Differentiation of Papillary Renal Cell Carcinoma Subtypes on MRI: Qualitative and Texture Analysis.
The objective of this study was to determine whether quantitative texture analysis of MR images would improve the ability to distinguish papillary renal cell carcinoma (RCC) subtypes, compared with analysis of qualitative MRI features alone. A total of 47 pathologically proven papillary RCC tumors were retrospectively evaluated, with 31 (66%) classified as type 1 tumors and 16 (34%) classified as type 2 tumors. MR images were reviewed by two readers to determine tumor size, signal intensity, heterogeneity, enhancement pattern, margins, perilesional stranding, vein thrombosis, and metastasis. Quantitative texture analysis of gray-scale images was performed. A logistic regression was derived from qualitative and quantitative features. Model performance was compared with and without texture features. The significant qualitative MR features noted were necrosis, enhancement appearance, perilesional stranding, and metastasis. A multivariable model based on qualitative features did not identify any factor as an independent predictor of a type 2 tumor. The logistic regression model for predicting papillary RCCs on the basis of qualitative and quantitative analysis identified probability of the 2D volumetric interpolated breath-hold examination (VIBE) sequence (AUC value, 0.87; 95% CI, 0.77-0.98) as an independent predictor of a type 2 tumor. No difference in the model AUC value was noted when texture features were included in the analysis; however, the model had increased sensitivity and an improved predictive value without loss of specificity. The addition of texture analysis to analysis of conventional qualitative MRI features increased the probability of predicting a type 2 papillary RCC tumor, which may be clinically important.


Dispersed lipid liquid crystalline phases stabilized by a hydrophobically modified cellulose.
Aqueous dispersions of monoolein (MO) with a commercial hydrophobically modified ethyl hydroxyethyl cellulose ether (HMEHEC) have been investigated with respect to the morphologies of the liquid crystalline nanoparticles. Only very low proportions of HMEHEC are accepted in the cubic and lamellar phases of the monoolein-water system. Due to the broad variation of composition and size of the commercial polymer, no other single-phase regions were found in the quasi-ternary system. Interactions of MO with different fractions of the HMEHEC sample induced the formation of lamellar and reversed hexagonal phases, identified from SAXD, polarization microscopy, and cryogenic TEM examinations. In excess water (more than 90 wt %) coarse dispersions are formed more or less spontaneously, containing particles of cubic phase from a size visible by the naked eye to small particles observed by cryoTEM. At high polymer/MO ratios, vesicles were frequently observed, often oligo-lamellar with inter-lamellar connections. After homogenization of the coarse dispersions in a microfluidizer, the large particles disappeared, apparently replaced by smaller cubic particles, often with vesicular attachments on the surfaces, and by vesicles or vesicular particles with a disordered interior. At the largest polymer contents no proper cubic particles were found directly after homogenization but mainly single-walled defected vesicles with a peculiar edgy appearance. During storage for 2 weeks, the dispersed particles changed toward more well-shaped cubic particles, even in dispersions with the highest polymer contents. In some of the samples with low polymer/MO ratio, dispersed particles of the reversed hexagonal type were found. A few of the homogenized samples were freeze-dried and rehydrated. Particles of essentially the same types, but with a less well-developed cubic character, were found after this treatment.


Inherited prion disease A117V is not simply a proteinopathy but produces prions transmissible to transgenic mice expressing homologous prion protein.
Prions are infectious agents causing fatal neurodegenerative diseases of humans and animals. In humans, these have sporadic, acquired and inherited aetiologies. The inherited prion diseases are caused by one of over 30 coding mutations in the human prion protein (PrP) gene (PRNP) and many of these generate infectious prions as evidenced by their experimental transmissibility by inoculation to laboratory animals. However, some, and in particular an extensively studied type of Gerstmann-Sträussler-Scheinker syndrome (GSS) caused by a PRNP A117V mutation, are thought not to generate infectious prions and instead constitute prion proteinopathies with a quite distinct pathogenetic mechanism. Multiple attempts to transmit A117V GSS have been unsuccessful and typical protease-resistant PrP (PrP(Sc)), pathognomonic of prion disease, is not detected in brain. Pathogenesis is instead attributed to production of an aberrant topological form of PrP, C-terminal transmembrane PrP ((Ctm)PrP). Barriers to transmission of prion strains from one species to another appear to relate to structural compatibility of PrP in host and inoculum and we have therefore produced transgenic mice expressing human 117V PrP. We found that brain tissue from GSS A117V patients did transmit disease to these mice and both the neuropathological features of prion disease and presence of PrP(Sc) was demonstrated in the brains of recipient transgenic mice. This PrP(Sc) rapidly degraded during laboratory analysis, suggesting that the difficulty in its detection in patients with GSS A117V could relate to post-mortem proteolysis. We conclude that GSS A117V is indeed a prion disease although the relative contributions of (Ctm)PrP and prion propagation in neurodegeneration and their pathogenetic interaction remains to be established.


Effect of metal ions on the kinetics of tyrosine oxidation catalysed by tyrosinase.
The conversion of tyrosine into dopa [3-(3,4-dihydroxyphenyl)alanine] is the rate limiting step in the biosynthesis of melanins catalysed by tyrosinase. This hydroxylation reaction is characterized by a lag period, the extent of which depends on various parameters, notably the presence of a suitable hydrogen donor such as dopa or tetrahydropterin. We have now found that catalytic amounts of Fe2+ ions have the same effect as dopa in stimulating the tyrosine hydroxylase activity of the enzyme. Kinetic experiments showed that the shortening of the induction time depends on the concentration of the added metal and the nature of the buffer system used and is not suppressed by superoxide dismutase, catalase, formate or mannitol. Notably, Fe3+ ions showed only a small delaying effect on tyrosinase activity. Among the other metals which were tested, Zn2+, Co2+, Cd2+ and Ni2+ had no detectable influence, whereas Cu2+ and Mn2+ exhibited a marked inhibitory effect on the kinetics of tyrosine oxidation. These findings are discussed in the light of the commonly accepted mechanism of action of tyrosinase.


Cow's milk protein allergy and other food hypersensitivities in infants.
Food hypersensitivity (FHS) is the umbrella term used to describe both food allergy, which involves the immune system, and food intolerances, which do not. It is therefore important that the diagnosis is made by a specialist health care professional such as a paediatrician or allergist. Some experienced dietitians and health visitors may be able to assist in making a diagnosis. The diagnostic work-up includes a medical history and blood tests/skin tests (where applicable). A food and symptom diary followed by a special test diet to identify the foods causing the infant's symptoms may also be needed. Once a diagnosis is made, dietary advice should be given to eliminate or reduce the intake of the offending foods. For cow's milk hypersensitivity in infants, this will include choosing the most appropriate specialised infant formula.


Assessment of inhibin B as a biomarker of testicular injury following administration of carbendazim, cetrorelix, or 1,2-dibromo-3-chloropropane in Wistar han rats.
Although histopathology is considered the gold standard for assessing testicular toxicity in the nonclinical setting, identification of noninvasive biomarkers for testicular injury are desirable to improve safety monitoring capabilities for clinical trials. Inhibin B has been investigated as a noninvasive biomarker for testicular toxicity. This study investigates the correlation of Inhibin B in Wistar Han rats with the onset and reversibility of testicular histopathology from classical testicular toxicants carbendazim, cetrorelix acetate (CTX), and 1,2-dibromo-3-chloropropane (DBCP). The dose regimen included Interim (day 8), Drug (day 29), and nondosing Recovery (day 58) Phases. Inhibin B was not effective at predicting the onset of carbendazim- or CTX-mediated testicular pathology in rats. Inhibin B was reduced by DBCP administration at the end of the Drug Phase only, acting as a leading indicator of the onset of testicular toxicity before the onset of germ cell depletion. However, since Inhibin B was only decreased at the end of the Dosing Phase and not at the Recovery Phase, when the onset of testicular pathology occurred, it is unclear if monitoring Inhibin B would provide sufficient advanced warning for the onset of testicular pathology. Furthermore, follicle stimulating hormone was decreased following CTX and DBCP administration in the Interim Phase and CTX in the Drug Phase. Inhibin B has limited predictive capacity as a leading testicular biomarker in rats.


Incidence of infectious complications associated with the use of histamine2-receptor antagonists in critically ill trauma patients.
To determine the impact of histamine2 (H2)-receptor antagonist use on the occurrence of infectious complications in severely injured patients. Some previous studies suggest an increased risk of nosocomial pneumonia associated with the use of H2-receptor blockade in critically ill patients, but other investigations suggest an immune-enhancing effect of H2-receptor antagonists. The purpose of this study was to determine whether H2-receptor antagonist use affects the overall incidence of infectious complications. Patients enrolled in a randomized trial comparing ranitidine with sucralfate for gastritis prophylaxis were examined for all infectious complications during their hospitalization. Data on the occurrence of pneumonia were prospectively collected, and other infectious complications were retrospectively obtained from the medical record. The relative risk of infectious complications associated with ranitidine use and total infectious complications were analyzed. Of 98 patients included, the charts of 96 were available for review. Sucralfate was given to 47, and 49 received ranitidine. Demographic factors were similar between the groups. Ranitidine use was associated with a 1.5-fold increased risk of developing any infectious complication (37 of 47 vs. 26 of 47; 95% confidence interval, 1.04 to 2.28). Infectious complications totaled 128 in the ranitidine-treated group and 50 in the sucralfate-treated group (p = 0.0014). These differences remained after excluding catheter-related infections (p = 0.0042) and secondary bacteremia (p = 0.0046). Ranitidine use in severely injured patients is associated with a statistically significant increase in overall infectious complications when compared with sucralfate. These results indicate that ranitidine should be avoided where possible in the prophylaxis of stress gastritis.


