Allergen reduction measures in houses of allergic asthmatic patients: effects of air-cleaners and allergen-impermeable mattress covers.
Recommendations for allergen avoidance or allergen reduction measures play an important part in the treatment of allergic asthmatic patients. The purpose of this study was to test recently developed air-cleaners with respect to their capacity to capture airborne allergen particles and to improve clinical parameters of asthmatic patients sensitized to aeroallergens. Forty five allergic asthmatic patients were studied in a double-blind procedure for 6 months. The patients were divided into three groups of 15 patients. In Group 1, the intervention consisted of the application of active air-cleaners in living-rooms and bedrooms. In Group 2, placebo air-cleaners were used in combination with allergen-impermeable mattress covers. In Group 3, the same intervention was performed as in Group 2 but with active air-cleaners. Allergen levels in mattress and floor dust were measured before, and 3 and 6 months after the interventions. After 6 months, the air-cleaners were dismantled and the filters were analysed for the amount of dust collected and allergen content. Immunological and lung function parameters were measured before, and 3 and 6 months after the interventions. Considerable amounts of airborne dust and allergenic particles were captured in the filters of the air-cleaners. Up to the 18.9 g of dust, 4,513 ng of house dust mite allergen, Der p 1, and 50,000 mU of cat allergen, Fel d 1, (in houses with cats) were collected by air-cleaners in living-rooms. Only in Group 3 (in which both active air-cleaners and mattress covers were used) was a small (less than 1 doubling dose) but statistically significant improvement of provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second (PC20) observed (from 5.96 to 9.02 mg x mL(-1)). The amount of dust and house dust mite allergen collected in the filters was significantly correlated with an improvement of peak flow variation. In combination with other allergen avoidance measures, the examined air-cleaners can contribute to diminished allergen exposure and improvement of airway hyperresponsiveness in asthmatic patients.


Identification and Characterization of the Lactating Mouse Mammary Gland Citrullinome.
Citrullination is a post-translational modification (PTM) in which positively charged peptidyl-arginine is converted into neutral peptidyl-citrulline by peptidylarginine deiminase (PAD or PADI) enzymes. The full protein citrullinome in many tissues is unknown. Herein, we used mass spectrometry and identified 107 citrullinated proteins in the lactation day 9 (L9) mouse mammary gland including histone H2A, α-tubulin, and β-casein. Given the importance of prolactin to lactation, we next tested if it stimulates PAD-catalyzed citrullination using mouse mammary epithelial CID-9 cells. Stimulation of CID-9 cells with 5 µg/mL prolactin for 10 min induced a 2-fold increase in histone H2A citrullination and a 4.5-fold increase in α-tubulin citrullination. We next investigated if prolactin-induced citrullination regulates the expression of lactation genes β-casein (Csn2) and butyrophilin (Btn1a1). Prolactin treatment for 12 h increased β-casein and butyrophilin mRNA expression; however, this increase was significantly inhibited by the pan-PAD inhibitor, BB-Cl-amidine (BB-ClA). We also examined the effect of tubulin citrullination on the overall polymerization rate of microtubules. Our results show that citrullinated tubulin had a higher maximum overall polymerization rate. Our work suggests that protein citrullination is an important PTM that regulates gene expression and microtubule dynamics in mammary epithelial cells.


Genomic change, retrotransposon mobilization and extensive cytosine methylation alteration in Brassica napus introgressions from two intertribal hybridizations.
Hybridization and introgression represent important means for the transfer and/or de novo origination of traits and play an important role in facilitating speciation and plant breeding. Two sets of introgression lines in Brassica napus L. were previously established by its intertribal hybridizations with two wild species and long-term selection. In this study, the methods of amplified fragment length polymorphisms (AFLP), sequence-specific amplification polymorphism (SSAP) and methylation-sensitive amplified polymorphism (MSAP) were used to determine their genomic change, retrotransposon mobilization and cytosine methylation alteration in these lines. The genomic change revealed by the loss or gain of AFLP bands occurred for ∼10% of the total bands amplified in the two sets of introgressions, while no bands specific for wild species were detected. The new and absent SSAP bands appeared for 9 out of 11 retrotransposons analyzed, with low frequency of new bands and their total percentage of about 5% in both sets. MSAP analysis indicated that methylation changes were common in these lines (33.4-39.8%) and the hypermethylation was more frequent than hypomethylation. Our results suggested that certain extents of genetic and epigenetic alterations were induced by hybridization and alien DNA introgression. The cryptic mechanism of these changes and potential application of these lines in breeding were also discussed.


The impact of resolution upon entropy and information in coarse-grained models.
By eliminating unnecessary degrees of freedom, coarse-grained (CG) models tremendously facilitate numerical calculations and theoretical analyses of complex phenomena. However, their success critically depends upon the representation of the system and the effective potential that governs the CG degrees of freedom. This work investigates the relationship between the CG representation and the many-body potential of mean force (PMF), W, which is the appropriate effective potential for a CG model that exactly preserves the structural and thermodynamic properties of a given high resolution model. In particular, we investigate the entropic component of the PMF and its dependence upon the CG resolution. This entropic component, SW, is a configuration-dependent relative entropy that determines the temperature dependence of W. As a direct consequence of eliminating high resolution details from the CG model, the coarsening process transfers configurational entropy and information from the configuration space into SW. In order to further investigate these general results, we consider the popular Gaussian Network Model (GNM) for protein conformational fluctuations. We analytically derive the exact PMF for the GNM as a function of the CG representation. In the case of the GNM, -TSW is a positive, configuration-independent term that depends upon the temperature, the complexity of the protein interaction network, and the details of the CG representation. This entropic term demonstrates similar behavior for seven model proteins and also suggests, in each case, that certain resolutions provide a more efficient description of protein fluctuations. These results may provide general insight into the role of resolution for determining the information content, thermodynamic properties, and transferability of CG models. Ultimately, they may lead to a rigorous and systematic framework for optimizing the representation of CG models.


Patient reported outcome measures (PROMs) following mastectomy with breast reconstruction or without reconstruction: a systematic review.
The cornerstone of reconstructive surgery following mastectomy is to restore cosmesis and improve physical and psychological health. Consequently, it has become essential for instruments that measure surgical outcomes to include the direct perspective of patients. Many reviews have failed to show significant improvements in quality of life domains following breast reconstruction compared to mastectomy alone. However, with advances in surgical techniques and patient reported outcome measure (PROM) assessment tools designed precisely for breast reconstruction patients, a modern systematic review is warranted. An electronic literature review was performed using CINAHL, Cochrane Library and Medline (using PubMed) comparing patient reported outcome measures of patients undergoing mastectomy alone versus patients undergoing mastectomy with breast reconstruction. Studies in the English and Portuguese languages since the year 2000 were included. The review was undertaken adhering to PRISMA guidelines with last entry on the 31/5/2018. Full text review yield 42 articles of relevance to the inclusion criteria. The most widely used PROM instruments such as Breast-Q, EORTC-Q30/Q23, Short Form 36, FACT-B and others are explored. The specific difficulties conducting such studies and biases identified are investigated further. Studies comparing mastectomy alone against mastectomy with reconstruction show difficulties forming groups with similar clinical and epidemiological characteristics. There are inherent limitations to performing a randomised controlled trial on this topic, including matching patient groups in terms of age, socioeconomical background and cancer staging, and this affects the results of the PROM instruments. Within these limitations, the literature suggests that PROM support the use of breast reconstruction following mastectomy but care must be made selecting patients. The finding is supported by the National Institute for Health and Clinical Excellence (NICE) guidelines which state that breast reconstruction should be offered to all women undergoing breast cancer surgery.


