocabulary, and lexical relationships. However, children of the DLD group mainly relied on a subset of their vocabulary knowledge, as measured in a lexical relation task on antonym, in understanding the text under the constraint of a limited grammatical knowledge.


Safeguards to prevent neurologic complications after epidural steroid injections: consensus opinions from a multidisciplinary working group and national organizations.
Epidural corticosteroid injections are a common treatment for radicular pain caused by intervertebral disc herniations, spinal stenosis, and other disorders. Although rare, catastrophic neurologic injuries, including stroke and spinal cord injury, have occurred with these injections. A collaboration was undertaken between the U.S. Food and Drug Administration Safe Use Initiative, an expert multidisciplinary working group, and 13 specialty stakeholder societies. The goal of this collaboration was to review the existing evidence regarding neurologic complications associated with epidural corticosteroid injections and produce consensus procedural clinical considerations aimed at enhancing the safety of these injections. U.S. Food and Drug Administration Safe Use Initiative representatives helped convene and facilitate meetings without actively participating in the deliberations or decision-making process. Seventeen clinical considerations aimed at improving safety were produced by the stakeholder societies. Specific clinical considerations for performing transforaminal and interlaminar injections, including the use of nonparticulate steroid, anatomic considerations, and use of radiographic guidance are given along with the existing scientific evidence for each clinical consideration. Adherence to specific recommended practices when performing epidural corticosteroid injections should lead to a reduction in the incidence of neurologic injuries.


SUMOylation of Bonus, the Drosophila homolog of Transcription Intermediary Factor 1, safeguards germline identity by recruiting repressive chromatin complexes to silence tissue-specific genes.
The conserved family of Transcription Intermediary Factors (TIF1) proteins consists of key transcriptional regulators that control transcription of target genes by modulating chromatin state. Unlike mammals that have four TIF1 members, Drosophila only encodes one member of the family, Bonus. Bonus has been implicated in embryonic development and organogenesis and shown to regulate several signaling pathways, however, its targets and mechanism of action remained poorly understood. We found that knockdown of Bonus in early oogenesis results in severe defects in ovarian development and in ectopic expression of genes that are normally repressed in the germline, demonstrating its essential function in the ovary. Recruitment of Bonus to chromatin leads to silencing associated with accumulation of the repressive H3K9me3 mark. We show that Bonus associates with the histone methyltransferase SetDB1 and the chromatin remodeler NuRD and depletion of either component releases Bonus-induced repression. We further established that Bonus is SUMOylated at a single site at its N-terminus that is conserved among insects and this modification is indispensable for Bonus's repressive activity. SUMOylation influences Bonus's subnuclear localization, its association with chromatin and interaction with SetDB1. Finally, we showed that Bonus SUMOylation is mediated by the SUMO E3-ligase Su(var)2-10, revealing that although SUMOylation of TIF1 proteins is conserved between insects and mammals, both the mechanism and specific site of modification is different in the two taxa. Together, our work identified Bonus as a regulator of tissue-specific gene expression and revealed the importance of SUMOylation as a regulator of complex formation in the context of transcriptional repression.


Dynamics of genomic-library enrichment and identification of solvent tolerance genes for Clostridium acetobutylicum.
A Clostridium acetobutylicum ATCC 824 genomic library was constructed using randomly sheared DNA. Library inserts conferring increased tolerance to 1-butanol were isolated using two protocols. Protocol I utilized a single round of butanol challenges in batch culture, while protocol II, which gave clearly superior outcomes, was based on the serial transfer of stationary-phase cultures into progressively higher butanol concentrations. DNA microarray analysis made a high-resolution assessment of the dynamic process of library enrichment possible for the first time. Protocol I yielded a library insert containing the entire coding region of the gene CAC0003 (which codes for a protein of unknown function) but also several DNA fragments containing promoter regions. Protocol II enabled the successful identification of DNA fragments containing several intact genes conferring preferential growth under conditions of butanol stress. Since expression using the employed library is possible only from natural promoters, among the enriched genes, we identified 16 genes that constitute the first cistron of a transcriptional unit. These genes include four transcriptional regulators (CAC0977, CAC1463, CAC1869, and CAC2495). After subcloning plasmids carrying the CAC0003 and CAC1869 genes, strains 824(pCAC0003) and 824(pCAC1869) exhibited 13% and an 81% increases, respectively, in butanol tolerance relative to the plasmid control strain. 824(pCAC1869) consistently grew to higher cell densities in challenged and unchallenged cultures and exhibited prolonged metabolism. Our serial enrichment approach provided a more detailed understanding of the dynamic process of library enrichment under conditions of selective growth. Further characterization of the genes identified in this study will likely enhance our understanding of the complex phenotype of solvent tolerance.