Sharing medical data for health research: the early personal health record experience.
Engaging consumers in sharing information from personally controlled health records (PCHRs) for health research may promote goals of improving care and advancing public health consistent with the federal Health Information Technology for Economic and Clinical Health (HITECH) Act. Understanding consumer willingness to share data is critical to advancing this model. The objective was to characterize consumer willingness to share PCHR data for health research and the conditions and contexts bearing on willingness to share. A mixed method approach integrating survey and narrative data was used. Survey data were collected about attitudes toward sharing PCHR information for health research from early adopters (n = 151) of a live PCHR populated with medical records and self-reported behavioral and social data. Data were analyzed using descriptive statistics and logistic regression to characterize willingness, conditions for sharing, and variations by sociodemographic factors. Narrative data were collected through semistructured focus group and one-on-one interviews with a separate sample of community members (n = 30) following exposure to PCHR demonstrations. Two independent analysts coded narrative data for major and minor themes using a shared rubric of a priori defined codes and an iterative inductive process. Findings were triangulated with survey results to identify patterns. Of PHCR users, 138 out of 151 (91%) were willing to share medical information for health research with 89 (59%) favoring an opt-in sharing model. Willingness to share was conditioned by anonymity, research use, engagement with a trusted intermediary, transparency around PCHR access and use, and payment. Consumer-determined restrictions on content and timing of sharing may be prerequisites to sharing. Select differences in support for sharing under different conditions were observed across social groups. No gender differences were observed; however differences in age, role, and self-rated health were found. For example, students were more likely than nonstudents to favor an opt-out sharing default (unadjusted odds ratio [OR] = 2.89, 95% confidence interval [CI] 1.10 - 7.62, P = .03). Participants over age 50 were less likely than younger participants to report that payment would increase willingness to share (unadjusted OR = 0.94, 95% CI 0.91 - 0.96, P < .001). Students were more likely than nonstudents to report that payment would increase their willingness to share (unadjusted OR 9.62, 95% CI 3.44 - 26.87, P < .001). Experiencing a public health emergency may increase willingness to share especially among persons over 50 (unadjusted OR 1.03, 95% CI 1.01 - 1.05, P = .02); however, students were less likely than non-students to report this attitude (unadjusted OR 0.13, 95% CI 0.05 - 0.36, P < .001). Finally, subjects with fair or poor self-rated health were less likely than those with good to excellent self-rated health to report that willingness to share would increase during a public health emergency (unadjusted OR 0.61, 95% CI 0.38 - 0.97, P = .04). Strong support for sharing of PCHR information for health research existed among early adopters and focus group participants, with support varying by social group under different conditions and contexts. Allowing users to select their preferred conditions for sharing may be vital to supporting sharing and fostering trust as may be development of safety monitoring mechanisms.


Sodium channels are required during in vivo sodium chloride hyperosmolarity to stimulate increase in intestinal endothelial nitric oxide production.
NaCl hyperosmolarity increases intestinal blood flow during food absorption due in large part to increased NO production. We hypothesized that in vivo, sodium ions enter endothelial cells during NaCl hyperosmolarity as the first step to stimulate an increase in intestinal endothelial NO production. Perivascular NO concentration ([NO]) and blood flow were determined in the in vivo rat intestinal microvasculature at rest and under hyperosmotic conditions, 330 and 380 mosM, respectively, before and after application of bumetanide (Na(+)-K(+)-2Cl(-) cotransporter inhibitor) or amiloride (Na(+)/H(+) exchange channel inhibitor). Suppressing amiloride-sensitive Na(+)/H(+) exchange channels diminished hypertonicity-linked increases in vascular [NO], whereas blockade of Na(+)-K(+)-2Cl(-) channels greatly suppressed increases in vascular [NO] and intestinal blood flow. In additional experiments we examined the effect of sodium ion entry into endothelial cells. We proposed that the Na(+)/Ca(2+) exchanger extrudes Na(+) in exchange for Ca(2+), thereby leading to the calcium-dependent activation of endothelial nitric oxide synthase (eNOS). We blocked the activity of the Na(+)/Ca(2+) exchanger during 360 mosM NaCl hyperosmolarity with KB-R7943; complete blockade of increased vascular [NO] and intestinal blood flow to hyperosmolarity occurred. These results indicate that during NaCl hyperosmolarity, sodium ions enter endothelial cells predominantly through Na(+)-K(+)-2Cl(-) channels. The Na(+)/Ca(2+) exchanger then extrudes Na(+) and increases endothelial Ca(2+). The increase in endothelial Ca(2+) causes an increase in eNOS activity, and the resultant increase in NO increases intestinal arteriolar diameter and blood flow during NaCl hyperosmolarity. This appears to be the major mechanism by which intestinal nutrient absorption is coupled to increased blood flow.


Evaluating the Efficiency of Breathing Exercises via Telemedicine in Post-Covid-19 Patients: Randomized Controlled Study.
The aim of the study was to evaluate the effectiveness of breathing exercises given by telemedicine in post-Covid-19 dyspneic individuals. Individuals in the intervention group (n: 26) were asked to perform breathing exercise three times a day for 5 weeks (one session performed via telemedicine each week). Individuals in the control group (n: 26) were given a brochure explaining the exercises. The St George's Respiratory Questionnaire, Pulmonary function tests, and six-minute-walk-tests were administered to all individuals at the beginning and end of the study. The posttest FEV1, FVC, MVV values were significantly higher than the pretest values in the intervention group (p2 < .001) whereas no significant differences were found in the control group. Six-minute-walk-distance increased by 54.27 m in the intervention group and 4.69 m in the control group. With breathing exercise training applied through telemedicine, improvements were observed in the pulmonary functions, quality of life, and exercise capacities of dyspneic post-Covid-19 individuals.


Pulmonary vasoactive effects of exogenous and endogenous AVP in conscious dogs.
Our objectives were to investigate the extent to which both exogenously administered and endogenously released arginine vasopressin (AVP) exert a direct, vasoactive influence on the pulmonary circulation of conscious dogs. Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed during normoxia in conscious dogs by stepwise constriction of the thoracic inferior vena cava (IVC) to reduce Q. In intact dogs, AVP infusion (7.6 ng X kg-1 X min-1 iv) increased (P less than 0.01) plasma AVP from 2.3 +/- 0.4 to 280 +/- 23 pg/ml, and increased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure minus pulmonary capillary wedge pressure, PAP-PCWP) over the entire range of Q studied. Following administration of autonomic nervous system antagonists and a converting-enzyme inhibitor, exogenous AVP again increased (P less than 0.01) PAP-PCWP over the entire range of Q. Generation of P/Q plots via IVC constriction resulted in systemic hypotension (58 +/- 4 mmHg) and a concomitant increase (P less than 0.01) in endogenous AVP release from 2.1 +/- 0.2 to 109 +/- 22 pg/ml. Following administration of the specific AVP receptor antagonist [d(CH2)5]AVP (10 micrograms/kg iv), systemic arterial pressure, but not PAP - PCWP, was decreased to significantly lower levels as Q was reduced during IVC constriction. A similar response was observed in dogs pretreated with the neurohumoral blockers. Thus exogenous administration of AVP results in active, non-flow-dependent pulmonary vasoconstriction. This effect is not dependent on reflex activation of the autonomic nervous system or on the increased production of angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)


[Unilateral or asymmetric PEX syndrome? An electron microscopy study].
The pseudoexfoliation (PEX) syndrome which is characterized by the accumulation of an abnormal extracellular material in intra- and extraocular tissues, clinically strictly manifests both unilateral and bilateral. However, the generalized nature of this matrix process does not support unilateral ocular manifestation. The aim of this study, therefore, was a detailed histopathological analysis of the apparently not involved fellow eyes in so-called "unilateral" PEX syndrome. For transmission electron microscopy, 5 pairs of donor eyes with slitlamp-microscopic, macroscopic and light microscopic evidence of unilateral PEX syndrome and 6 normal control eyes were studied. For immunohistochemistry, light and electron microscopic antibodies against LTBP-1 and HNK-1, two well-known markers for PEX deposits, were used. All apparently not involved contralateral eyes showed ultrastructural changes in the iris, in the ciliary body and in the trabecular meshwork. These changes include deposits of typical PEX fibrils on iris and ciliary epithelia as well as in the iris dilator muscle, microfibrillar precursors in the periphery of iris vessels, degenerative changes of the iris pigment epithelium and of the dilator muscle and an increased accumulation of extracellular matrix components around iris vessels, in the dilator muscle and in the juxta-canalicular connective tissue of the trabecular meshwork. In all contralateral and PEX eyes, but not in the control eyes, LTBP-1 and HNK-1 positive deposits could be identified in the periphery of iris vessels and in the dilator by light- and electron microscopic immunolabeling. The observed alterations in contralateral eyes in so-called "unilateral" PEX syndrome support the concept that the PEX syndrome is a generalized, basically bilateral disease which may present in a clinically asymmetric manifestation. This should be considered in the clinical management of these patients.


Evaluation of the defense system in chloroplasts to photooxidative stress caused by paraquat using transgenic tobacco plants expressing catalase from Escherichia coli.
We evaluated the defense system in chloroplasts to photooxidative stress imposed by paraquat treatment under illumination in transgenic tobacco plants with increased tolerance to drought stress at a high light intensity produced by catalase from Escherichia coli targeted to chloroplasts [Shikanai et al. (1998) FEBS Lett. 428: 47]. At 24 h after the paraquat application, Chl was destroyed in the wild-type plants, but not in transgenic plants. Photosynthetic activities monitored by CO2 fixation and Chl fluorescence were much less affected by the paraquat treatment in transgenic lines. The activities of chloroplastic ascorbate peroxidase (APX) isoenzymes decreased in parallel with the depletion of ascorbate (AsA) in leaves in both lines. Paraquat treatment had no effect on the transcript level of chloroplastic APX isoenzymes, while it significantly lowered the level of their proteins. These data suggest that the depletion of AsA in chloroplasts under severe stress conditions inactivates and degrades chloroplastic APX isoenzymes.


Myocardial feature tracking reduces observer-dependence in low-dose dobutamine stress cardiovascular magnetic resonance.
To determine whether quantitative wall motion assessment by CMR myocardial feature tracking (CMR-FT) would reduce the impact of observer experience as compared to visual analysis in patients with ischemic cardiomyopathy (ICM). 15 consecutive patients with ICM referred for assessment of hibernating myocardium were studied at 3 Tesla using SSFP cine images at rest and during low dose dobutamine stress (5 and 10 μg/kg/min of dobutamine). Conventional visual, qualitative analysis was performed independently and blinded by an experienced and an inexperienced reader, followed by post-processing of the same images by CMR-FT to quantify subendocardial and subepicardial circumferential (Eccendo and Eccepi) and radial (Err) strain. Receiver operator characteristics (ROC) were assessed for each strain parameter and operator to detect the presence of inotropic reserve as visually defined by the experienced observer. 141 segments with wall motion abnormalities at rest were eligible for the analysis. Visual scoring of wall motion at rest and during dobutamine was significantly different between the experienced and the inexperienced observer (p<0.001). All strain values (Eccendo, Eccepi and Err) derived during dobutamine stress (5 and 10 μg/kg/min) showed similar diagnostic accuracy for the detection of contractile reserve for both operators with no differences in ROC (p>0.05). Eccendo was the most accurate (AUC of 0.76, 10 μg/kg/min of dobutamine) parameter. Diagnostic accuracy was worse for resting strain with differences between operators for Eccendo and Eccepi (p<0.05) but not Err (p>0.05). Whilst visual analysis remains highly dependent on operator experience, quantitative CMR-FT analysis of myocardial wall mechanics during DS-CMR provides diagnostic accuracy for the detection of inotropic reserve regardless of operator experience and hence may improve diagnostic robustness of low-dose DS-CMR in clinical practice.