Roles of connexins in atherosclerosis and ischemia-reperfusion injury.
Connexins are members of a large family of transmembrane proteins that oligomerize to form connexons or hemichannels, and connexons of adjacent cells dock to make gap junction channels. These channels allow the exchange of ions and small metabolites between the cytosol and extracellular space, or between the cytosols of neighbouring cells. Connexins are important in cardiovascular physiology; they support conducted vascular responses and allow for coordinated contraction of the heart. Four main connexins are expressed in the cardiovascular system: Cx37, Cx40, Cx43 and Cx45. Their expression pattern is not uniform and depends on intrinsic and environmental factors. Significant changes in the expression pattern, the cellular localization and the opening of connexin channels have been described during the development of atherosclerosis and after ischemia and reperfusion. In this review, we provide an overview of the roles of different connexins in these pathologies.


Optimizing methods for linking cinematic features to fMRI data.
One of the challenges of naturalistic neurosciences using movie-viewing experiments is how to interpret observed brain activations in relation to the multiplicity of time-locked stimulus features. As previous studies have shown less inter-subject synchronization across viewers of random video footage than story-driven films, new methods need to be developed for analysis of less story-driven contents. To optimize the linkage between our fMRI data collected during viewing of a deliberately non-narrative silent film 'At Land' by Maya Deren (1944) and its annotated content, we combined the method of elastic-net regularization with the model-driven linear regression and the well-established data-driven independent component analysis (ICA) and inter-subject correlation (ISC) methods. In the linear regression analysis, both IC and region-of-interest (ROI) time-series were fitted with time-series of a total of 36 binary-valued and one real-valued tactile annotation of film features. The elastic-net regularization and cross-validation were applied in the ordinary least-squares linear regression in order to avoid over-fitting due to the multicollinearity of regressors, the results were compared against both the partial least-squares (PLS) regression and the un-regularized full-model regression. Non-parametric permutation testing scheme was applied to evaluate the statistical significance of regression. We found statistically significant correlation between the annotation model and 9 ICs out of 40 ICs. Regression analysis was also repeated for a large set of cubic ROIs covering the grey matter. Both IC- and ROI-based regression analyses revealed activations in parietal and occipital regions, with additional smaller clusters in the frontal lobe. Furthermore, we found elastic-net based regression more sensitive than PLS and un-regularized regression since it detected a larger number of significant ICs and ROIs. Along with the ISC ranking methods, our regression analysis proved a feasible method for ordering the ICs based on their functional relevance to the annotated cinematic features. The novelty of our method is - in comparison to the hypothesis-driven manual pre-selection and observation of some individual regressors biased by choice - in applying data-driven approach to all content features simultaneously. We found especially the combination of regularized regression and ICA useful when analyzing fMRI data obtained using non-narrative movie stimulus with a large set of complex and correlated features.


The novel component Kgd4 recruits the E3 subunit to the mitochondrial α-ketoglutarate dehydrogenase.
The mitochondrial citric acid cycle is a central hub of cellular metabolism, providing intermediates for biosynthetic pathways and channeling electrons to the respiratory chain complexes. In this study, we elucidated the composition and organization of the multienzyme complex α-ketoglutarate dehydrogenase (α-KGDH). In addition to the three classical E1-E3 subunits, we identified a novel component, Kgd4 (Ymr31/MRPS36), which was previously assigned to be a subunit of the mitochondrial ribosome. Biochemical analyses demonstrate that this protein plays an evolutionarily conserved role in the organization of mitochondrial α-KGDH complexes of fungi and animals. By binding to both the E1-E2 core and the E3 subunit, Kgd4 acts as a molecular adaptor that is necessary to a form a stable α-KGDH enzyme complex. Our work thus reveals a novel subunit of a key citric acid-cycle enzyme and shows how this large complex is organized.


Psychological distress and risk for dementia.
The concept of mild cognitive impairment (MCI) primarily emphasizes changes in individuals' mental abilities, but it has recently been suggested that neuropsychiatric symptoms should also be considered important factors in age-related neurodegeneration. Psychological distress, defined as a reaction of an individual to external and internal stresses, is characterized by a mixture of psychological symptoms. It also may be considered a neuropsychiatric symptom encompassing depression, anxiety, and apathy. This paper reviews and summarizes recent evidence and relevant issues regarding the presence of psychological distress in healthy older adults and MCI patients and its relationship to risk for developing dementia. Results presented in this review show that psychological distress and depressive, anxious, and apathetic symptoms can be present in MCI and may predict progression to dementia. This article also provides suggestions for future research.


Artificial modulation of the gating behavior of a K+ channel in a KvAP-DNA chimera.
We present experiments where the gating behavior of a voltage-gated ion channel is modulated by artificial ligand binding. We construct a channel-DNA chimera with the KvAP potassium channel reconstituted in an artificial membrane. The channel is functional and the single channel ion conductivity unperturbed by the presence of the DNA. However, the channel opening probability vs. bias voltage, i.e., the gating, can be shifted considerably by the electrostatic force between the charges on the DNA and the voltage sensing domain of the protein. Different hybridization states of the chimera DNA thus lead to different response curves of the channel.


Avoidance of certain systematic pitfalls in the detection of HLA-DR antibodies defining find specificities.
A selective screening program has been established to identify rapidly and effectively the fine specificity of HLA-DR antibodies in pregnancy anti-HLA sera. Following initial HLA-A, B, C screening sera with extra- or multispecific reactions were selected and specifically tested after platelet absorption on isolated B- and T-lymphocyte populations of the serum donor's husband. Identification of the HLA-DR serum. Multispecific anti-DR sera were defined and rendered operationally monospecific by titration. Some critical steps in a reliable assessment of HLA-DR typing reagents could be worked out. Weak HLA-A, B antibodies, B-cell auto- and Lewis antibodies may cause positive reactivity preferentially or even selectively on B lymphocytes. Of particular importance was the hidden presence of HLA-C specific antibodies, since they cannot be absorbed out of stored platelets. In addition they are not readily detectable through screening on typed panel cells. Because of the frequently very high linkage disequilibrium between HLA-B and HLA-C alleles it is difficult to select appropriately dissecting panel cells. The two points demonstrated above gain even more weight when isolated T and B cell populations are used for HLA-DR typing, because HLA-C antibodies preferentially kill B cells. In this fashion contaminating HLA-C antibodies are not only difficult to detect but can mimic the presence of HLA-DR antibodies.


International data-sharing for radiotherapy research: an open-source based infrastructure for multicentric clinical data mining.
Extensive, multifactorial data sharing is a crucial prerequisite for current and future (radiotherapy) research. However, the cost, time and effort to achieve this are often a roadblock. We present an open-source based data-sharing infrastructure between two radiotherapy departments, allowing seamless exchange of de-identified, automatically translated clinical and biomedical treatment data.


A model intraocular lens.
With so many different kinds of intraocular lenses from which to choose, the cataract surgeon is often faced with a difficult decision--which is the best lens for the patient. Although, there is no perfect intraocular lens, we attempt to delineate several desirable features. These include pliability, inert ultraviolet-filtering lens material, compact design, and posterior concavity to facilitate laser surgery. Successful blending of these features can make a well-tolerated intraocular lens.


Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry.
A panel of primary syncytium-inducing (SI) human immunodeficiency virus type 1 isolates that infected several CD4+ T-cell lines, including MT-2 and C8166, were tested for infection of blood-derived macrophages. Infectivity titers for C8166 cells and macrophages demonstrated that primary SI strains infected macrophages much more efficiently than T-cell line-adapted HIV-1 strains such as LAI and RF. These primary SI strains were therefore dual-tropic. Nine biological clones of two SI strains, prepared by limiting dilution, had macrophage/C8166 infectivity ratios similar to those of their parental viruses, indicating that the dual-tropic phenotype was not due to a mixture of non-SI/macrophage-tropic and SI/T-cell tropic viruses. We tested whether the primary SI strains used either Lestr (fusin) or CCR5 as coreceptors. Infection of cat CCC/CD4 cells transiently expressing Lestr supported infection by T-cell line-adapted strains including LAI, whereas CCC/CD4 cells expressing CCR5 were sensitive to primary non-SI strains as well as to the molecularly cloned strains SF-162 and JR-CSF. Several primary SI strains, as well as the molecularly cloned dual-tropic viruses 89.6 and GUN-1, infected both Lestr+ and CCR5+ CCC/CD4 cells. Thus, these viruses can choose between Lestr and CCR5 for entry into cells. Interestingly, some dual-tropic primary SI strains that infected Lestr+ cells failed to infect CCR5+ cells, suggesting that these viruses may use an alternative coreceptor for infection of macrophages. Alternatively, CCR5 may be processed or presented differently on cat cells so that entry of some primary SI strains but not others is affected.


Highly variable reproductive isolation among pairs of Catostomus species.
Hybridization between diverged taxa tests the strength of reproductive isolation and can therefore reveal mechanisms of reproductive isolation. However, it remains unclear how consistent reproductive isolation is across species' ranges and to what extent reproductive isolation might remain polymorphic as species diverge. To address these questions, we compared outcomes of hybridization across species pairs of Catostomus fishes in three rivers in the Upper Colorado River basin, where an introduced species, C. commersoni, hybridizes with at least two native species, C. discobolus and C. latipinnis. We observed substantial heterogeneity in outcomes of hybridization, both between species pairs and across geographically separate rivers within each species pair. We also observed hybridization of additional related species with our focal species, suggesting that reproductive isolation in this group involves interactions of multiple evolutionary and ecological factors. These findings suggest that a better understanding of the determinants of variation in reproductive isolation is needed and that studies of reproductive isolation in hybrids should consider how the dynamics and mechanisms of reproductive isolation vary over ecological space and over evolutionary time. Our results also have implications for the conservation and management of native catostomids in the Colorado River basin. Heterogeneity in outcomes of hybridization suggests that the threat posed by hybridization and genetic introgression to the persistence of native species probably varies with extent of reproductive isolation, both across rivers and across species pairs.


Changes in [3H]muscimol binding in substantia nigra, entopeduncular nucleus, globus pallidus, and thalamus after striatal lesions as demonstrated by quantitative receptor autoradiography.
A quantitative autoradiographic technique for measuring the binding of [3H]muscimol to central nervous system GABA receptors is described using tritium-sensitive film. [3H]Muscimol binding was studied in primary and secondary striatal projection areas of rat brain following kainic acid lesions of the striatum. Seven days after the lesion, binding affinities in the striatum and its projection areas were not altered significantly. There was a loss of [3H]muscimol receptors in the striatum. Receptors increased in numbers in the ipsilateral globus pallidus (19%), entopeduncular nucleus (22%), and substantia nigra pars reticulata (38%). [3H]Muscimol binding was decreased in the ipsilateral anteroventrolateral and ventromedial (8%) thalamic nuclei. [3H]Muscimol binding in other brain areas (layer IV of the cerebral cortex, central gray, superior colliculus, and stratum moleculare of hippocampus) was not affected. The findings suggest that a loss of striatal innervation resulted in increased numbers of GABA receptors in striatal projection sites. It is further suggested that loss of inhibitory striatal inputs to neurons in the entopeduncular nucleus and substantia nigra pars reticulata may activate GABAergic projections to thalamus and thus result in decreased numbers of thalamic GABA receptors.


Metabolic characterization of the genus Brucella. II. Oxidative metabolic patterns of the described biotypes.
Meyer, Margaret E. (University of California, Davis), and H. S. Cameron. Metabolic characterization of the genus Brucella. II. Oxidative metabolic patterns of the described biotypes. J. Bacteriol. 82:396-400. 1961.-The oxidative metabolism of the biotypes of Brucella abortus and Brucella suis was compared to that of typical strains of these species. It was found that the biotypes of B. abortus display a metabolic pattern identical to that of B. abortus type I, irrespective of their differences in susceptibility to the bacteriostatic action of basic fuchsin and thionin. It was also found that a characteristic feature which distinguishes all of the biotypes of B. suis from the other species was their ability to oxidize l-arginine, dl-citrulline, and dl-ornithine. The three biotypes of B. suis can be differentiated from each other by discrete differences in their utilization of l-lysine and l-glutamic acid. Data on the oxidative rates obtained on eight amino acid and four carbohydrate substrates by 47 strains of the described biotypes are presented in support of these conclusions.


Mathematical modelling of the formation of coated vesicles. A theoretical geometrical approach.
The mechanism by which flat hexagonal lattices of clathrin trimers transform into pentagonal/hexagonal spheres remains a mystery. In light of the geometrical nature of this process we have pursued a mathematical approach to the question. Through the geometrical analysis of flat hexagonal lattices we have discovered three possible forms of transformation to introduce curvature into the centre of the lattice: hub-centre transformation; hub-edge transformation; fringe transformation. Hub-edge and fringe transformations are used first to close the lattice while introducing localized curvature at the edges of the lattice. Hub-centre transformation is used after closure to relax the severely localized curvature generated during closure. This scheme not only maximizes the size of the coated vesicle generated, but also minimizes the number of transformations, thus minimizing the energy expended.


Comparison of annual cost between brand and generic ocular beta-adrenergic blockers.
We conducted a study of the annual cost of various ophthalmic products used in Japan for treating glaucoma including six of brands and generic ocular beta-adrenergic blockers (38 products). The total number of drops in one bottle of each solution was counted drop by drop. The cost per drop was calculated by dividing the government-controlled standard prices by the total number of drops in one bottle. The annual cost of ophthalmic solution was calculated by multiplying the cost per drop by the number of drops typically used per day. The total number of drops of the ophthalmic solutions in one bottle ranged from 108 to 168. The yearly cost of the beta-adrenergic blockers studied ranged widely, from yen 5392 to yen 27236. Differences in the total number of drops and the usage effect on the annual cost of ophthalmic solutions were found. The annual cost depended on not only the price of the products but also on the total number of drops in one bottle and the usage. Annual cost data may be helpful in selecting ophthalmic products for treating glaucoma in Japan.


A Review of Exercise as Medicine in Cardiovascular Disease: Pathology and Mechanism.
Physical inactivity and resultant lower energy expenditure contribute unequivocally to cardiovascular diseases, such as coronary artery disease and stroke, which are considered major causes of disability and mortality worldwide. The aim of the study was to investigate the influence of physical activity (PA) and exercise on different aspects of health - genetics, endothelium function, blood pressure, lipid concentrations, glucose intolerance, thrombosis, and self - satisfaction. Materials and. In this article, we conducted a narrative review of the influence PA and exercise have on the cardiovascular system, risk factors of cardiovascular diseases, searching the online databases; Web of Science, PubMed and Google Scholar, and, subsequently, discuss possible mechanisms of this action. Based on our narrative review of literature, discussed the effects of PA on telomere length, nitric oxide synthesis, thrombosis risk, blood pressure, serum glucose, cholesterol and triglycerides levels, and indicated possible mechanisms by which physical training may lead to improvement in chronic cardiovascular diseases. PA is effective for the improvement of exercise tolerance, lipid concentrations, blood pressure, it may also reduce the serum glucose level and risk of thrombosis, thus should be advocated concomitant to, or in some cases instead of, traditional drug-therapy.