Design principles of a conditional futile cycle exploited for regulation.
In this report, we characterize the design principles of futile cycling in providing rapid adaptation by regulatory proteins that act as environmental sensors. In contrast to the energetically wasteful futile cycles that are avoided in metabolic pathways, here we describe a conditional futile cycle exploited for a regulatory benefit. The FNR (fumarate and nitrate reduction) cycle in Escherichia coli operates under two regimes - a strictly futile cycle in the presence of O2 and as a pathway under anoxic conditions. The computational results presented here use FNR as a model system and provide evidence that cycling of this transcription factor and its labile sensory cofactor between active and inactive states affords rapid signaling and adaptation. We modify a previously developed mechanistic model to examine a family of FNR models each with different cycling speeds but mathematically constrained to be otherwise equivalent, and we identify a trade-off between energy expenditure and response time that can be tuned by evolution to optimize cycling rate of the FNR system for a particular ecological context. Simulations mimicking experiments with proposed double mutant strains offer suggestions for experimentally testing our predictions and identifying potential fitness effects. Our approach provides a computational framework for analyzing other conditional futile cycles, which when placed in their larger biological context may be found to confer advantages to the organism.


Comparison of intracellular location and stimulus reaction times of forisomes in sieve tubes of four legume species.
Forisomes in legumes are responsible for fast sieve-element occlusion in response to injury to the vascular system. This prevents uncontrolled leakage of phloem sap and protects against invasion of pathogens. Here we compared forisomes of four different legumes (Pisum sativum, Vicia faba, Trifolium pratense and Medicago sativa) by their location (basal, central, apical) in the sieve element and reactivity to a distant heat stimulus. In each species, the majority of forisomes was located basally. Yet, we found differences in intracellular location: forisomes are distributed more evenly in the sieve elements of Pisum. After burning, basally located forisomes of the four species reacted with dispersion, followed by a spontaneous recondensation with similar reaction times. The results suggest universal forisome behaviour in fabacean species.


Angiotensin II receptor alterations during pregnancy in rabbits.
Despite activation of the renin-angiotensin system during pregnancy, renal and peripheral vascular blood flows increase, and the systemic blood pressure and the pressor response to exogenous angiotensin II (Ang II) fall. Gestational alterations in Ang II receptors could contribute to these changes. Ang II binding parameters were determined utilizing 125I-Ang II in vascular (glomeruli and mesenteric arteries) and nonvascular (adrenal glomerulosa) tissues from 24- to 28-day pregnant rabbits. Comparisons were made utilizing tissues from nonpregnant rabbits. Binding site concentrations (N) and dissociation constants (Kd) were obtained by Scatchard analyses of binding inhibition data. In glomeruli from nonpregnant and pregnant rabbits, N was 515 +/- 84 and 300 +/- 54 fmol X mg-1 protein (P less than 0.005; n = 8), respectively. Kd did not differ (P greater than 0.05). In mesenteric artery membranes from nonpregnant (n = 3) and pregnant (n = 4) rabbits, N was 304 +/- 21 and 112 +/- 23 fmol X mg-1 (P less than 0.005), respectively. Kd did not differ. Neither N nor Kd differed in adrenal glomerulosa tissues (n = 6). Meclofenamate (M) inhibits prostaglandin synthesis, reduces plasma renin activity, and enhances the pressor response to infused Ang II in pregnant rabbits. Administration of M to pregnant rabbits increased N in glomerular and in mesenteric artery membranes from 298 +/- 16 to 381 +/- 8 fmol X mg-1 (n = 3) and from 144 +/- 13 to 218 +/- 13 fmol X mg-1 (n = 4), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Estimating the probability of abusive head trauma: a pooled analysis.
To determine which combinations of clinical features assist in distinguishing abusive head trauma (AHT) from nonabusive head trauma. Individual patient data from 6 comparative studies of children younger than 3 years with intracranial injury were analyzed to determine the association between AHT and combinations of apnea; retinal hemorrhage; rib, skull, and long-bone fractures; seizures; and head and/or neck bruising. An aggregate analysis of data from these studies used multiple imputation of combined clinical features using a bespoke hotdeck imputation strategy, which accounted for uncertainty arising from missing information. Analyzing 1053 children (348 had AHT), excluding nonsignificant variables (gender, age, skull fractures), for a child with an intracranial injury and 1 or 2 of the 6 features, the positive predictive value (PPV) of AHT varies from 4% to 97% according to the different combinations. Although rarely recorded, apnea is significantly associated with AHT (odds ratio [OR]: 6.89 [confidence interval: 2.08-22.86]). When rib fracture or retinal hemorrhage was present with any 1 of the other features, the OR for AHT is >100 (PPV > 85%). Any combination of 3 or more of the 6 significant features yielded an OR of >100 (PPV for AHT > 85%). Probabilities of AHT can be estimated on the basis of different combinations of clinical features. The model could be further developed in a prospective large-scale study, with an expanded clinical data set, to contribute to a more refined tool to inform clinical decisions about the likelihood of AHT.