[The use of bilateral mammary artery in myocardial revascularization. The risk factors emergent from a multivariate analysis conducted on 474 patients].
The internal mammary artery is used as coronary artery graft conduit because of its superior patency. According to some authors, the bilateral IMA can increase perioperative morbidity. The aim of this study was to determine the risk factors increasing perioperative mortality and morbidity in the use of bilateral IMA. We analyzed the data of 474 patients operated consecutively with the use of bilateral IMA between January 1987 and December 1995 at the Department of Cardiac Surgery of the Varese Hospital. The univariate analysis was done on 17 ordinal variables using a "Fisher exact test" and on 4 continuous variables by "pooled-variance t-test" to investigate risk factors for mortality, mediastinitis, superficial wound infection and aseptic dehiscence of the sternum; a p-value lower than 0.1 was used as cut-off point to introduce the variables into a stepwise multiple logistic regression analysis. From the univariate analysis are: postoperative low-output syndrome (p = 0.01), LVEF (p = 0.02) and number of grafts (p = 0.04) are correlated to hospital mortality (1.5%); obesity (p < 0.001) and peripheral arteriopathy (p = 0.009) are correlated to postoperative mediastinitis (5%); obesity (p < 0.001), peripheral arteriopathy (p = 0.009), surgeon (p = 0.001), year of operation (p < 0.001), reoperation for bleeding (p = 0.004) and length of extracorporeal circulation (p = 0.02) are correlated to superficial wound infection (7%); obesity (p = 0.002) and COPD (p = 0.05) are correlated to aseptic dehiscence of the sternum (2%). The multivariate analysis identified low LVEF as the only independent risk factor for hospital mortality (p = 0.03), whereas obesity (p = 0.01) and peripheral vasculopathy (p = 0.03) proved to be correlated to postoperative mediastinitis; obesity (p < 0.001), year of the operation (p < 0.001), low LVEF (p = 0.007) and reoperation for bleeding (p = 0.01) were correlated to superficial infection of the wound and obesity turned out to be the only risk factor for aseptic dehiscence for the sternum (p = 0.003). The infection of the wound did not increase mortality, but it did increase the mean postoperative length of hospital stay (6 days for patients free of any complications of the wound versus 29.7 days for patients with complications of the wound). In patients with bilateral mammary grafts, obesity is the main risk factor for complications of the wound and this event greatly increases the length of the patient's hospital stay. Consequently, we suggest that bilateral mammary artery grafts be used carefully in this subset of patients.


Simple Generation of Suspensible Secondary Microplastic Reference Particles via Ultrasound Treatment.
In the environment the weathering of plastic debris is one of the main sources of secondary microplastic (MP). It is distinct from primary MP, as it is not intentionally engineered, and presents a highly heterogeneous analyte composed of plastic fragments in the size range of 1 μm-1 mm. To detect secondary MP, methods must be developed with appropriate reference materials. These should share the characteristics of environmental MP which are a broad size range, multitude of shapes (fragments, spheres, films, fibers), suspensibility in water, and modified particle surfaces through aging (additional OH, C=O, and COOH). To produce such a material, we bring forward a rapid sonication-based fragmentation method for polystyrene (PS), polyethylene terephthalate (PET), and polylactic acid (PLA), which yields up to 105/15 mL dispersible, high purity MP particles in aqueous media. To satisfy the claim of a reference material, the key properties-composition and size distribution to ensure the homogeneity of the samples, as well as shape, suspensibility, and aging -were analyzed in replicates (N = 3) to ensure a robust production procedure. The procedure yields fragments in the range of 100 nm-1 mm (<20 μm, 54.5 ± 11.3% of all particles). Fragments in the size range 10 μm-1 mm were quantitatively characterized via Raman microspectroscopy (particles = 500-1,000) and reflectance micro Fourier transform infrared analysis (particles = 10). Smaller particles 100 nm-20 μm were qualitatively characterized by scanning electron microcopy (SEM). The optical microscopy and SEM analysis showed that fragments are the predominant shape for all polymers, but fibers are also present. Furthermore, the suspensibility and sedimentation in pure MilliQ water was investigated using ultraviolet-visible spectroscopy and revealed that the produced fragments sediment according to their density and that the attachment to glass is avoided. Finally, a comparison of the infrared spectra from the fragments produced through sonication and naturally aged MP shows the addition of polar groups to the surface of the particles in the OH, C=O, and COOH region, making these particles suitable reference materials for secondary MP.


Enzymically mediated bioprecipitation of uranium by a Citrobacter sp. : a concerted role for exocellular lipopolysaccharide and associated phosphatase in biomineral formation.
A Citrobacter sp. accumulated uranyl ion (UO2(2+)) via precipitation with phosphate ligand liberated by phosphatase activity. The onset and rate of uranyl phosphate deposition were promoted by NH4(+), forming NH(4)UO(2)PO(4), which has a lower solubility product than NaUO(2)PO(4). This acceleration decoupled the rate-limiting chemical crystallization process from the biochemical phosphate ligand generation. This provided a novel approach to monitor the cell-surface-associated changes using atomic-force microscopy in conjunction with transmission electron microscopy and electron-probe X-ray microanalysis, to visualize deposition of uranyl phosphate at the cell surface. Analysis of extracted surface materials by (31)P NMR spectroscopy showed phosphorus resonances at chemical shifts of 0.3 and 2.0 p.p.m., consistent with monophosphate groups of the lipid A backbone of the lipopolysaccharide (LPS). Addition of fUO2(2+) to the extract gave a yellow precipitate which contained uranyl phosphate, while addition of Cd(2+) gave a chemical shift of both resonances to a single new resonance at 3 p.p.m. Acid-phosphatase-mediated crystal growth exocellularly was suggested by the presence of acid phosphatase, localized by immunogold labelling, on the outer membrane and on material exuded from the cells. Metal deposition is proposed to occur via an initial nucleation with phosphate groups localized within the LPS, shown by other workers to be produced exocellularly in association with phosphatase. The crystals are further consolidated with additional, enzymically generated phosphate in close juxtaposition, giving high loads of LPS-bound uranyl phosphate without loss of activity and distinguishing this from simple biosorption, or periplasmic or cellular metal accumulation mechanisms. Accumulation of 'tethered' metal phosphate within the LPS is suggested to prevent fouling of the cell surface by the accumulated precipitate and localization of phosphatase exocellularly is consistent with its possible functions in homeostatis and metal resistance.


Making One Health a Reality--Crossing Bureaucratic Boundaries.
A One Health approach requires that nontraditional partners with differing mandates collaborate and communicate effectively. Barriers to such redefined relationships range from personality and institutional cultural and value differences to impediments that require changes in agency-specific policies. This article reviews interagency One Health collaborations, nationally and internationally. It presents a series of case studies that describe situations in which barriers were overcome, thus culminating in successful One Health outcomes. The case studies illustrate challenges, tipping points, and externally enabling factors that help institutionalize cross-bureaucratic working relationships. Likewise, the cases demonstrate the added value of taking a One Health approach to solving (or preventing) public health problems.


Vaccines for Patients with COPD.
Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic obstruction of lung airflow limitation. This disease is currently the fourth higher cause of death in the world, and it is predicted to be the third by the year 2020. Patients with COPD are frequently exposed to Human Rhinovirus, Respiratory Syncytial and Influenza Virus, as well as to Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. These infectious agents are responsible for exacerbations increasing morbidity and mortality in COPD patients. Prevention of infectious exacerbations by vaccination would improve quality of life and patient survival. A literature search: "vaccination of COPD patients" was performed using Medline, the Cochrane Library and other Non-Indexed Citations for this review. This article presents a brief overview of the different studies found, on the new patents, and the future strategies on the field.


Unilateral complete articulated ossification and aberrant thickening of the stylohyoid chain.
Eagle's syndrome is a rare clinical entity associated with craniofacial and cervical pain. It is caused by an elongated or deviated styloid process and/or calcification/ossification of the stylohyoid ligament. Complete ossification and aberrant thickening of the stylohyoid chain is the most unusual manifestation. We report a patient who presented with complaints of foreign body sensation, dysphagia and moderate submandibular pain caused by unilateral complete ossification, abnormal thickening and hypertrophy of the stylohyoid chain. This case was also unique in that histopathological investigation demonstrated mature bone with both compact and cancellous bone as well as bone marrow.


The cessation in pregnancy incentives trial (CPIT): study protocol for a randomized controlled trial.
Seventy percent of women in Scotland have at least one baby, making pregnancy an opportunity to help most young women quit smoking before their own health is irreparably compromised. By quitting during pregnancy their infants will be protected from miscarriage and still birth as well as low birth weight, asthma, attention deficit disorder and adult cardiovascular disease. In the UK, the NICE guidelines: 'How to stop smoking in pregnancy and following childbirth' (June 2010) highlighted that little evidence exists in the literature to confirm the efficacy of financial incentives to help pregnant smokers to quit. Its first research recommendation was to determine: Within a UK context, are incentives an acceptable, effective and cost-effective way to help pregnant women who smoke to quit? This study is a phase II exploratory individually randomized controlled trial comparing standard care for pregnant smokers with standard care plus the additional offer of financial voucher incentives to engage with specialist cessation services and/or to quit smoking during pregnancy.Participants (n = 600) will be pregnant smokers identified at maternity booking who, when contacted by specialist cessation services, agree to having their details passed to the NHS Smokefree Pregnancy Study Helpline to discuss the trial. The NHS Smokefree Pregnancy Study Helpline will be responsible for telephone consent and follow-up in late pregnancy. The primary outcome will be self reported smoking in late pregnancy verified by cotinine measurement. An economic evaluation will refine cost data collection and assess potential cost-effectiveness while qualitative research interviews with clients and health professionals will assess the level of acceptance of this form of incentive payment. The research questions are: What is the likely therapeutic efficacy? Are incentives potentially cost-effective? Is individual randomization an efficient trial design without introducing outcome bias? Can incentives be introduced in a way that is feasible and acceptable? This phase II trial will establish a workable design to reduce the risks associated with a future definitive phase III multicenter randomized controlled trial and establish a framework to assess the costs and benefits of financial incentives to help pregnant smokers to quit. Current Controlled Trials ISRCTN87508788.