The Role of Diffusion-Weighted Imaging in the Evaluation of the Whole Brain in Isolated Unilateral Polymicrogyria.
The aim is to evaluate normal-appearing brain regions in isolated unilateral polymicrogyria patients and compare them with controls by using diffusion-weighted imaging and apparent diffusion coefficient. The diffusion-weighted images (b = 0-1000 s/mm2) of 10 pediatric patients (7 boys, 3 girls; mean age = 5.8 ± 4.3 years) with isolated unilateral polymicrogyria and age-sex matched 10 control patients were assessed retrospectively. There was a significant increase in apparent diffusion coefficient values of white matter underlying polymicrogyria, uninvolved white matter, deep gray matter (thalami, lentiform nuclei, caudate nuclei) and corpus callosum in polymicrogyria patients compared to control group (P < .01). The whole brain might be affected in isolated unilateral polymicrogyria patients. The abnormal deep gray matter in polymicrogyria patients would indicate a new point of view for pediatric neurologists about the probability of additional future neurological disorders.


Self-limited blastomycosis: a report of 39 cases.
We report 39 patients with pulmonary blastomycosis who were not treated with specific antifungal chemotherapy. Fourteen of these patients were recognized during an epidemic of blastomycosis in 1972 and did not have culturally proven disease. The remaining 25 patients were all proven instances of blastomycosis, 24 of whom had pulmonary disease only. Over a median observation period of 42 months (range: 12 to 168) one patient relapsed 52 months after the original diagnosis, while all of the others have remained clinically well. It is our belief that certain patients with blastomycosis limited to the lungs may safely be followed without specific antifungal chemotherapy until clearing occurs. These include patients with mild or no symptoms and those who have been more symptomatic but are already improving when the diagnosis is established. Worsening of the clinical picture, or evidence of extrapulmonary disease requires immediate antifungal chemotherapy.


Diclofenac sodium loaded PLGA nanoparticles for inflammatory diseases with high anti-inflammatory properties at low dose: Formulation, characterization and in vivo HET-CAM analysis.
The development of a new drug active substance is not only time-consuming and expensive, but also a chain of operations that often fails. However, increasing the bioavailability, effectiveness, safety, or targeting the drugs used in clinic by various methods, such as nanoparticles (NPs), may be a more effective way of using them in clinic. In addition, NP formulations are becoming increasingly popular in modern medical treatments. Angiogenesis, formation of new capillaries from a pre-existing one, fundamentally occurs in physiological processes such as wound healing, embryogenesis and menstrual cycle, also has a vital role in pathology of cancer, psoriasis, diabetic retinopathy and chronic inflammation. The Hen's Egg Test on the Chorioallantoic Membrane (HET-CAM) assay is a useful, well established and animal alternative in vivo procedure for evaluation of anti-inflammatory potentials and anti-irritant properties of nano drug delivery systems. In this study, diclofenac sodium (DS) loaded PLGA NPs were prepared and characterized. The particle size (PS) of DS-loaded PLGA NPs was between 114.7 and 124.8 nm and all NPs were monodisperse with negative zeta potential values. The encapsulation efficiency was in range of 41.4-77.8%. In vitro dissolution studies of NPs showed up to 24 h of DS release after the first 3 h of burst effect. The 3 h burst effect and 24 h release kinetics studied with DDSolver were found to be predominantly driven not only by one mechanism, by a combined mechanism of Fickian and non-Fickian. Solid state structures of formulations were clarified by DSC and FT-IR analysis. PS, EE% and release rates were found to be affected by the amount of DS added to the formulations. Increasing the amount of DS added to the formulations increased PS, while the EE% decreased. The release rates were affected by PS and the formulation with the lowest PS value showed slower release. The anti-inflammatory activity of optimum formulation (NP-1) was examined using in vivo HET-CAM assay. The anti-inflammatory activity results indicated that NP-1 coded NP formulation showed significantly good anti-inflammatory potential at low dose. As a result, a low dose high anti-inflammatory effect was achieved with the NP structure of DS. To the best of our knowledge this is the first study on in vivo anti-inflammatory activities of DS loaded PLGA NPs by HET-CAM.


Metformin improved health-related quality of life in ethnic Chinese women with polycystic ovary syndrome.
Few studies have assessed whether the amelioration of the clinical signs of polycystic ovary syndrome (PCOS) achieved by treatment leads to improvement in the health-related quality of life (HRQoL) of patients. This study was aimed to examine the HRQoL of ethnic Chinese women with PCOS who received metformin treatment. This prospective study was conducted at a medical center in Taiwan. Study participants aged 18-45 years were diagnosed as having PCOS according to the Rotterdam criteria, and all received metformin treatment. Their HRQoL was assessed using generic (WHOQOL-Bref) and PCOS-specific (Chi-PCOSQ) instruments. Mixed effect models were used to examine the effects of metformin on repeatedly measured HRQoL. Additional analyses using stratified patients characteristics (overweight vs. normal; hyperandrogenism vs. non-hyperandrogenism) were done. We recruited 109 participants (56 % were overweight, 80 % had hyperandrogenism). Among the domain scores of WHOQOL-Bref, the psychological domain score was the lowest one (12.64 ± 2.2, range 4-20). Weight (3.25 ± 1.59, range 1-7) and infertility (3.38 ± 1.93, range 1-7) domain scores were relatively low among the domain scores of Chi-PCOSQ. Overweight and hyperandrogenic patients had significantly lower HRQoL as compared with those of normal weight and non-hyperandrogenic patients, respectively. Metformin significantly improved the physical domain of WHOQOL-Bref (p = 0.01), and the infertility (p = 0.043) and acne and hair loss aspects (p = 0.008) of PCOS-specific HRQoL. In the subgroup analysis, significantly improved HRQoL following metformin treatment appeared for only overweight and hyperandrogenism subgroups. Metformin might improve health-related quality of life of polycystic ovary syndrome women by ameliorating psychological disturbances due to acne, hair loss and infertility problems, especially for overweight and hyperandrogenic patients.


Effects of dietary intake of garlic on intestinal trematodes.
The current strategy for the control of helminth infections relies on chemotherapy. However, resistance appearance is promoting the necessity of developing new drugs against trematodes. Herein, potential trematocidal effects of garlic (Allium sativum) are investigated in the context of intestinal foodborne trematodes, employing the Echinostoma caproni-mouse model. Daily administration of dietary doses of garlic was conducted in three groups of mice: (i) before infection (prophylaxis), (ii) after infection (therapeutic) and (iii) both, before and after infection (continuous). A fourth group of mice, not exposed to garlic, was used as control. No differences in worm recovery, fecundity and local cytokine expression profiles were found with respect to control infections. However, considerable alterations in tegument structure, including swelling, furrowing, vacuolization and changes in secretory bodies were detected in garlic-exposed parasites using scanning and transmission electron microscopy. Protein secretion was markedly reduced in response to garlic, whereas up-regulation of several proteins, such as major vault protein and tER-ATPase, was observed in treated worms. The results presented herein provide new insights in the anthelminthic activity of bioactive garlic compounds and the manner that parasites respond to toxins.