A multi-event model to study stage-dependent dispersal in radio-collared hares: when hunting promotes costly transience.
Behavioral ecologists have often assumed that dispersal is costly mainly because of unfamiliarity with traversed habitats during dispersal and energy costs of the movement per se; thus, dispersers that have successfully settled should experience survival rates comparable to those of philopatric individuals. In this paper, we tested that hypothesis using 152 radio-collared European hares in a harvested population. We developed a multi-event capture recapture model, combining telemetry data and recoveries and separately modeling the foray probability, the settlement probability, and the permanent dispersal probability. The parameterization introduced here raises the possibility of separately testing effects on survival and dispersal probabilities at each stage of dispersal (departure, transience, and settlement). In accordance with our expectations, we reveal that dispersers incur higher mortality risks during transience and the early settlement period than philopatric individuals or settled dispersers. We also found that dispersers suffer from higher risks of being shot. Those results illustrate that unfamiliarity with the habitat during transience makes dispersal costly and that settled dispersers may enjoy survival rates comparable to those of philopatric individuals. Surprisingly, we also found that individuals have a higher probability of foraying during the hunting season. We suggest that hunting and related disturbances increase dispersal costs both by increasing mortality risk during transience and (perhaps) by increasing movement rates. We emphasize the need to take human pressures into account as factors that may drive the demographics of movements in populations.


Effect of sotalol on haemodynamics and renin-angiotensin-aldosterone system in hypertensive patients.
1. Twenty-three hypertensive patients were treated by sotalol, a pure beta-adrenergic receptor blocking agent. The drug produced a significant decrease of blood pressure in nineteen patients. 2. On average, cardiac index decreased but not significantly; heart rate decreased and stroke index increased significantly. Total peripheral resistance varied in both directions. 3. Sotalol determined a fall in plasma renin concentration (only significant in the high-renin group), a fall in plasma angiotensin II concentration and in urinary excretion rate of aldosterone accompanied by a rise in plasma potassium concentration. 4. The fall of blood pressure was not correlated with the decreases of renin and angiotensin II concentrations or excretion rate of aldosterone. However, in the placebo period plasma angiotensin II concentration was significantly correlated with total peripheral resistance; during sotalol treatment the variations of these two parameters seemed also to be correlated. 5. There was a poor correlation between decreases of cardiac output and of blood pressure; it was impossible to foresee the magnitude of the lowering of the blood pressure from the initial cardiac index. 6. The association of a diuretic with sotalol enhanced the hypotensive effect of the beta-receptor blocking drug, without significant increase of plasma renin and angiotensin II concentrations.