Ejection of structural zinc leads to inhibition of γ-butyrobetaine hydroxylase.
γ-Butyrobetaine hydroxylase (BBOX) is a 2-oxoglutarate and Fe(II) dependent oxygenase that catalyses an essential step during carnitine biosynthesis in animals. BBOX is inhibited by ejection of structural zinc by a set of selenium containing analogues. Previous structural analyses indicated that an undisrupted N-terminal zinc binding domain of BBOX is required for catalysis. Ebselen is a relatively potent BBOX inhibitor, an observation which may in part reflect its cardioprotective properties.


Prospective study of restless legs syndrome and risk of depression in women.
Most research on the association between restless legs syndrome (RLS) and depression has involved cross-sectional data. The objective of the present study was to evaluate this issue prospectively among Nurses' Health Study participants. A total of 56,399 women (mean age = 68 years) who were free of depression symptoms at baseline (2002) were followed until 2008. Physician-diagnosed RLS was self-reported. During 300,155 person-years of follow-up, the authors identified 1,268 incident cases of clinical depression (regular use of antidepressant medication and physician-diagnosed depression). Women with RLS at baseline were more likely to develop clinical depression (multivariate-adjusted relative risk (RR) = 1.5, 95% confidence interval (CI): 1.1, 2.1; P = 0.02) than those without RLS. The presence of RLS at baseline was also associated with higher scores on the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) and the 15-item Geriatric Depression Scale (GDS-15) thereafter. Multivariable-adjusted mean differences were 1.00 (standard error, 0.12) for CESD-10 score and 0.47 (standard error, 0.07) for GDS-15 score between women with RLS and those without RLS (P < 0.0001). In conclusion, women with physician-diagnosed RLS had an increased risk of developing clinical depression and clinically relevant depression symptoms. Further prospective studies using refined approaches to ascertainment of RLS and depression are warranted.


Environmental Factors Driving the Spatial Distribution Pattern of Venerable Trees in Sichuan Province, China.
Venerable trees are important natural resources and cultural heritage, offering historical, ecological, social and economic value. However, global warming and anthropogenic activities have threatened their welfare and survival. A comprehensive understanding of their current and future spatial patterns, vis-á-vis environmental conditions, can inform the co-management of sustainable resource use and conservation. We employed the existing spatial occurrence data and environmental variables (bioclimate and elevation) to simulate the optimal habitats for venerable trees in China's Sichuan Province. We evaluated the current and future climate scenarios of 2100 with double CO2 concentration. The BIOCLIM and QGIS spatial analyses assessed the primary factors of geographical distribution. The results identified 10,720 venerable trees from 123 species, 81 genera and 42 families. Cupressus funebris dominated, with the maximum importance value, followed by Ginkgo biloba, Ficus virens var. sublanceolata, and Phoebe zhennan. The elevation distribution of tree abundance and species richness demonstrated a unimodal pattern, skewing to the low-elevation end, with a concentration in the 600-1500 m low-medium altitude. The majority of trees and excellent habitats were found in eastern Sichuan with a less harsh terrain and climate. The bio3 (isothermality) and bio7 (temperature annual range) factors significantly influenced tree occurrence. Temperature imposed a greater effect on distribution than moisture under the current climate scenario. For the future climate-change scenario, the suitable habitats were predicted to maintain an overall stable pattern, with largely contiguous expansions of better habitats. However, climate warming would shrink the excellent habitats on the plains. The findings can inform strategies and guidelines for venerable-tree conservation in Sichuan. Furthermore, vulnerable areas could be identified. The future range expansion sites could be enlisted to cultivate new trees to replenish the venerable-tree pool. Habitat patches that remain sustainable could provide refugia with the potential for protected-area designation.


Influences on children's oral health: a conceptual model.
Despite marked improvements over the past century, oral health in America is a significant problem: caries is the most common chronic disease of childhood. Much oral health research examines influences primarily in the oral cavity or focuses on a limited number of individual-level factors. The purpose of this article was to present a more encompassing conceptual model of the influences on children's oral health. The conceptual model presented here was derived from the population health and social epidemiology fields, which have moved toward multilevel, holistic approaches to analyze the complex and interactive causes of children's health problems. It is based on a comprehensive review of major population and oral health literatures. A multilevel conceptual model is described, with the individual, family, and community levels of influence on oral health outcomes. This model incorporates the 5 key domains of determinants of health as identified in the population health literature: genetic and biological factors, the social environment, the physical environment, health behaviors, and dental and medical care. The model recognizes the presence of a complex interplay of causal factors. Last, the model incorporates the aspect of time, recognizing the evolution of oral health diseases (eg, caries) and influences on the child-host over time. This conceptual model represents a starting point for thinking about children's oral health. The model incorporates many of the important breakthroughs by social epidemiologists over the past 25 years by including a broad range of genetic, social, and environmental risk factors; multiple pathways by which they operate; a time dimension; the notion of differential susceptibility and resilience; and a multilevel approach. The study of children's oral health from a global perspective remains largely in its infancy and is poised for additional development. This work can help inform how best to approach and improve children's oral health.


Effect of bivalirudin on aortic valve intervention outcomes study: a two-centre registry study comparing bivalirudin and unfractionated heparin in balloon aortic valvuloplasty.
We sought to assess if bivalirudin use during balloon aortic valvuloplasty (BAV) would affect clinical outcomes compared with heparin. We compared the outcomes of consecutive patients who underwent elective or urgent BAV with intraprocedural use of bivalirudin or heparin at two high-volume centres. All in-hospital events post BAV were adjudicated by an independent, blinded clinical events committee. Of 427 patients, 223 patients (52.2%) received bivalirudin and 204 (47.8%) received heparin. Compared with patients who received heparin, patients who received bivalirudin had significantly less major bleeding (4.9% vs. 13.2%, p=0.003). Net adverse clinical events (NACE, major bleeding or major adverse cardiovascular events [MACE]) were also reduced (11.2% vs. 20.1%, p=0.01). There was no significant difference in the rates of MACE (mortality, myocardial infarction or stroke, 6.7% vs. 11.3%, p=0.1), or vascular complications (major, 2.7% vs. 2.0%; minor, 4.5% vs. 4.9%; p=0.83). After multivariate analysis controlling for vascular preclosure, the use of bivalirudin remained independently associated with reduced major bleeding (OR 0.37; 95% CI: 0.16 to 0.84; p=0.02) while the association was attenuated in propensity-adjusted analysis (OR 0.44, 95% CI: 0.18 to 1.07, p=0.08). In this registry of patients with severe aortic stenosis, bivalirudin as compared to heparin resulted in improved in-hospital outcomes post BAV in terms of reduced major bleeding, similar MACE and reduced NACE. If verified in a randomised study and extended to the transcatheter aortic valve implantation (TAVI) population, these results might indicate a potential benefit for patients undergoing such procedures.


Trends In Substance Use And Related Disorders: Analysis of the Epidemiological Survey of Substance Abuse 1995 to 2018.
Changes in the use of psychoactive substances and medications and in the occurrence of substance-related disorders enable assessment of the magni- tude of the anticipated negative consequences for the population. Trends were analyzed in the consumption of tobacco, alcohol, cannabis and other illegal drugs, analgesics, and hypnotics/sedatives, as well as trends in substance-related disorders, as coded according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The data were derived from nine waves of the German Epidemiological Survey of Substance Abuse (Epidemiologischer Sucht- survey, ESA) from 1995 to 2018. The data were collected in written form or by means of a combination of paper and internet-based questionnaires or telephone interviews. The estimated prevalence rates of tobacco and alcohol consumption and the use of hypnotics/sedatives decreased over time. On the other hand, increasing prevalence rates were observed for the consumption of cannabis and other illegal drugs and the use of analgesics. The trends in substance-related disorders showed no statistically significant changes compared to the reference values for the year 2018, except for higher prevalence rates of nicotine dependence, alcohol abuse and dependence, analgesic dependence, and hypnotic/sedative dependence in the year 2012 only. Trends in tobacco and alcohol consumption imply a future decline in the burden to society from the morbidity, mortality, and economic costs related to these substances. An opposite development in cannabis use cannot be excluded. No increase over time was seen in the prevalence of analgesic dependence, but the observed increase in the use of analgesics demands critical attention.


Early Neolithic pastoral land use at Alsónyék-Bátaszék, Hungary (Starčevo culture): New insights from stable isotope ratios.
The earliest introduction of livestock (cattle, goats, sheep, pigs) into the Carpathian Basin was an important step towards farming expansion into continental Europe. This spread beyond the environments of the southern Balkans was accompanied by a reduction in the spectrum of cultivated crops, changes in the relative representation of different domestic animals, and, most likely, adaptations of husbandry practices. How the earliest farmers in the Carpathian Basin kept their domestic stock is still understudied. We explored early animal management and land use strategies at the Starčevo settlement at Alsónyék-Bátaszék, Hungary (Early Neolithic, ca. 5800-5600 cal BC). Settled at the intersection of wide alluvial plains, waterlogged meadows and marshes to the east, and forested hills to the west, early farmers at Alsónyék had a wide variety of options for nourishing their livestock. We performed stable isotope ratio analysis of bone collagen (n = 99; δ13C, δ15N) and tooth enamel (nteeth = 28, sequentially sampled for δ13C and δ18O) from wild and domestic animals to locate them in the landscape and investigate herding practices on a seasonal scale. The bone collagen isotope ratios mostly indicate feeding in open environments. However, results from the sequential analysis of cattle and sheep enamel suggest diverse dietary strategies for winters, including consumption of forest resources, consumption of summer hay and grazing in an open environment. Most pigs appear to have had herbivorous diets, but several individuals likely supplemented their diet with animal protein. Stable isotope ratio results from the Lengyel phase at Alsónyék (ca. 4800-4300 cal BC) suggest more access to animal protein for pigs, and feeding in more open areas by wild boar, red deer and cattle compared to the Starčevo phase. This study's results demonstrate considerable variability in early animal husbandry practices at Alsónyék.