Possible health impacts of Bt toxins and residues from spraying with complementary herbicides in genetically engineered soybeans and risk assessment as performed by the European Food Safety Authority EFSA.
MON89788 was the first genetically engineered soybean worldwide to express a Bt toxin. Under the brand name Intacta, Monsanto subsequently engineered a stacked trait soybean using MON89788 and MON87701-this stacked soybean expresses an insecticidal toxin and is, in addition, tolerant to glyphosate. After undergoing risk assessment by the European Food Safety Authority (EFSA), the stacked event was authorised for import into the EU in June 2012, including for use in food and feed. This review discusses the health risks associated with Bt toxins present in these genetically engineered plants and the residues left from spraying with the complementary herbicide. We have compared the opinion published by EFSA [1] with findings from other publications in the scientific literature. It is evident that there are several issues that EFSA did not consider in detail and which will need further assessment: (1) There are potential combinatorial effects between plant components and other impact factors that might enhance toxicity. (2) It is known that Bt toxins have immunogenic properties; since soybeans naturally contain many allergens, these immunogenic properties raise specific questions. (3) Fully evaluated and reliable protocols for measuring the Bt concentration in the plants are needed, in addition to a comprehensive set of data on gene expression under varying environmental conditions. (4) Specific attention should be paid to the herbicide residues and their interaction with Bt toxins. The case of the Intacta soybeans highlights several regulatory problems with Bt soybean plants in the EU. Moreover, many of the issues raised also concern other genetically engineered plants that express insecticidal proteins, or are engineered to be resistant to herbicides, or have those two types of traits combined in stacked events. It remains a matter of debate whether the standards currently applied by the risk assessor, EFSA, and the risk manager, the EU Commission, meet the standards for risk analysis defined in EU regulations such as 1829/2003 and Directive 2001/18. While this publication cannot provide a final conclusion, it allows the development of some robust hypotheses that should be investigated further before such plants can be considered to be safe for health and the environment. In general, the concept of comparative risk assessment needs some major revision. Priority should be given to developing more targeted approaches. As shown in the case of Intacta, these approaches should include: (i) systematic investigation of interactions between the plant genome and environmental stressors as well as their impact on gene expression and plant composition; (ii) detailed investigations of the toxicity of Bt toxins; (iii) assessment of combinatorial effects taking into account long-term effects and the residues from spraying with complementary herbicides; (iv) investigation into the impact on the immune and hormonal systems and (v) investigation of the impact on the intestinal microbiome after consumption. Further and in general, stacked events displaying a high degree of complexity due to possible interactions should not undergo a lower level of risk assessment than the parental plants.


20 years of the Mexican Health and Aging Study.
The Mexican Health and Aging Study (MHAS) is a longitudinal study using a national sample of approximately 15,000 community-dwelling adults aged 50 years old and older in Mexico. Spanning over 20 years (2001-2021), six waves of data collection establish the MHAS as the leading data platform for the study of aging in Latin America.


Biochemical and genome sequence analyses of Megasphaera sp. strain DISK18 from dental plaque of a healthy individual reveals commensal lifestyle.
Much of the work in periodontal microbiology in recent years has focused on identifying and understanding periodontal pathogens. As the majority of oral microbes have not yet been isolated in pure form, it is essential to understand the phenotypic characteristics of microbes to decipher their role in oral environment. In this study, strain DISK18 was isolated from gingival sulcus and identified as a Megasphaera species. Although metagenomics studies revealed Megasphaera species as a major group within the oral habitat, they have never been isolated in cultivable form to date. Therefore, we have characterized the DISK18 strain to better understand its role in the periodontal ecosystem. Strain Megasphaera sp. DISK18 displayed the ability to adhere and self-aggregate, which are essential requisite features for inhabiting and persisting in oral cavity. It also coaggregated with other pioneer oral colonizers like Streptococcus and Lactobacillus species but not with Veillonella. This behaviour points towards its role in the ecologic succession of a multispecies biofilm as an early colonizer. The absence of virulence determining genes as observed in whole genome sequence analysis coupled with an inability to degrade collagen reveals that Megasphaera sp. strain DISK18 is likely not a pathogenic species and emphasizes its commensal lifestyle.


Contribution of Atmospheric Rivers to Antarctic Precipitation.
Atmospheric rivers (ARs) are efficient mechanisms for transporting atmospheric moisture from low latitudes to the Antarctic Ice Sheet (AIS). While AR events occur infrequently, they can lead to extreme precipitation and surface melt events on the AIS. Here we estimate the contribution of ARs to total Antarctic precipitation, by combining precipitation from atmospheric reanalyses and a polar-specific AR detection algorithm. We show that ARs contribute substantially to Antarctic precipitation, especially in East Antarctica at elevations below 3,000 m. ARs contribute substantially to year-to-year variability in Antarctic precipitation. Our results highlight that ARs are an important component for understanding present and future Antarctic mass balance trends and variability.


Treatment of intracranial foreign body.
Craniospinal penetrating foreign body (FB) injuries are interesting, but rarely observed, cases. They are important in terms of the complications that they may cause. The etiologies of craniospinal penetrating injuries and intracranial FB are also different. Though a sewing needle is more rarely seen in an intracranial FB, it may occur as atttempted infanticide or as a result of an accident especially in early childhood before the closure of fontanels. We detected an intracranial sewing needle in the head radiograph of a case admitted to the emergency department for another reason. We present this case since this is a rare injury and the etiologies of craniospinal penetrating foreign body have different characteristics.


Undernutrition decreases serine palmitoyltransferase activity in developing rat hypothalamus.
Undernutrition reduces the hypothalamic ganglioside concentration. This may be attributed to some modifications in the contents of precursors of sphingolipid biosynthesis in undernourished rats. The present study evaluated the serine palmitoyl transferase activity (SPT; EC 22.214.171.124) during the development of the rat hypothalamus. This work also shows the L-[3-(14)C]serine metabolic labeling of hypothalamic sphingolipids in normal and undernourished rats at weaning. The SPT activity was determined in microsomal fractions obtained from the hypothalamus of normal rats (diet: 25% protein) and pre- and postnatally undernourished rats (diet: 8% protein since pregnancy) at 21 days of gestational age and at 7, 14, and 21 days of postnatal life. The enzymatic activity was lower in the hypothalamus of undernourished than in the hypothalamus of control rats since the 7th postnatal day. Incorporation of the precursor L-[3-(14)C]serine into sphingolipid fraction was lower in the hypothalamus of undernourished rats than in the hypothalamus of control rats on the 21st postnatal day which coincided with the age of the highest difference in SPT activity between normal and undernourished rats. These results indicate that undernutrition reduces the biosynthesis of the main sphingolipids during the period of brain growth spurt.


Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors.
Formation of a mature thymic epithelial microenvironment is an essential prerequisite for the generation of a functionally competent T cell pool. It is likely that recently identified thymic epithelial precursors undergo phases of proliferation and differentiation to generate mature cortical and medullary thymic microenvironments. The mechanisms regulating development of immature thymic epithelial cells are unknown. Here we provide evidence that expansion of embryonic thymic epithelium is regulated by the continued presence of mesenchyme. In particular, mesenchymal cells are shown to mediate thymic epithelial cell proliferation through their provision of fibroblast growth factors 7 and 10. In contrast, differentiation of immature thymic epithelial cells, including acquisition of markers of mature cortical and medullary epithelium, occurs in the absence of ongoing mesenchymal support. Collectively, our data define a role for mesenchymal cells in thymus development, and indicate distinct mechanisms regulate proliferation and differentiation of immature thymic epithelial cells. In addition, our findings may aid in studies aimed at developing strategies to enhance thymus reconstitution and functioning in clinical certain contexts where thymic epithelial cell function is perturbed.