Different indices to express biodegradability in organic solid wastes.
Respiration indices are suggested in literature as the most suitable stability determination and are proposed as a biodegradability measure in this work. An improved dynamic respiration index methodology is described in this work. This methodology was applied to 58 samples of different types of waste including municipal solid wastes and wastewater sludge, both raw materials and samples collected in a mechanical-biological treatment plant at different stages of biodegradation. The information obtained allowed to establish a qualitative classification of wastes in three categories: highly biodegradable, moderately biodegradable, and wastes of low biodegradability. Results were analyzed in terms of long and short-term indices and index expression: dynamic respiration indices expressed as average oxygen uptake rate (mg O(2) g(-1) dry matter [DM] h(-1)) at 1 and 24 h of maximum activity (DRI(1h), DRI(24h)); and cumulative oxygen consumption in 24 h of maximum activity and 4 d (AT(24h), AT(4)). The statistical comparison of indices and wastes is also presented. Raw sludge presented the highest biodegradability followed by the organic fraction of municipal solid waste and anaerobically digested sludge. All indices correlated well but different correlations were found for the different wastes analyzed. The information in the dynamic respiration profile allows for the calculation of different indices that provide complementary information. The combined analysis of DRI(24h) and AT(4) is presented here as the best tool for biodegradable organic matter content characterization and process requirements estimation.


Segmentation of atherosclerotic carotid plaque in ultrasound video.
The degree of stenosis of the common carotid artery (CCA) but also the characteristics of the arterial wall including plaque size, composition and elasticity represent important predictors used in the assessment of the risk for future cardiovascular events. This paper proposes and evaluates an integrated system for the segmentation of atherosclerotic carotid plaque in ultrasound video of the CCA based on normalization, speckle reduction filtering (with the hybrid median filter) and parametric active contours. The algorithm is initialized in the first video frame of the cardiac cycle with human assistance and the moving atherosclerotic plaque borders are tracked and segmented in the subsequent frames. The algorithm is evaluated on 10 real CCA digitized videos from B-mode longitudinal ultrasound segments and is compared with the manual segmentations of an expert, for every 20 frames in a time span of 3-5 seconds, covering in general 2 cardiac cycles. The segmentation results are very satisfactory with a true negative fraction (TNF) of 79.3%, a true-positive fraction (TPF) of 78.12%, a false-positive fraction (FPF) of 6.7% and a false-negative fraction (FNF) of 19.6% between the ground truth and the presented plaque segmentations, a Williams index (KI) of 80.3%, an overlap index of 71.5%, a specificity of 0.88±0.09, a precision of 0.86±0.10 and an effectiveness measure of 0.77±0.09. The results show that integrated system investigated in this study could be successfully used for the automated video segmentation of the carotid plaque.


The Protective Effect of SLNP on Hepatic Fibrosis Induced by Thioacetamide in Rats.
The incidence of non-alcoholic fatty liver disease (NAFLD) has increased in recent years. Hepatic fibrosis (HF) is an important step in the progression of NAFLD to cirrhosis and even carcinoma and is also recognized as a possible reversal phase. We previously found that the aqueous extract of Sedum Lineare Thunb. has hepatoprotective effects. This study investigated the hepatoprotective effect and mechanism of the Sedum Lineare Thunb. n-butanol phase (SLNP) on HF in rats. Animals were intraperitoneally injected with thioacetamide solution twice a week for 8 weeks to prepare an HF model and were administered the corresponding drugs or an equal volume of normal saline by intragastric administration once a day for 8 weeks. Liver function, hydroxyproline and malondialdehyde (MDA) content, superoxide dismutase (SOD), Na+-K+-ATPase, and Ca2+-Mg2+-ATPase were analyzed using colorimetric methods. Moreover, mRNA expression and protein levels in the liver tissue were detected via quantitative polymerase chain reaction and western blotting, respectively. The results showed that SLNP could effectively improve the liver function of rats with HF and significantly reduce the content of hydroxyproline; the mRNA expression and protein levels of alpha-smooth muscle actin (α-SMA), collagen I, III, and IV, transforming growth factor beta 1 (TGF-β1), Smad2/3, and Smad4 were also significantly reduced. Simultaneously, SLNP significantly increased the activities of SOD, Na+-K+- ATPase, and Ca2+-Mg2+-ATPase in the rat liver tissues, whereas it reduced the levels of MDA and SOD in the serum and liver tissues. This study revealed that SLNP elicits an anti-fibrotic effect by inhibiting oxidative stress and suppressing stellate cell activation, thereby reducing the formation and deposition of the extracellular matrix. The TGF-β1/SMADs signaling pathway may be involved in this process.