Risk of hypotony in noninfectious uveitis.
We sought to describe the risk and risk factors for hypotony in a noninfectious uveitis cohort. Retrospective cohort study. Patients with noninfectious uveitis seen between 1979 and 2007 at 4 academic ocular inflammation specialty clinics. Data were collected from medical records by trained, certified, expert reviewers. Hypotony (<5 mmHg) and low intraocular pressure (<8 mmHg), each sustained for ≥ 2 visits spanning ≥ 30 days. During follow-up, 126 of 6785 patients (1.86%) developed hypotony at the rate of 0.61% (95% confidence interval [CI], 0.50-0.75%) per eye-year. Cataract surgery was associated with a 7.5-fold risk (adjusted hazard ratio [aHR], 7.51; 95% CI, 3.97-14.23) of incident hypotony. Phacoemulsification, the type of cataract surgery associated with the least hypotony risk still was associated with nearly 5-fold higher hypotony incidence (aHR, 4.87; 95% CI, 2.25-10.55). Increased risk was observed in children (aHR, 2.92; 95% CI, 1.20-7.10) with respect to young adults, and duration of uveitis of >5 years (aHR, 3.08; 95% CI, 1.30-7.31) with respect to uveitis of <6 month duration. Band keratopathy, ≥ 3+ vitreous cells, exudative retinal detachment, posterior synechia, and a history of pars plana vitrectomy also were associated with greater hypotony incidence. With respect to anterior uveitis, intermediate uveitis (aHR, 0.17; 95% CI, 0.05-0.56) and posterior uveitis (aHR, 0.11; 95% CI, 0.03-0.45) were associated with lower hypotony risk, whereas panuveitis (aHR, 1.25; 95% CI, 0.67-2.35) was similar. Approximately five-sixths (84.1%) of eyes presenting with hypotony had a visual acuity of ≤ 20/200 (aOR for visual acuity ≤ 20/200, 13.85; 95% CI, 7.23-26.53). Risk factors for prevalent hypotony were similar. The risk of hypotony is low among eyes with noninfectious uveitis, but is more frequently observed in cases with anterior segment inflammation. Signs of present or past inflammation were associated with greater risk, suggesting excellent inflammatory control may reduce the risk of hypotony. Prior ocular surgery also was associated with higher risk; cataract surgery in particular was associated with much higher risk of hypotony. Lower risk of hypotony with phacoemulsification than with alternative cataract surgery approaches suggests the phacoemulsification approach is preferable.


Using a common cause strategy for quality improvement: improving hypnotic prescribing in general practice within a Quality Improvement Collaborative.
A common cause strategy is an essential conceptual approach for understanding variation and what might be contributing to it as well as informing the redesign of processes and systems to reduce inappropriate and unintended variation. This article describes what a common cause strategy for improvement is and the steps required for this approach. We describe a practical example of how this is applied in a real-life situation. The first step in a common cause strategy is to look more deeply at this common cause variation to see whether special causes can be exposed using stratification. The second step is to seek to understand existing variation by understanding the processes and systems leading to the observed problem. Finally there is a need to redesign processes to reduce inappropriate and unintended variation in any agreed measures by agreeing and incorporating critical inputs and outputs from a provider-patient perspective in the context of systems thinking.


Nationwide study on trends in unplanned hospital attendance and deaths during the 7 weeks after the onset of the COVID-19 pandemic in Denmark.
The impact of a pandemic on unplanned hospital attendance has not been extensively examined. The aim of this study is to report the nationwide consequences of the COVID-19 pandemic on unplanned hospital attendances in Denmark for 7 weeks after a 'shelter at home' order was issued. We merged data from national registries (Civil Registration System and Patient Registry) to conduct a study of unplanned (excluding outpatient visits and elective surgery) hospital-based healthcare and mortality of all Danes. Using data for 7 weeks after the 'shelter at home' order, the incidence rate of unplanned hospital attendances per week in 2020 was compared with corresponding weeks in 2017-2019. The main outcome was hospital attendances per week as incidence rate ratios. Secondary outcomes were general population mortality and risk of death in-hospital, reported as weekly mortality rate ratios (MRRs). From 2 438 286 attendances in the study period, overall unplanned attendances decreased by up to 21%; attendances excluding COVID-19 were reduced by 31%; non-psychiatric by 31% and psychiatric by 30%. Out of the five most common diagnoses expected to remain stable, only schizophrenia and myocardial infarction remained stable, while chronic obstructive pulmonary disease exacerbation, hip fracture and urinary tract infection fell significantly. The nationwide general population MRR rose in six of the recorded weeks, while MRR excluding patients who were COVID-19 positive only increased in two. The COVID-19 pandemic and a governmental national 'shelter at home' order was associated with a marked reduction in unplanned hospital attendances with an increase in MRR for the general population in two of 7 weeks, despite exclusion of patients with COVID-19. The findings should be taken into consideration when planning for public information campaigns.


Approach to Resource Management and Physical Strength Predict Differences in Helping: Evidence From Two Small-Scale Societies.
Helping behavior is likely to have evolved to increase chances of survival of an individual and their group. Nevertheless, populations differ significantly in their eagerness to help, and little is known about populational and inter-individual determinants of these differences. Previous studies indicated that economic and physiological factors might influence helping behavior. The aim of the present study was to investigate the effects of approach to resource management of a society (immediate-return economy vs. delayed-return economy), prenatal androgenization (based on second-to-fourth digit ratio), and physical strength (based on hand grip strength) on helping behavior toward others. Helping was assessed in terms of both general eagerness to help and differential helping toward: (1) kin, (2) other group members indiscriminately, (3) friends, and (4) those from whom help was obtained in the past. Based on data collected in two small-scale societies (n = 306), we found that people in the egalitarian immediate-return society (the Hadza hunter-gatherers of Tanzania) displayed helping behavior significantly more often than people in a more stratified delayed-return economy (Yali horticulturalists of Papua). Additionally, our results revealed that physical strength was a significant predictor of helping behavior in women but not in men. We discuss our findings in the light of the adaptive value of helping behavior.


Cellular determinants of reduced adaptability of the aging brain: neurotransmitter utilization and cell signaling responses after MDMA lesions.
Senescence is accompanied by the loss of neurons and synapses, and the maintenance of function depends on adaptive change at the levels of synaptic activity and cellular responsiveness. In the current study, we administered the neurotoxin MDMA, to young and aged mice and assessed the effects on indices of neuronal activity and cell signaling mediated through adenylyl cyclase. Young mice given MDMA showed 80% depletion of dopamine in the caudate and 30% depletion in the cerebral cortex; measurements of dopamine turnover indicated a compensatory upregulation of the activity of the remaining neurons in the caudate but downregulation in the cerebral cortex. Serotonin levels were comparatively less affected but serotonin turnover was decreased significantly in both regions. At the level of cell signaling, the young mice showed heterologous upregulation of adenylyl cyclase activity and a consequent enhancement of responses mediated through neurotransmitter receptors. In aged mice, MDMA treatment produced the same degree of lesioning but substantially different changes in neuronal activity and cell signaling. In the cerebral cortex, dopamine turnover was increased, and serotonin turnover decreased, effects opposite in direction to those seen in young mice. In the aged group, MDMA elicited heterologous loss of adenylyl cyclase responses instead of displaying the supersensitivity that had been seen in the young group. The aging brain thus displays maladaptation to the loss of monoaminergic input, effects that may augment the functional impairment associated with neurodegenerative disorders or stroke.


Combined normal-phase and reversed-phase liquid chromatography/ESI-MS as a tool to determine the molecular diversity of A-type procyanidins in peanut skins.
Peanut skins, a byproduct of the peanut butter industry, are a rich source of proanthocyanidins, which might be used in food supplements. Data on the molecular diversity of proanthocyanidins in peanut skins is limited and conflicting with respect to the ratio of double- (A-type) versus single-linked (B-type) flavan-3-ol units. NP- and RP-HPLC-MS were used as tools to analyze the molecular diversity of proanthocyanidins in a 20% (v/v) methanol extract of peanut skins. NP-HPLC was used to prepurify monomeric to pentameric fractions, which were further separated and characterized by RP-HPLC-MS. With this method, 83 different proanthocyanidin molecular species were characterized and quantified. Furthermore, it was possible to determine that A-type procyanidin oligomers were predominant and represented 95.0% (w/w) of the extract. In addition, the position of the A-linkages in 16 trimers and 27 tetramers could be determined, which in this case appeared to occur at all possible positions. The majority of trimers and tetramers with one or more A-linkage always had an A-linkage at the terminal unit.


A clinical review of hyperopia in young children. The Hyperopic Infants' Study Group, THIS Group.
Hyperopia is the most common refractive error of children. Children with mild (or even moderate) levels of hyperopia usually do not experience visual problems resulting from this hyperopia. However, children with moderate-to-high degrees of hyperopia are at significantly increased risk for the development of amblyopia and strabismus. It is this association with these visually threatening disorders that makes hyperopia in children an important public health problem. In addition, even lesser degrees of hyperopia may affect the child's ability to perform well in near-related tasks, such as reading. The effect hyperopia has on an individual child is dependent on a variety of factors, including the magnitude of hyperopia, the age of the individual, the status of the accommodative and convergence system, and the demands placed on the visual system. Early detection and treatment of hyperopia may help prevention of potential complications from adversely impacting the child's vision. Although much is known about childhood hyperopia and its effects on vision, there is also much that is not known. The natural history, ocular biometry, relationship to accommodative function, the indications for treatment, and the most effective treatment modalities are among the underlying issues and clinical considerations awaiting more complete understanding.


The evolution of polyandry: intrinsic sire effects contribute to embryo viability.
Females typically mate with more than one male despite the costs incurred, thus questioning Bateman's principle. A series of genetic benefits have been proposed to account for the evolution of polyandry, including the acquisition of viability genes for offspring. The 'intrinsic male quality' hypothesis suggests that polyandry increases the probability that females produce offspring sired by males that bestow high viability on their offspring. Heritable variation in viability is the basic requirement for the occurrence of this genetic benefit. By using a half-sib breeding design with a species of cricket in which polyandry is known to increase hatching success, we present clear experimental evidence that intrinsic male quality contributes to embryo viability. Despite recent support for the evolution of polyandry based on compatibility of genotypes between males and females, we show that hatching success is not determined by an interaction between paternal and maternal genotypes but rather that sons inherit paternal genes that influence the viability of eggs laid by their mates. Moreover, our data implicate a potential role for indirect genetic effects of male accessory gland products on embryo viability. Additive genetic contributions to embryo viability may be an important factor underlying the frequently observed benefits of polyandrous behaviour.