OpenCyto: an open source infrastructure for scalable, robust, reproducible, and automated, end-to-end flow cytometry data analysis.
Flow cytometry is used increasingly in clinical research for cancer, immunology and vaccines. Technological advances in cytometry instrumentation are increasing the size and dimensionality of data sets, posing a challenge for traditional data management and analysis. Automated analysis methods, despite a general consensus of their importance to the future of the field, have been slow to gain widespread adoption. Here we present OpenCyto, a new BioConductor infrastructure and data analysis framework designed to lower the barrier of entry to automated flow data analysis algorithms by addressing key areas that we believe have held back wider adoption of automated approaches. OpenCyto supports end-to-end data analysis that is robust and reproducible while generating results that are easy to interpret. We have improved the existing, widely used core BioConductor flow cytometry infrastructure by allowing analysis to scale in a memory efficient manner to the large flow data sets that arise in clinical trials, and integrating domain-specific knowledge as part of the pipeline through the hierarchical relationships among cell populations. Pipelines are defined through a text-based csv file, limiting the need to write data-specific code, and are data agnostic to simplify repetitive analysis for core facilities. We demonstrate how to analyze two large cytometry data sets: an intracellular cytokine staining (ICS) data set from a published HIV vaccine trial focused on detecting rare, antigen-specific T-cell populations, where we identify a new subset of CD8 T-cells with a vaccine-regimen specific response that could not be identified through manual analysis, and a CyTOF T-cell phenotyping data set where a large staining panel and many cell populations are a challenge for traditional analysis. The substantial improvements to the core BioConductor flow cytometry packages give OpenCyto the potential for wide adoption. It can rapidly leverage new developments in computational cytometry and facilitate reproducible analysis in a unified environment.


Breast feeding, pacifier use and infant development at 12 months of age: a birth cohort study in Brazil.
Many studies suggest that breast feeding confers developmental and intellectual advantages on children. In a recent study, however, no association was found between breast feeding and intelligence in adult life after adjustment for other variables, and the use of pacifier in infancy was the most important predictor of intelligence. We analysed the associations between breast-feeding duration, pacifier use and suspected developmental delay at 12 months of age in a birth cohort in Pelotas, southern Brazil. All 5304 hospital births occurring during 1993 were studied and a sample was followed up at 1, 3, 6 and 12 months of age. Breast-feeding practices and use of pacifiers were assessed at each visit, as well as suspected developmental delay, measured by the Denver II test. The prevalence of developmental delay was analysed, through logistic regression, according to breast-feeding status and pacifier use, accounting for the possible confounding effect of other variables. The prevalence of suspected developmental delay at 12 months was 34.1%, being slightly higher among children who used pacifiers at 6 months than among non-users (35.3% and 28.7% respectively). There was a marked negative association between breast-feeding duration and developmental delay, with children breast fed for 9 months or more presenting significantly less suspected developmental delay (25.5%) than those breast fed for less than 1 month (42.4%). The effects of multiple variables were tested, and only high parity, smoking during pregnancy, birthweight, gestational age, pacifier use and breast-feeding duration remained significantly associated with suspected developmental delay. The effect of pacifier use, however, disappeared after adjusting for breast-feeding duration, suggesting that breast feeding, and not pacifiers, affects child development.


Investigating the relationship between quality of life and hope in family caregivers of hemodialysis patients and related factors.
Family caregivers of hemodialysis patients are the first and most crucial source of care at home. They experience many problems in the care of hemodialysis patients, which can affect their quality of life and hope, affecting the quality of care provided to patients. This study aimed to determine the relationship between quality of life and hope in family caregivers of hemodialysis patients. A cross-sectional (descriptive-analytical) study performed on 300 family caregivers in the east of Mazandaran province in Iran. Data were collected using the Family Caregiver Quality of Life (FQOL), SF8 and adult hope scale. Data analysis was performed in SPSS version 16, and a P-value of below 0.05 was considered statistically significant. The results showed that, there was a direct and significant relationship between hope and quality of life. However, the quality of life was significantly lower in suburban residents, the unemployed, spouses, people with lower education and income levels, caregivers who cannot leave their patients alone, those living with their patients in the same house, and those taking care of male patients, compared to other participants (P < 0.05). Suburban residents, the unemployed, people with an insufficient level of income, and those living with their patients in the same house had significantly lower hope, compared to other subjects. Since an increase of hope and quality of life of caregivers can cause improved quality of patient care, it is recommended that hope-based educational programs and interventions be implemented for caregivers.


Group-I intron family in the nuclear ribosomal RNA small subunit genes of Cenococcum geophilum isolates.
A family of optional group-I introns was found near the 3' end of the nuclear small subunit rRNA genes in 61 out of 70 isolates of the deuteromycete mycorrhizal fungus Cenococcum geophilum. DNA sequence polymorphisms among the introns (termed CgSSU introns) from ten of the isolates were studied. The sequences, ranging in size from 488 to 514 nucleotides, were from 93.2% to 99.6% similar to each other. Mutations were less common in predicted base-paired regions (33% of all mutations) than in free-standing regions (67%). The introns were self-spliced in vitro and were closest to subgroup IC1 according to sequence and predicted secondary structure. Group-I intron pairing regions P1 through P10, including core regions P, Q, R and S, were present in all ten CgSSU introns studied. No lengthy open reading frames were found in any of the introns, indicating that the introns do not encode a protein, and therefore may not be mobile. It is likely that a single intron entered a progenote of C. geophilum and changed as the species evolved.


Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in nonimmune pediatric travelers: results of an international, randomized, open-label study.
Atovaquone-proguanil has been shown to be effective and well tolerated for malaria prophylaxis in residents of countries of endemicity and in nonimmune adult travelers, but data about traveling children are limited. In a randomized, open-label, multicenter prophylaxis trial, 221 nonimmune pediatric travelers (age, 2-17 years) received either atovaquone-proguanil or chloroquine-proguanil. Safety and clinical outcome were evaluated 7, 28, and 60 days after travel. By posttravel day 7, a total of 39 (35%) of 110 atovaquone-proguanil and 41 (37%) of 111 chloroquine-proguanil recipients reported > or =1 adverse event. The data indicate that, over the course of treatment, fewer atovaquone-proguanil recipients had treatment-related adverse events (8% vs. 14%), including gastrointestinal complaints (5% vs. 10%). Two subjects discontinued prophylaxis because of drug-related adverse events; both had received chloroquine-proguanil. Observed compliance with prophylaxis was similar before and during travel, but it was higher for atovaquone-proguanil in the posttravel period. No study participant developed malaria. Atovaquone-proguanil was well tolerated and is an important addition to the limited arsenal of prophylactic agents available to children.


Vagoglossopharyngeal-associated syncope due to a retained bullet in the jugular foramen.
Gunshot wounds (GSWs) to the head are frequently fatal. Rarely, the bullet may lodge in the skull base and not cause significant brain injury. Typically, the bullet fragments are felt to be inert and do not require operative extirpation if they are within the bony confines of the skull base. We report the case of a bullet in the jugular foramen causing recurrent syncope that resolved after surgical removal of the bullet. The medical records from a patient who suffered a GSW to the head were retrospectively reviewed and the treatment and outcome documented. In 2000, a 20-year-old man suffered a GSW to the head. Immediate evaluation revealed the bullet in the right skull base at the jugular foramen, but no parenchymal brain injury. One year after the GSW, he began to experience stereotypical spells resulting in loss of consciousness. Extensive cardiovascular workup was normal. In 2002, the patient underwent removal of the bullet. He has been syncope-free since the operation and returned to his career in the military. We believe the retained bullet in this patient was irritating the IX-X cranial nerves, resulting in syncope, similar to the mechanism in vagoglossopharyngeal neuralgia. Removing the bullet relieved the irritation and stopped the syncopal spells.