Inter-rater reliability of the infectious disease modeling reproducibility checklist (IDMRC) as applied to COVID-19 computational modeling research.
Infectious disease computational modeling studies have been widely published during the coronavirus disease 2019 (COVID-19) pandemic, yet they have limited reproducibility. Developed through an iterative testing process with multiple reviewers, the Infectious Disease Modeling Reproducibility Checklist (IDMRC) enumerates the minimal elements necessary to support reproducible infectious disease computational modeling publications. The primary objective of this study was to assess the reliability of the IDMRC and to identify which reproducibility elements were unreported in a sample of COVID-19 computational modeling publications. Four reviewers used the IDMRC to assess 46 preprint and peer reviewed COVID-19 modeling studies published between March 13th, 2020, and July 30th, 2020. The inter-rater reliability was evaluated by mean percent agreement and Fleiss' kappa coefficients (κ). Papers were ranked based on the average number of reported reproducibility elements, and average proportion of papers that reported each checklist item were tabulated. Questions related to the computational environment (mean κ = 0.90, range = 0.90-0.90), analytical software (mean κ = 0.74, range = 0.68-0.82), model description (mean κ = 0.71, range = 0.58-0.84), model implementation (mean κ = 0.68, range = 0.39-0.86), and experimental protocol (mean κ = 0.63, range = 0.58-0.69) had moderate or greater (κ > 0.41) inter-rater reliability. Questions related to data had the lowest values (mean κ = 0.37, range = 0.23-0.59). Reviewers ranked similar papers in the upper and lower quartiles based on the proportion of reproducibility elements each paper reported. While over 70% of the publications provided data used in their models, less than 30% provided the model implementation. The IDMRC is the first comprehensive, quality-assessed tool for guiding researchers in reporting reproducible infectious disease computational modeling studies. The inter-rater reliability assessment found that most scores were characterized by moderate or greater agreement. These results suggest that the IDMRC might be used to provide reliable assessments of the potential for reproducibility of published infectious disease modeling publications. Results of this evaluation identified opportunities for improvement to the model implementation and data questions that can further improve the reliability of the checklist.


Associations between calf mortality during days 1 to 90 and herd-level cow and production variables in large Swedish dairy herds.
The aim of the study was to describe large Swedish dairy herds with high and low mortality risk in calves during the first 90 d of life, using herd-level data, and to evaluate if high calf mortality risk is associated with other herd-level management variables that influence cow health. A total of 57 Swedish dairy herds met the inclusion criteria of affiliation to the Swedish official milk recording scheme, herd size of ≥140 and ≥160 cows in 2008/2009 and 2009/2010, and calf mortality risks, classified as high (HM; calf mortality risk at least 3.5% in 2008/2009 and 5.5% in 2009/2010; n=28) or low (LM; calf mortality risk less than <1.5% in 2008/2009 and 2009/2010; n=29), and were thus included in the study. The data used in this study were collected from the Swedish Dairy association during the milking year 2009/2010. For LM herds, the calf mortality risk ranged from 0 to 1.46 (median=0.66) in 2008/2009 and from 0 to 1.48 (median=0.67) in 2009/2010. For HM herds, the calf mortality risk ranged from 3.57 to 11.52 (median=6.15) in 2008/2009 and from 5.88 to 18.23 (median=8.39) in 2009/2010. Median age at death was 28 d for HM and 37 d for LM herds. Associations between type of herd (HM or LM) and the production variables were evaluated using multi-correspondence analysis and logistic regression models covering the areas "mortality and culling," "health," "herd/production variables," and "fertility." Herds with HM risks during d 1 to 90 were associated with higher on-farm mortality rate in cows, lower average milk yield, higher incidence of antibiotic treatment, and a higher proportion of purchased animals. These results indicate that herds with HM risk during d 1 to 90 have coexisting issues concerning cow management and health. Future research is needed to evaluate if identifying HM herds and working with advisory and preventive manners at these herds also can be positive for a reduction of on-farm mortality and antibiotic usage, which are important issues from a global perspective.