Anchor polymerase chain reaction display: a high-throughput method to resolve, score, and isolate dimorphic genetic markers based on interspersed repetitive DNA elements.
Genes which confer a disease when mutated, or for which population variability contributes to a quantitative trait such as longevity or disease susceptibility, can be localized in the genetic map by use of an appropriately dense set of polymorphic DNA markers. Here we describe an anchor PCR method for high-throughput genotyping, which can be used to amplify the DNA segments flanking an interspersed repetitive sequence such as a transposon, and to limit the number of product bands per reaction to facilitate marker resolution. We used this method to amplify and display DNA fragments flanking the Tc1 transposable elements from different strains of the nematode Caenorhabditis elegans, varying widely in insert number, and to analyze marker segregation in recombinant inbred lines generated from an interstrain cross. Since essentially all eukaryotic genomes contain abundant interspersed repeat families, many of which are dimorphic (for presence or absence of specific elements) among populations, this method can be used for rapid genotyping and fine-scale chromosomal mapping in many species, including those for which extensive mapping and sequencing data do not yet exist.


Scoping Review on the Impact of Outbreaks on Sexual and Reproductive Health Services: Proposed Frameworks for Pre-, Intra-, and Postoutbreak Situations.
Recent experiences from global outbreaks have highlighted the severe disruptions in sexual and reproductive health services that expose women and girls to preventable health risks. Yet, to date, there is no review studying the possible impact of outbreaks on sexual and reproductive health (SRH). Methodology. Studies reporting outbreaks impacting sexual and reproductive health and pregnancy outcomes were identified using MEDLINE, Embase, and ISI-WoS. Reported impacts were reviewed at systems, community, and legislative levels. The initial run listed 4423 studies; the 37 studies that met all inclusion criteria were mainly from Latin America and Africa. Studies on outbreaks of diseases like Zika and Ebola have documented declines in facility-based deliveries, contraceptive use, and antenatal and institutional care due to burdened healthcare system. Service usage was also impacted by a lack of trust in the healthcare system and system shocks, including workforce capacity and availability. At the community level, poverty and lack of awareness were critical contributors to poor access to SRH services. Assessing the target population's knowledge, attitude, beliefs, and behavior and using health literacy principles for communication were fundamental for designing service delivery. Online resources for SRH services were an acceptable medium of information among young adults. In outbreak situations, SRH and pregnancy outcomes were improved by implementing laboratory surveillance, free-of-cost contraceptive services, improved screening through professional training, and quality of care. In addition, mobile health clinics were reported to be effective in remote areas. Knowledge Contribution. In outbreaks, the interventions are categorized into preoutbreak, during, and postoutbreak periods. The proposed steps can help to improve and do course correction in emergencies. Though conducted before the COVID-19 crisis, the authors believe that lessons can be drawn from the paper to understand and mitigate the impact of the pandemic on sexual and reproductive health services.


The use of live attenuated influenza vaccine ts-1(E) in man.
Live temperature-sensitive influenza virus vaccines were tested in two volunteer experiments. The vaccine virus was originally derived from a temperature-sensitive mutant of influenza A/Great Lakes/1965 (H2N2) produced by chemical mutagenesis with 5-fluorouracil. The ts lesions of this strain were subsequently transferred (HI) antibody. Only 9 men (13%) were infected, presumably as a result of over-attenuation of the virus and/or insufficient titer of the inoculum. In the second experiment (1974), 20 young adults were given 0.5 ml per nostril of vaccine containing a recombinant of influenza A/Udorn/307/72 clone 24 (10(5.5) TCID50/ml) with an in vitro shutoff temperature of 38 degree C. Virus was shed by seven volunteers (maximum titer, 10(2.5)TCID50/ml). None of 21 isolates contained revertant wild type virus. Serum HI and antieuraminidase (NI) and nasal wash neutralizing antibody responses occurred in 11 (55%), 7 (35%), and 8 (40%) volunteers, respectively. Post-vaccination serum HI and NI and nasal neutralizing antibody geometric mean titers were 3.0, 9.4, and 1.7 lob2, respectively. Seven volunteers judged they had colds (symptom scores 4-32). Rhinitis and mild pharyngeal discomfort were the only consistent complaints and fever was absent. The findings in the latter trial will be compared with results of volunteer experiments with Udorn/72 ts-1-(E) in other laboratories and to studies with standard inactivated influenza vaccines given parenterally.


Protective Effect of Brown Alga Phlorotannins against Hyper-inflammatory Responses in Lipopolysaccharide-Induced Sepsis Models.
Brown algae have been recognized as a food ingredient and health food supplement in Japan and Korea, and phlorotannins are unique marine phenol compounds produced exclusively by brown algae. Sepsis is a whole-body inflammatory condition with a mortality rate of 30-40%. Here, we investigated the effects of a phlorotannin-rich extract of the edible brown alga Ecklonia cava against hyper-inflammatory response in LPS-induced septic shock mouse model. E. cava extract significantly increased the survival rate and attenuated liver and kidney damage in the mice. In addition, E. cava attenuated serum levels of NO, PGE2, and HMGB-1. In macrophages, treatment with E. cava extract down-regulated iNOS, COX-2, TNF-α, IL-6, and HMGB-1. In addition, E. cava suppressed the NIK/TAK1/IKK/IκB/NFκB pathway. Moreover, E. cava increased Nrf2 and HO-1 expression. HO-1 knockdown using siRNA restored the extract-suppressed NO and PGE2 production. Dieckol, a major compound in the extract, reduced mortality, tissue toxicity, and serum levels of the inflammatory factors in septic mice. These data suggest that brown algae phlorotannins suppress septic shock through negative regulation of pro-inflammatory factors via the NIK/TAK1/IKK/IκB/NFκB and Nrf2/HO-1 pathways.


Leishmania major elongation factor 1B complex has trypanothione S-transferase and peroxidase activity.
In the Trypanosomatidae, trypanothione has subsumed many of the roles of glutathione in defense against chemical and oxidant stress. Crithidia fasciculata lacks glutathione S-transferase, but contains an unusual trypanothione S-transferase activity that is associated with eukaryotic translation elongation factor 1B (eEF1B). Here we describe the cloning, expression, and reconstitution of the purified alpha, beta, and gamma subunits of eEF1B from Leishmania major. Individual subunits lacked trypanothione S-transferase activity. Only eEF1B, formed by reconstitution or co-expression of the three subunits, was able to conjugate a variety of electrophilic substrates to trypanothione or glutathionylspermidine, but not glutathione. In contrast to the C. fasciculata eEF1B, the L. major enzyme also displayed peroxidase activity against a variety of organic hydroperoxides. The enzyme showed no activity with hydrogen peroxide and greatest activity with linoleic acid hydroperoxide (1 unit mg(-1)). Kinetic studies suggest a ternary complex mechanism, with Km values of 140 mum for trypanothione and 7.4 mm for cumene hydroperoxide and kcat=25 s(-1). Immunofluorescence studies indicate that the enzyme may be localized to the surface of the endoplasmic reticulum. These results suggest that, in addition to its role in protein synthesis, the Leishmania eEF1B may help protect the parasite from lipid peroxidation.


Aspects of laser light scattering from skin tissue with application to laser Doppler blood flow measurement.
Studies of both intensity and Doppler shifted linewidths of light scattered from skin tissue have been made using photon correlation spectroscopy and optical fibre techniques. Measurements as a function of the separation of input and detecting fibre positions show characteristic features. These features are interpreted in terms of the positions of the scattering red blood cells and the tissue structure. Evidence is given for an interpretation of the differences in the scattered light for scattering from superficial vessels including capillary loops and from deeper lying larger vessels and shunts. Measurements using various laser wavelengths are discussed. The results of this study are important in the development of laser light scattering instruments for the measurement of peripheral blood flow and microcirculation.


Comparison of Recent Practice Guidelines for the Management of Patients With Asymptomatic Carotid Stenosis.
Despite the publication of several national/international guidelines, the optimal management of patients with asymptomatic carotid stenosis (AsxCS) remains controversial. This article compares 3 recently released guidelines (the 2020 German-Austrian, the 2021 European Stroke Organization [ESO], and the 2021 Society for Vascular Surgery [SVS] guidelines) vs the 2017 European Society for Vascular Surgery (ESVS) guidelines regarding the optimal management of AsxCS patients.The 2017 ESVS guidelines defined specific imaging/clinical parameters that may identify patient subgroups at high future stroke risk and recommended that carotid endarterectomy (CEA) should or carotid artery stenting (CAS) may be considered for these individuals. The 2020 German-Austrian guidelines provided similar recommendations with the 2017 ESVS Guidelines. The 2021 ESO Guidelines also recommended CEA for AsxCS patients at high risk for stroke on best medical treatment (BMT), but recommended against routine use of CAS in these patients. Finally, the SVS guidelines provided a strong recommendation for CEA+BMT vs BMT alone for low-surgical risk patients with >70% AsxCS. Thus, the ESVS, German-Austrian, and ESO guidelines concurred that all AsxCS patients should receive risk factor modification and BMT, but CEA should or CAS may also be considered for certain AsxCS patient subgroups at high risk for future ipsilateral ischemic stroke.


The significance of pigment epithelial detachment in central serous chorioretinopathy.
To investigate the significance of the presence and form of pigment epithelial detachment in the course of central serous chorioretinopathy as well as corticosteroid use as a risk in our patient cohort. Retrospective, single center study of central serous chorioretinopathy patients between January 2013 and January 2019 recording corticosteroid use prior to onset and presence and type of pigment epithelial detachment (flat-irregular, dome-shaped, none) in relationship to disease course. We analyzed 53 eyes of 53 consecutive central serous chorioretinopathy patients treated in our department. Mean patient age was 53 ± 13 years. A flat-irregular pigment epithelial detachment was associated with either chronic or recurrent central serous chorioretinopathy, whereas the absence of a pigment epithelial detachment correlated positively with acute central serous chorioretinopathy (chi-square test, p < 0.05). Of the 53 patients, 10 reported corticosteroid use, 40 denied steroid use, and 3 patients failed to make a clear statement. Corticosteroid use was not correlated with the onset of central serous chorioretinopathy (Student's t-test, p = 0.0001, chi-square test, p < 0.005). A small, flat-irregular pigment epithelial detachment could be a marker for chronic or recurrent central serous chorioretinopathy, whereas the absence of pigment epithelial detachment could favor acute central serous chorioretinopathy. Advanced imaging studies may provide more information on the exact characteristics and nature of pigment epithelial detachments. Corticosteroid use as possible disease trigger was not confirmed in this study.