The MCCB impairment profile for schizophrenia outpatients: results from the MATRICS psychometric and standardization study.
The MATRICS Psychometric and Standardization Study was conducted as a final stage in the development of the MATRICS Consensus Cognitive Battery (MCCB). The study included 176 persons with schizophrenia or schizoaffective disorder and 300 community residents. Data were analyzed to examine the cognitive profile of clinically stable schizophrenia patients on the MCCB. Secondarily, the data were analyzed to identify which combination of cognitive domains and corresponding cut-off scores best discriminated patients from community residents, and patients competitively employed vs. those not. Raw scores on the ten MCCB tests were entered into the MCCB scoring program which provided age- and gender-corrected T-scores on seven cognitive domains. To test for between-group differences, we conducted a 2 (group)×7 (cognitive domain) MANOVA with follow-up independent t-tests on the individual domains. Classification and regression trees (CART) were used for the discrimination analyses. Examination of patient T-scores across the seven cognitive domains revealed a relatively compact profile with T-scores ranging from 33.4 for speed of processing to 39.3 for reasoning and problem-solving. Speed of processing and social cognition best distinguished individuals with schizophrenia from community residents; speed of processing along with visual learning and attention/vigilance optimally distinguished patients competitively employed from those who were not. The cognitive profile findings provide a standard to which future studies can compare results from other schizophrenia samples and related disorders; the classification results point to specific areas and levels of cognitive impairment that may advance work rehabilitation efforts.


Interaction between PAK and nck: a template for Nck targets and role of PAK autophosphorylation.
The kinase PAK binds tightly to the SH3 domain of its partner PIX via a central proline-rich sequence. A different N-terminal sequence allows alphaPAK to bind an SH3 domain of the adaptor Nck. The Nck SH3[2] domain interacts equally with an 18-mer PAK-derived peptide and full-length alphaPAK. Detailed analysis of this binding by saturation substitution allows related Nck targets to be accurately identified from sequence characteristics alone. All Nck SH3[2] binding proteins, including PAK, NIK, synaptojanin, PRK2, and WIP, possess the motif PXXPXRXXS; in the case of PAK, serine phosphorylation at this site negatively regulates binding. We show that kinase autophosphorylation blocks binding by both Nck and PIX to alphaPAK, thus providing a mechanism to regulate PAK interactions with its SH3-containing partners. One cellular consequence of the regulatable binding of PAK is facilitation of its cycling between cytosolic and focal complex sites.


The Lexical Stroop Sort (LSS) picture-word task: a computerized task for assessing the relationship between language and executive functioning in school-aged children.
The relationship between language development and executive function (EF) in children is not well understood. The Lexical Stroop Sort (LSS) task is a computerized EF task created for the purpose of examining the relationship between school-aged children's oral language development and EF. To validate this new measure, a diverse sample of school-aged children completed standardized oral language assessments, the LSS task, and the widely used Dimensional Change Card Sort (DCCS; Zelazo, 2006) task. Both EF tasks require children to sort stimuli into categories based on predetermined rules. While the DCCS largely relies on visual stimuli, the LSS employs children's phonological loop to access their semantic knowledge base. Accuracy and reaction times were recorded for both tasks. Children's scores on the LSS task were correlated with their scores on the DCCS task, and a similar pattern of relationships emerged between children's vocabulary and the two EF tasks, thus providing convergent validity for the LSS. However, children's phonological awareness was associated with their scores on the LSS, but not with those on the DCCS. In addition, a mediation model was used to elucidate the predictive relationship between phonological awareness and children's performance on the LSS task, with children's vocabulary fully mediating this relationship. The use of this newly created and validated LSS task with different populations, such as preschoolers and bilinguals, is also discussed.


Accumulated means analysis: a novel method to determine reliability of behavioral studies using continuous focal sampling.
During the past decade, the behavioral needs, and especially the social needs, of laboratory animals have received increasing attention. New captive care guidelines have been developed, and these advocate group housing of laboratory animals whenever possible and appropriate. Analyses of behavioral observations are commonly used to assess the effects of experimental manipulations on behavioral responses. In studies of animal welfare, stress levels and effects on well being can be measured in this manner. Collecting the proper amount of data both to allow statistical analyses and to optimize time investment in data collection is a practical concern in behavioral research. The aim of the present study was to develop a simple method to estimate how much behavioral data should be collected in order to achieve a preset level of reliability across observations. This paper examines the behavior of 12 rhesus monkeys (Macaca mulatta) housed in two small social groups. Each monkey was observed for a total of two hours in 10 minute observation periods spread over 12 days. Accumulated Means Analysis, in which the accumulated mean for a behavior across successive observation sessions must meet several criteria, is proposed as a method to assess reliability across observations, thereby providing information concerning the optimum number of observational data sessions that need to be collected. The data in this study indicate that this optimum number of observations varies with the behavior being measured and with the group observed, as does the value of the Accumulated Means Analysis technique. Six hours of observation of rhesus macaques may be sufficient to provide the type of simple, yet reliable time budget (for a specific window of time) needed by those managing groups of primates. Accumulated Means Analysis should be applicable to behavioral data collected during multiple time periods on other non-human primate species, both in captivity and in the field.


Synergistic interactions of the plant cell death pathways induced by Phytophthora infestans Nepl-like protein PiNPP1.1 and INF1 elicitin.
Cell death plays a ubiquitous role in plant-microbe interactions, given that it is associated with both susceptible and resistance interactions. A class of cell death-inducing proteins, termed Nepl-like proteins (NLPs), has been reported in bacteria, fungi, and oomycetes. These proteins induce nonspecific necrosis in a variety of dicotyledonous plants. Here, we describe three members of the NLP family from the oomycete Phytophthora infestans (PiNPP1.1, PiNPP1.2, and PiNPP1.3). Using agroinfection with a binary Potato virus X vector, we showed that PiNPP1.1 induces cell death in Nicotiana benthamiana and the host plant tomato. Expression analyses indicated that PiNPP1.1 is up-regulated during late stages of infection of tomato by P. infestans. We compared PiNPP1.1 necrosis-inducing activity to INF1 elicitin, a well-studied protein that triggers the hypersensitive response in Nicotiana spp. Using virus-induced gene silencing, we showed that the cell death induced by PiNPP1.1 is dependent on the ubiquitin ligase-associated protein SGT1 and the heat-shock protein HSP90. In addition, cell death triggered by PiNPP1.1 but not that by INF1 was dependent on the defense-signaling proteins COI1, MEK2, NPR1, and TGA2.2, suggesting distinct signaling requirements. Combined expression of PiNPP1.1 and INF1 in N. benthamiana resulted in enhanced cell death, suggesting synergistic interplay between the two cell-death responses. Altogether, these results point to potentially distinct but interacting cell-death pathways induced by PiNPP1.1 and INF1 in plants.


Consecutive thermal and wet conditioning treatments of sedimentary stabilized cementitious materials from HPSS® technology: Effects on leaching and microstructure.
Soil and sediment contamination is recognised as one of the most relevant environmental problems caused by past industrial activities and unsustainable waste disposal practices, highlighting the need to develop or improve effective remediation techniques to support sustainable management strategies. In this context, the remediation of sediments dredged from the Mincio river (Italy) contaminated by mercury and heavy hydrocarbons (C12-40) was carried out by applying and implementing the High Performance Solidification/Stabilization technology, aimed at producing safe and reusable cement-based granular materials. The technology was improved by decreasing both the temperature and time of the thermal desorption treatment (from 280 to 110 °C and from 4-16 h to 70 min, respectively) and by including a wet conditioning step to the process. Temperature and time reduction allowed to diminish the degradation of the cementitious phases of the granules (usually related to the high temperatures employed in the process), while the wet conditioning step allowed to improve their mechanical properties, as well as to further reduce the leaching of contaminants. The physical-chemical properties of the granules and contaminant leaching in water were investigated by Inductively Coupled Plasma Mass and Optical Emission Spectrometry, Ultraviolet-Visible spectroscopy, Gas Chromatography, X-Ray Powder Diffraction, and Scanning Electron Microscopy, in order to identify the optimal parameters for both thermal and wet conditioning processes. The overall results showed that the use of consecutive thermal and wet conditioning treatment on sedimentary cementitious materials from the High Performance Solidification/Stabilization technology led to the removal of volatile pollutants and to the improvement of granule quality, thus providing a final material that satisfied all the Italian regulatory requirements for reuse. Therefore, the findings obtained in this study may contribute to the development of sustainable management strategies for contaminated soils and sediments, leading to their valorisation through the transformation into reusable materials.