An isobolographic analysis of the antinociceptive effect of systemically and intrathecally administered combinations of clonidine and opiates.
The antinociceptive interaction of opiate analgesics with clonidine was examined with the tail-flick and 55 degrees C hot plate tests. Male Sprague-Dawley rats received fixed ratios of clonidine to fentanyl, meperidine or morphine by i.v. and intrathecal injection. Data are expressed as percentage of maximal possible effect and the dose producing 50 percentage of maximal possible effect for each drug or drug combination is used to index potency. The rank order of potency in both tests after i.v. administration is fentanyl much greater than clonidine greater than meperidine greater than or equal to morphine and after intrathecal administration it is morphine greater than fentanyl much greater than clonidine much greater than meperidine. Isobolographic analysis shows that the effect of clonidine combined with an opiate is additive after i.v. administration; the exception is that morphine and clonidine are synergistic in the hot plate test. The intrathecal combinations of clonidine with morphine or meperidine produces a supra-additive antinociceptive effect in the tail-flick test but not in the hot plate test. Fentanyl does so in both tests. These data confirm a positive interaction between clonidine and opiates in producing antinociception. This interaction may be additive or synergistic, depending on route of administration and the nociceptive test used. The timing of injections and pharmacokinetic factors may also influence the results. Moreover, these results suggest that the interaction between the opiate and alpha-2 adrenergic receptors occurs within the spinal cord.


Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases.
Activation of the translation initiation factor 4E (eIF4E) promotes malignant transformation and metastasis. Signaling through the AKT-mTOR pathway activates eIF4E by phosphorylating the inhibitory 4E binding proteins (4E-BP). This liberates eIF4E and allows binding to eIF4G. eIF4E can then be phosphorylated at serine 209 by the MAPK-interacting kinases (Mnk), which also interact with eIF4G. Although dispensable for normal development, Mnk function and eIF4E phosphorylation promote cellular proliferation and survival and are critical for malignant transformation. Accordingly, Mnk inhibition may serve as an attractive cancer therapy. We now report the identification of a potent, selective and orally bioavailable Mnk inhibitor that effectively blocks 4E phosphorylation both in vitro and in vivo. In cultured cancer cell lines, Mnk inhibitor treatment induces apoptosis and suppresses proliferation and soft agar colonization. Importantly, a single, orally administered dose of this Mnk inhibitor substantially suppresses eIF4E phosphorylation for at least 4 hours in human xenograft tumor tissue and mouse liver tissue. Moreover, oral dosing with the Mnk inhibitor significantly suppresses outgrowth of experimental B16 melanoma pulmonary metastases as well as growth of subcutaneous HCT116 colon carcinoma xenograft tumors, without affecting body weight. These findings offer the first description of a novel, orally bioavailable MNK inhibitor and the first preclinical proof-of-concept that MNK inhibition may provide a tractable cancer therapeutic approach.


Mechanism of lidocaine block of late current in long Q-T mutant Na+ channels.
Inherited long Q-T syndrome is a ventricular arrhythmia associated with delayed repolarization and the risk of sudden death. The chromosome 3-linked form of the disease (LQT3) is associated with mutations in the cardiac Na+ channel (N1325S or R1644H; or deletion of residues 1,505-1,507, delta KPQ) that increase late inward currents and may cause delayed repolarization. Late currents arise from dispersed reopenings (N1325S and R1644H) or from reopenings combined with prolonged bursts (delta KPQ). Therefore, we tested whether lidocaine blockade of late current varied among the different LQT3 mutant channels. We found that lidocaine preferentially blocked late over peak current and that the blockade was equally effective in all three channels, expressed in Xenopus oocytes. Lidocaine inhibited both dispersed reopenings and bursting in single channels without affecting mean open times. In the absence of drug, inactivating prepulses inhibited bursting but not dispersed reopenings. We suggest that lidocaine block of late current in LQT3 channels acts via a common mechanism involving stabilization of inactivation. Therefore, blockers that target the inactivated state may be effective therapeutic agents in all three biophysical phenotypes of LQT3.