Heterogeneous growth-induced prestrain in the heart.
Even when entirely unloaded, biological structures are not stress-free, as shown by Y.C. Fung׳s seminal opening angle experiment on arteries and the left ventricle. As a result of this prestrain, subject-specific geometries extracted from medical imaging do not represent an unloaded reference configuration necessary for mechanical analysis, even if the structure is externally unloaded. Here we propose a new computational method to create physiological residual stress fields in subject-specific left ventricular geometries using the continuum theory of fictitious configurations combined with a fixed-point iteration. We also reproduced the opening angle experiment on four swine models, to characterize the range of normal opening angle values. The proposed method generates residual stress fields which can reliably reproduce the range of opening angles between 8.7±1.8 and 16.6±13.7 as measured experimentally. We demonstrate that including the effects of prestrain reduces the left ventricular stiffness by up to 40%, thus facilitating the ventricular filling, which has a significant impact on cardiac function. This method can improve the fidelity of subject-specific models to improve our understanding of cardiac diseases and to optimize treatment options.


Advances on the determination of thresholds of Cu phytotoxicity in field-contaminated soils in central Chile.
To better determine phytotoxicity thresholds for metals in the soil, studies should use actual field-contaminated soil samples rather than metal-spiked soil preparations. However, there are surprisingly few such data available for Cu phytotoxicity in field-contaminated soils. Moreover, these studies differ from each other with regards to soil characteristics and experimental setups. This study aimed at more accurately estimating Cu phytotoxicity thresholds using field-collected agricultural soils (Entisols) from areas exposed to contamination from Cu mining. For this purpose, the exposure to Cu was assessed by measuring total soil Cu, soluble Cu, free Cu2+ activity, and Cu in the plant aerial tissues. On the other hand, two bioassay durations (short-term and long-term), three plant species (Avena sativa L., Brassica rapa CrGC syn. Rbr, and Lolium perenne L.), and five biometric endpoints (shoot length and weight, root length and weight, and number of seed pods) were considered. Overall plant growth was best predicted by total Cu content of the soil. Despite some confounding factors, it was possible to determine EC10, EC25 and EC50 of total Cu in the soil. Brassica rapa was more sensitive than Avena sativa for all endpoints, while Lolium perenne was of intermediate sensitivity. For the short-term bioassay (21 days for all three species), the averaged EC10, EC25 and EC50 values of total soil Cu (in mg kg-1) were 356, 621, and 904, respectively. For the long-term bioassay (62 days for oat and 42 days for turnip), the averaged EC10, EC25 and EC50 values of total soil Cu (in mg kg-1) were 355, 513, and 688, respectively. The obtained results indicate that chronic test is a suitable method for assessing Cu phytotoxicity in field-contaminated soils.


The effect of tunicamycin on interferon-alpha production in a human lymphoblastoid cell line (Namalwa).
Tunicamycin alters the biological properties of human interferon-alpha (HuIFN-alpha) produced in its presence by changing the mixture of IFN-alpha subtypes produced. When IFN mRNA extracted from treated cells was microinjected into oocytes the product was also altered. However, treatment of the oocytes with tunicamycin did not alter the properties of the IFN-alpha produced.


Financial volatility trading using recurrent neural networks.
We simulate daily trading of straddles on financial indexes. The straddles are traded based on predictions of daily volatility differences in the indexes. The main predictive models studied are recurrent neural nets (RNN). Such applications have often been studied in isolation. However, due to the special character of daily financial time-series, it is difficult to make full use of RNN representational power. Recurrent networks either tend to overestimate noisy data, or behave like finite-memory sources with shallow memory; they hardly beat classical fixed-order Markov models. To overcome data nonstationarity, we use a special technique that combines sophisticated models fitted on a larger data set, with a fixed set of simple-minded symbolic predictors using only recent inputs. Finally, we compare our predictors with the GARCH family of econometric models designed to capture time-dependent volatility structure in financial returns. GARCH models have been used to trade volatility. Experimental results show that while GARCH models cannot generate any significantly positive profit, by careful use of recurrent networks or Markov models, the market makers can generate a statistically significant excess profit, but then there is no reason to prefer RNN over much more simple and straightforward Markov models. We argue that any report containing RNN results on financial tasks should be accompanied by results achieved by simple finite-memory sources combined with simple techniques to fight nonstationarity in the data.


[Cerebral hemodynamics in patients with bilateral lesions of the carotid bifurcation].
Sixty-eight patients with bilateral damage to bifurcations of the carotid arteries, of them 22 with attendant damage to the vertebral arteries, were subjected to operation on one carotid artery. An analysis of the findings of dopplerography, angiography and intraoperative electromanometry revealed the following factors affecting the retrograde pressure (RP) in the internal carotid artery (ICA): the state of the contralateral ICA, the functional state of the anterior connective artery of the brain, intracranial localization of injury and the attendant involvement of the vertebral arteries. There was no correlation between the RP in the ICA and the level of artificial hypertension.


A case series on the effectiveness of lurasidone in patients with stuttering.
The prevalence of stuttering is approximately 1% of the population, affecting an estimated 3 million individuals in the United States. The dopamine hypothesis of stuttering explains that abnormally increased cerebral dopamine affects the balanced levels that maintain the basal ganglia circuits, which helps with timing cues in initiating speech. This is especially significant when considering treatment strategies. We report a reduction in stuttering with lurasidone, a potent D2 receptor antagonist with a relatively favorable adverse effects profile. We conducted a non-randomized, open-label study of lurasidone in patients with stuttering (N = 7). Patients self-reported stuttering severity, locus of control, and avoidance using the Subjective Screening of Stuttering (SSS) scale and were assessed with the Clinical Global Impression (CGI) Scale. We observed a notable, statistically significant improvement in all areas of stuttering, as rated by the SSS scale. According to the CGI-Improvement Scale, 2 patients were scored as "very much improved" and 5 were scored as "much improved." This open-label study of lurasidone in patients with stuttering showed improvement in subjective symptoms, in CGI scores, and on the SSS scale.


Influence of Soil Phosphate on the Accumulation and Toxicity of Arsenic and Antimony in Choy Sum Cultivated in Individually and Co-contaminated Soils.
Fertilizers containing phosphate (PO43- ) are commonly used within the agricultural industry and are known to increase the bioavailability and mobility of metalloids like arsenic (As). This may increase plant uptake of As and hence pose a risk to human health. Arsenic and antimony (Sb) often co-occur in contaminated soils; however, little is known about the interactions between As and Sb with PO43- on their bioavailability, accumulation, and toxicity in plants. The present study investigated individual and combined As and Sb-contaminated soils across 2 soil PO43- concentrations using a commonly consumed leafy vegetable, choy sum (Brassica chinensis var. parachinensis). Increased soil PO43- had no clear influence on the bioavailability of As or Sb (derived from a sequential extraction procedure). At high PO43- concentration, B. chinensis accumulated higher amounts of As in the shoots and roots in both individual and co-contaminated soil, whereas Sb accumulation increased only when Sb was the only contaminant. When As was the only contaminant, the translocation of As from roots to shoots decreased as soil PO43- increased. Increased soil PO43- had no influence on Sb translocation from root to shoot. Although As was toxic (impaired growth) at low PO43- soil concentration, no toxicity was observed in the high-PO43- soil. No toxicity was observed for Sb in either low- or high-PO43- soils. Increased soil PO43- concentration ameliorated or masked As toxicity to plant growth and led to higher As concentration in the plant's edible parts. The addition of high soil PO43- concentrations ameliorated or masked As toxicity to plant growth in both individually and As + Sb co-contaminated soil; however, the plant's edible parts accumulated higher As and Sb concentrations. Environ Toxicol Chem 2020;39:1233-1243. © 2020 SETAC.


Demographic situation of population ageing in Nepal.
Advances in medical technology have led to increases in the life expectancy as well as increases in the number of older people, which makes population ageing an international priority in the 21st century. However, very little is known about the elderly in Nepal, one of the poorest countries of the world. Although the proportion of elderly is increasing both in absolute numbers and as a proportion of Nepal's total population, traditional family norms and values of supporting the elderly are eroding at an alarming rate. The objective of this paper is to illustrate population aging in Nepal using census data, other reports for the purpose of further research and inquiry.


Switching of pseudorotaxanes and catenanes incorporating a tetrathiafulvalene unit by redox and chemical inputs
An acyclic polyether 1a, incorporating a central tetrathiafulvalene (TTF) electron donor unit and two 4-tert-butylphenoxy groups at its termini, has been synthesized. Two macrocyclic polyethers containing two different electron donors, namely a TTF unit with, in one case, a 1,4-dioxybenzene ring (2a), and, in the other case (2b), a 1,5-dioxynaphthalene ring system, have also been synthesized. These two macrocyclic polyethers have been mechanically interlocked in kinetically controlled template-directed syntheses with cyclobis(paraquat-p-phenylene) cyclophane (3(4+)) to afford the [2]catenanes 2a/3(4+) and 2b/3(4+), respectively. X-ray crystallography reveals that the [2]-catenane 2b/3(4+) has the TTF unit of 2b located inside the cavity of 3(4+). The spectroscopic (UV/vis and 1H NMR) and electrochemical properties of compounds 1a, 2a, 2b, 2a/3(4+), and 2b/3(4+) and of the [2]pseudorotaxane 1a.3(4+) were investigated. The absorption and emission properties of the mono- and dioxidized forms of the TTF unit in these various species have also been studied. The results obtained in acetonitrile solution can be summarized as follows. (a) While TTF2+ exhibits a strong fluorescence, no emission can be observed for the TTF2+ units contained in the polyethers and in their pseudorotaxanes and catenanes. (b) A donor-acceptor absorption band is observed upon two-electron oxidation of the TTF unit in the macrocyclic polyethers 2a and 2b. (c) The spontaneous self-assembly of 1a and 3(4+) to give the [2]pseudorotaxane 1a.3(4+) is strongly favored (Kass. = 5 x 10(5) L mol-1) but slow (at 296 K, k = 11.3 L mol-1 s-1 and delta G++ = 15.9 kcal mol-1) because of the steric hindrance associated with the bulky end groups of 1a. (d) In the pseudorotaxane 1a.3(4+), the reversible displacement of the cyclophane from the TTF unit in the threadlike substrate occurs on oxidation/reduction of its electroactive components. (e) Switching between the two translational isomers of the catenanes 2a/3(4+) and 2b/3(4+) occurs by cyclic oxidation and reduction of the TTF unit contained in 2a and in 2b, respectively. (f) Addition of o-chloroanil to the pseudorotaxane 1a.3(4+) and to the catenanes 2a/3(4+) and 2b/3(4+) causes the displacement of the TTF unit from the cavity of the cyclophane 3(4+) because of the formation of an adduct between the TTF unit and o-chloroanil.