Stimulation of the amyloidogenic pathway by cytoplasmic superoxide radicals in an Alzheimer's disease mouse model.
Oxidative stress is involved in the pathogenesis of neurodegeneration. Amyloid β (Aβ) oligomer as an intermediate of aggregates causes memory loss in Alzheimer's disease (AD). We have suggested that oxidative stress plays an important role in Aβ oligomerization and cognitive impairment using a human amyloid precursor protein (hAPP) transgenic AD mice lacking cytoplasmic superoxide dismutase (hAPP/Sod1-/-). Recently, clinical trials revealed inhibitors of Aβ production from hAPP as promising therapeutics, but the relationship between oxidative stress and Aβ metabolism remains unclear. Here we found that Sod1 deficiency enhanced β-cleavage of hAPP, suggesting that it increased Aβ production in hAPP/Sod1-/- mice. In contrast, Aβ degradation did not decrease in hAPP/Sod1-/- as compared with hAPP/Sod1+/+ mice. Furthermore, we successfully detected in situ superoxide radicals associated with increased protein carbonylation in hAPP/Sod1-/-. These results suggest that cytoplasmic oxidative stress is involved in Aβ production as well as aggregation during AD progression.


Copper-Driven Deselenization: A Strategy for Selective Conversion of Copper Ion to Nanozyme and Its Implication for Copper-Related Disorders.
Synthetic organic molecules, which can selectively convert excess intracellular copper (Cu) ions to nanozymes with an ability to protect cells from oxidative stress, are highly significant in developing therapeutic agents against Cu-related disorder like Wilson's disease. Here, we report 1,3-bis(2-hydroxyethyl)-1 H-benzoimidazole-2-selenone (1), which shows a remarkable ability to remove Cu ion from glutathione, a major cytosolic Cu-binding ligand, and thereafter converts it into copper selenide (CuSe) nanozyme that exhibits remarkable glutathione peroxidase-like activity, at cellular level of H2O2 concentration, with excellent cytoprotective effect against oxidative stress in hepatocyte. Cu-driven deselenization of 1, under physiologically relevant conditions, occurred in two steps. The activation of C═Se bond by metal ion is the crucial first step, followed by cleavage of the metal-activated C═Se bond, initiated by the OH group of N-(CH2)2OH substituent through neighboring group participation (deselenization step), resulted in the controlled synthesis of various types of Cu2-xSe nanocrystals (NCs) (nanodisks, nanocubes, and nanosheets) and tetragonal Cu3Se2 NCs, depending upon the oxidation state of the Cu ion used to activate the C═Se bond. Deselenization of 1 is highly metal-selective. Except Cu, other essential metal ions, including Mn2+, Fe2+, Co2+, Ni2+, or Zn2+, failed to produce metal selenide under identical reaction conditions. Moreover, no significant change in the expression level of Cu-metabolism-related genes, including metallothioneines MT1A, is observed in liver cells co-treated with Cu and 1, as opposed to the large increase in the concentrations of these genes observed in cells treated with Cu alone, suggesting the participation of 1 in Cu homeostasis in hepatocyte.


A trial of disclosing physicians' financial incentives to patients.
Concern regarding financial conflict of interest for physicians has led to calls for disclosure of financial incentives to patients. However, limited data on the outcomes of disclosure exist to guide policy. This randomized trial was conducted among 8000 adult patients at 2 multispecialty group practices based in the Boston, Mass, and Los Angeles, Calif, areas. Intervention patients were mailed a compensation disclosure letter written by the chief medical officer of their physician group, and all patients were surveyed approximately 3 months later. Disclosure patients were significantly more able to identify correctly the compensation model of their primary care physician, in Boston (adjusted odds ratio, 2.30; 95% confidence interval, 1.92-2.75) and in Los Angeles (adjusted odds ratio, 1.37; 95% confidence interval, 1.03-1.82). Disclosure patients also had more confidence in their ability to judge the possible influence of incentives on their health care: in Boston, 32.5% vs 17.8% (P<.001); and in Los Angeles, 31.8% vs 26.4% (P = .20). The disclosure intervention did not change trust in primary care physicians overall. However, of patients who remembered receiving the disclosure, 21.4% in Boston and 24.4% in Los Angeles responded that the disclosure had increased trust either greatly or somewhat, while in both cities less than 5% of patients responded that the information decreased trust. Patients' loyalty to their physician group was higher among disclosure patients in Boston (73.4% vs 70.2%; P = .03) and Los Angeles (74.1% vs 66.9%; P = .08). Among diverse patient populations, a single mailed disclosure letter from physician groups was associated with improved knowledge of physicians' compensation models. Patients' trust in their physicians was unharmed, and their loyalty to their physician group was strengthened. For physician groups with similar compensation programs, disclosure to patients should be considered an effective method to enhance the patient-physician relationship.


Celiac disease diagnosis in patients with giardiasis: high value of antitransglutaminase antibodies.
The main objective of this study is to assess the presence of celiac disease (CD) in patients with giardiasis and to evaluate the tools for diagnosis of CD in these patients. A total of 40 patients with giardiasis were evaluated. Celiac disease was confirmed or discarded by intestinal biopsy and serological markers. Antigliadin antibodies were determined by ELISA and antitransglutaminase antibodies by one-step immunochromatographic assay and ELISA. Out of the 40 patients with giardiasis 37 showed normal intestinal mucosa. In this group, IgA antibodies to gliadin were positive in 7 patients, yielding a specificity of 82%. All of them were negative for transglutaminase antibodies by the immunochromatographic assay and by ELISA (specificity of 100%). The remaining 3 patients showed a subtotal intestinal villous atrophy consistent with CD, however, only two presented IgA antibodies to transglutaminase and gliadin. Due to its low specificity antigliadin antibodies are not useful for the screening of CD in patients with giardiasis. On the other hand, antitransglutaminase antibodies are highly specific and sensitive. One-step immunochromatographic assay is an easy and economic alternative. The findings of villous atrophy must be supported by other markers of CD to achieve the diagnosis of CD in these patients.


Alterations in Corneal Sensory Nerves During Homeostasis, Aging, and After Injury in Mice Lacking the Heparan Sulfate Proteoglycan Syndecan-1.
To determine the impact of the loss of syndecan 1 (SDC1) on intraepithelial corneal nerves (ICNs) during homeostasis, aging, and in response to 1.5-mm trephine and debridement injury. Whole-mount corneas are used to quantify ICN density and thickness over time after birth and in response to injury in SDC1-null and wild-type (WT) mice. High-resolution three-dimensional imaging is used to visualize intraepithelial nerve terminals (INTs), axon fragments, and lysosomes in corneal epithelial cells using antibodies against growth associated protein 43 (GAP43), βIII tubulin, and LAMP1. Quantitative PCR was performed to quantify expression of SDC1, SDC2, SDC3, and SDC4 in corneal epithelial mRNA. Phagocytosis was assessed by quantifying internalization of fluorescently labeled 1-μm latex beads. Intraepithelial corneal nerves innervate the corneas of SDC1-null mice more slowly. At 8 weeks, ICN density is less but thickness is greater. Apically projecting intraepithelial nerve terminals and lysosome-associated membrane glycoprotein 1 (LAMP1) are also reduced in unwounded SDC1-null corneas. Quantitative PCR and immunofluorescence studies show that SDC3 expression and localization are increased in SDC1-null ICNs. Wild-type and SDC1-null corneas lose ICN density and thickness as they age. Recovery of axon density and thickness after trephine but not debridement wounds is slower in SDC1-null corneas compared with WT. Experiments assessing phagocytosis show reduced bead internalization by SDC1-null epithelial cells. Syndecan-1 deficiency alters ICN morphology and homeostasis during aging, reduces epithelial phagocytosis, and impairs reinnervation after trephine but not debridement injury. These data provide insight into the mechanisms used by sensory nerves to reinnervate after injury.