Effect of fullerene C60 on ATPase activity and superprecipitation of skeletal muscle actomyosin.
Creation of new biocompatible nanomaterials, which can exhibit the specific biological effects, is an important complex problem that requires the use of last accomplishments of biotechnology. The effect of pristine water-soluble fullerene C60 on ATPase activity and superprecipitation reaction of rabbit skeletal muscle natural actomyosin has been revealed, namely an increase of actomyosin superprecipitation and Mg2+, Ca(2+)- and K(+)-ATPase activity by fullerene was investigated. We conclude that this finding offers a real possibility for the regulation of contraction-relaxation of skeletal muscle with fullerene C60.


Fragmentation of polymer nanocomposites: modulation by dry and wet weathering, fractionation, and nanomaterial filler.
In recent years, an increasing number of polymeric composites incorporating engineered nanomaterials (ENMs) have reached the market. Such nano-enabled products (NEPs) present enhanced performance through improved mechanical, thermal, UV protection, electrical, and gas barrier properties. However, little is known about how environmental weathering impacts ENM release, especially for high-tonnage NEPs like kaolin products, which have not been extensively examined by the scientific community. Here we study the simulated environmental weathering of different polymeric nanocomposites (epoxy, polyamide, polypropylene) filled with organic (multiwalled carbon nanotube, graphene, carbon black) and inorganic (WS2, SiO2, kaolin, Fe2O3, Cu-phthalocyanines) ENMs. Multiple techniques were employed by researchers at three laboratories to extensively evaluate the effect of weathering: ultraviolet-visible spectroscopy (UV-vis), Fourier transform infrared spectroscopy (FTIR), optical microscopy, contact angle measurements, gravimetric analysis, analytical ultracentrifugation (AUC), transmission electron microscopy (TEM), scanning electron microscopy (SEM) and Raman spectroscopy. This work aimed to elucidate the extent to which weathering protocol (i.e. wet vs. dry) and diverse filler characteristics modulate fragment release and polymer matrix degradation. In doing so, it expanded the established NanoRelease protocol, previously used for analyzing fragment emission, by evaluating two significant additions: (1) simulated weathering with rain events and (2) fractionation of sample leachate prior to analysis. Comparing different composite materials and protocols demonstrated that the polymer matrix is the most significant factor in NEP aging. Wet weathering is more realistic than dry weathering, but dry weathering seems to provide a more controlled release of material over wet. Wet weathering studies could be complicated by leaching, and the addition of a fractionation step can improve the quality of UV-vis measurements.


Age-related changes of cystatin C expression and polarized secretion by retinal pigment epithelium: potential age-related macular degeneration links.
Cystatin C, a potent cysteine proteinase inhibitor, is abundantly secreted by the RPE and may contribute to regulating protein turnover in the Bruch's membrane (BrM). A cystatin C variant associated with increased risk of developing AMD and Alzheimer's disease (AD) presents reduced secretion levels from RPE. The purpose of this study was to analyze the effects of age and the accumulation of advanced glycation end-products (AGEs) on the expression and secretion of cystatin C by the RPE. Confluent monolayers of human fetal RPE (hfRPE) cells were cultured using an in vitro model mimicking extracellular AGE accumulation. Cystatin C expression, secretion, and its polarity were analyzed following culture on AGE-containing BrM mimics (AGEd versus non-AGEd). Monolayer barrier properties were assessed by transepithelial resistance measurements. The relative level of cystatin C protein expression in human RPE in situ was assessed immunohistochemically in relation to age. Advanced glycation end product-exposed RPE monolayers presented significantly decreased cystatin C expression and secretion. Basolateral secretion was fully established by week 8 in non-AGEd conditions. In AGEd cultures, polarity of secretion was impaired despite maintenance of physiological barrier properties of the monolayer. In the macula region of RPE/choroid segments from human eyes, the level of cystatin C protein was reduced with increasing donor age. Exposure to AGEs reduces expression of cystatin C and affects its normal secretion in cultured RPE. Age-related changes of cystatin C in the RPE from the posterior pole may compromise its extracellular functions, potentially contributing to AMD pathogenesis.


Cross-linked forms of the isolated N-terminal domain of the lethal factor are potent inhibitors of anthrax toxin.
The proteins that comprise anthrax toxin self-assemble at the mammalian cell surface into a series of toxic complexes, each containing a heptameric form of protective antigen (PA) plus up to a total of three molecules of the enzymatic moieties of the toxin (lethal factor [LF] and edema factor [EF]). These complexes are trafficked to the endosome, where the PA heptamer forms a pore in the membrane under the influence of low pH, and bound LF and EF unfold and translocate through the pore to the cytosol. To explore the hypothesis that the PA pore can translocate multiple, cross-linked polypeptides simultaneously, we cross-linked LF(N), the N-terminal domain of LF, via an introduced cysteine at its N or C terminus and characterized the products. Both dimers and trimers of LF(N) retained the ability to bind to PA pores and block ion conductance, but they were unable to translocate across the membrane, even at high voltages or with a transmembrane pH gradient. The multimers were remarkably potent inhibitors of toxin action in mammalian cells (20- to 50-fold more potent than monomeric LF(N)) and in a zebrafish model system. These findings show that the PA pore cannot translocate multimeric, cross-linked polypeptides and demonstrate a new approach to generating potent inhibitors of anthrax toxin.


Guidelines, algorithms, and evidence-based psychopharmacology training for psychiatric residents.
The authors describe a course of instruction for psychiatry residents that attempts to provide the cognitive and informational tools necessary to make scientifically grounded decision making a routine part of clinical practice. In weekly meetings over two academic years, the course covers the psychopharmacology of various psychiatric disorders in 32 3-hour modules. The first half of each module is a case conference, and the second is a literature review of papers related to the case. The case conference focuses on the extent to which past treatment has been consistent with evidence-supported guidelines and algorithms, and the discussants make recommendations that take the relevant scientific evidence into consideration. The second half of each module focuses on two papers: 1) a published guideline, algorithm, or review article and 2) a research study. Residents absorb a comprehensive overview of recommended clinical practices and acquire skills in assessing knowledge that affects decision making. Satisfaction with the course is rated highly. The course appears useful by its face validity, but research comparing the attitudes and practice outcomes of graduates of this course compared with recipients of other training methods is needed.


Endoplasmic reticulum calcium signaling in nerve cells.
The endoplasmic reticulum (ER) is an important organelle involved in various types of signaling in nerve cells. The ER serves as a dynamic Ca2+ pool being thus involved in rapid signaling events associated with cell stimulation by either electrical (action potential) or chemical (neurotransmitters) signals. This function is supported by Ca2+ release channels (InsP3 and ryanodine receptors) and SERCA Ca2+ pumps residing in the endomembrane. In addition the ER provides a specific environment for the posttranslational protein processing and transport of various molecules towards their final destination. In parallel, the ER acts as a "calcium tunnel," which facilitates Ca2+ movements within the cell by avoiding cytoplasmic routes. Finally the ER appears as a source of numerous signals aimed at the nucleus and involved in long-lasting adaptive cellular responses. All these important functions are controlled by intra-ER free Ca2+ which integrates various signaling events and establishes a link between fast signaling, associated with ER Ca2+ release/uptake, and long-lasting adaptive responses relying primarily on the regulation of protein synthesis. Disruption of ER Ca2+ homeostasis triggers several forms of cellular stress response and is intimately involved in neurodegeneration and neuronal cell death.


Improving the Thermostability of Thermomyces lanuginosus Lipase by Restricting the Flexibility of N-Terminus and C-Terminus Simultaneously via the 25-Loop Substitutions.
(1) Lipases are catalysts widely applied in industrial fields. To sustain the harsh treatments in industries, optimizing lipase activities and thermal stability is necessary to reduce production loss. (2) The thermostability of Thermomyces lanuginosus lipase (TLL) was evaluated via B-factor analysis and consensus-sequence substitutions. Five single-point variants (K24S, D27N, D27R, P29S, and A30P) with improved thermostability were constructed via site-directed mutagenesis. (3) The optimal reaction temperatures of all the five variants displayed 5 °C improvement compared with TLL. Four variants, except D27N, showed enhanced residual activities at 80 °C. The melting temperatures of three variants (D27R, P29S, and A30P) were significantly increased. The molecular dynamics simulations indicated that the 25-loop (residues 24-30) in the N-terminus of the five variants generated more hydrogen bonds with surrounding amino acids; hydrogen bond pair D254-I255 preserved in the C-terminus of the variants also contributes to the improved thermostability. Furthermore, the newly formed salt-bridge interaction (R27…E56) in D27R was identified as a crucial determinant for thermostability. (4) Our study discovered that substituting residues from the 25-loop will enhance the stability of the N-terminus and C-terminus simultaneously, restrict the most flexible regions of TLL, and result in improved thermostability.


Stability of ring patterns arising from two-dimensional particle interactions.
Pairwise particle interactions arise in diverse physical systems ranging from insect swarms to self-assembly of nanoparticles. In the presence of long-range attraction and short-range repulsion, such systems can exhibit bound states. We use linear stability analysis of a ring equilibrium to classify the morphology of patterns in two dimensions. Conditions are identified that assure the well-posedness of the ring. In addition, weakly nonlinear theory and numerical simulations demonstrate how a ring can bifurcate to more complex equilibria including triangular shapes, annuli, and spot patterns with N-fold symmetry. Many of these patterns have been observed in nature, although a general theory has been lacking, in particular how small changes to the interaction potential can lead to large changes in the self-organized state.