Evaluation of a stress coping course for psychological resilience among a group of university nursing students.
This study was conducted to evaluate a stress coping course for psychological resilience among a group of university nursing students. This was a quantitative study that had a pretest/posttest design without a control group. Data were collected from 78 first-year nursing students using a Stress Self-assessment Checklist and the Psychological Resilience Questionnaire (PRQ). A significant increase was determined in the subscales of self-perception and social resources of PRQ following the course (P ≤ 0.05). The findings emphasized that more attention should be given to the potential role of psychological resilience in dealing with the inevitable sources of stress in the education of nursing students.


Antiproliferative effects of cucurbitacin B in breast cancer cells: down-regulation of the c-Myc/hTERT/telomerase pathway and obstruction of the cell cycle.
Naturally occurring cucurbitacins have been shown to have anticancer, antimicrobial and anti-inflammatory activities. In this study, we determined the effects of cucurbitacin B extracted from the Thai herb Trichosanthes cucumerina L. on telomerase regulation in three human breast cancer cell lines (T47D, SKBR-3, and MCF-7) and a mammary epithelium cell line (HBL-100). Cell viability after treatment with cucurbitacin B, which is an active ingredient of this herb, was assessed. Telomeric Repeat Amplification Protocol (TRAP) assays and RT-PCR (qualitative and realtime) were performed to investigate activity of telomerase as well as expression of human telomerase reverse transcriptase (hTERT) and c-Myc. The c-Myc protein level was also determined in SKBR-3 and HBL-100 cells. Our results show that the cucurbitacin B inhibits growth and telomerase activity in the three breast cancer cell lines and exerts an obvious inhibitory effect in the estrogen receptor (ER)-negative breast cancer SKBR-3 cells. The expression of hTERT and c-Myc were also inhibited by cucurbitacin B, In addition, a clear reduction of c-Myc protein was observed after treatment in SKBR-3 cells even with a concentration of cucurbitacin B that was ten-times lower compared to the concentration used for HBL-100. Our findings imply that cucurbitacin B exerts an anticancer effect by inhibiting telomerase via down regulating both the hTERT and c-Myc expression in breast cancer cells.


Accountability in nurse education.
Accountability has assumed a higher profile in these changing times and clearly this multifaceted concept is inextricably linked to professionalization. In addition, major changes have taken place in nurse education, resulting in role changes for the nurse teacher. Consequently, nurse teachers will have to examine more closely the many facets of accountability.


Steroidogenic factor-1 controls the aldose reductase akr1b7 gene promoter in transgenic mice through an atypical binding site.
Aldo-keto-reductase 1B7/mouse vas deferens protein (AKR1B7/MVDP) is expressed in rodent steroidogenic glands and in the mouse vas deferens. In steroidogenic organs, AKR1B7/MVDP scavenges isocaproaldehyde produced from the cholesterol side-chain cleavage reaction. Akr1b7/mvdp is responsive to ACTH in adrenals and to androgens in vas deferens. Using transgenic mice, we previously delimited the regulatory DNA sequences necessary for expression in both organs and identified by cell transfections, a cryptic steroidogenic factor-1 (SF-1) response element (SFRE) at -102 that overlaps a proximal androgen-responsive element. To address its in vivo functions in adrenals, we devised a transgenic mouse study using wild-type and mutant akr1b7 promoters driving the chloramphenol acetyltransferase reporter gene. Adrenal expression in adults was impaired in all lines mutant for -102 SFRE. This effect is linked to impaired SF-1 binding and not to impaired androgen receptor binding, because akr1b7 expression is not affected in adrenals of androgen receptor-defective Tfm mice. Triphasic developmental patterns of both AKR1B7 and wild-type transgene expression paralleled changes in SF-1 levels/binding activity; expression was maximal in late embryos, minimal in 6- to 15-d-old neonates, and thereafter progressively restored. Differences in developmental expression between wild-type and mutant transgenes revealed that requirement for the -102 SFRE appears stage specific, as its integrity is an absolute prerequisite for reinduction of gene expression after postnatal d 15. Further, mutation of this site did not affect transgene responsiveness to ACTH. These findings demonstrate a new function for SFRE in vivo, via influencing promoter sensibility to postnatal changes of SF-1 contents, in controlling promoter strength in adults without affecting adrenal targeting, hormonal control, or early gene expression.


Evaluation of the use of captopril on peritoneal fibrosis induced in rats by the use of glucose solution 4.25%.
Chronic renal failure has alarming incidence all over the world in this century. Among the modalities of dialytic treatment, peritoneal dialysis has a major spot. This method of dialytic treatment may present complications, and among those is peritoneal fibrosis. It occurs in patients submitted to peritoneal dialysis along years. It's most dangerous form is sclerosing encapsulant peritonitis, wich leads to a need of change in modality and many times lead to death. Study the influence of using captopril on the peritoneal fibrosis induced in rats using solution with glucoses 4.25%. Prospective controlled study in 20 non-uremic Wistar rats. The animals received a peritoneal infusion of 10 ml/100g of peritoneal dialysis solution glucose 4.25% on a daily basis. The animals were divided in two groups: experimental and control. The experimental group received captopril 30 mg/kg/d, by a gastric tube. The control group did not receive any drug. The follow-up was 21 and 49 days. At the end, one surgical procedure was performed to get histological samples of visceral and parietal peritoneum. The samples were analyzed using Hematoxylin Eosin and Sirius Red, to evaluate the severity of the fibrosis. The analysis showed that the intensity of the fibrosis, the peritoneal thickness and the cell number in experimental and control groups were not statistically significant different in experimental and control groups. Our findings indicate that captopril do not decrease the intensity of fibrosis on the peritoneal membrane that happens on rats on peritoneal dialysis.


A double application approach to ophthalmia neonatorum prophylaxis.
To investigate if a second drop of 2.5% povidone-iodine ophthalmic solution placed within the first postnatal day would achieve better prophylaxis against ophthalmia neonatorum than a single drop applied at birth. A masked, prospective, controlled trial was conducted over a 2 year period in a Kenyan hospital. Randomisation was achieved by alternating weeks of one or two eye drop application to both eyes. All 719 neonates received one drop of the povidone-iodine solution to both eyes at birth, while 317 received a second drop at hospital discharge or 24 (SD 4) hours after delivery, whichever was first. All infants developing conjunctivitis within a month after birth underwent microbiological analysis using Gram and Giemsa stains, direct fluorescent antibody assay for Chlamydia trachomatis, and culture. Of the neonates receiving the one eye drop application, 18.4% returned with a red eye with discharge, 4.0% had organisms found on the initial smear, and 8.2% had a positive culture. The corresponding proportions for the multidrop group were 24.3%, 4.7%, and 10.4%. Of those returning with an inflamed eye, there were no cases of Neisseria gonorrhoeae, 4.2% in the single dose group and 3.9% in the double dose group were positive for C trachomatis, and 5.4% and 6.5% respectively for Staphylococcus aureus. At discharge, the eyelid oedema score of the double dose group was mildly greater than the single dose group (1.4 (0.67) v 1.2 (0.73), p=0.0002). There was no statistically significant difference between the groups in any other category. There is no advantage to administering povidone-iodine prophylaxis against ophthalmia neonatorum twice in the first postnatal day over a single application at birth.


Radiographic and scintigraphic evaluation of spondylosis in the equine thoracolumbar spine: a retrospective study.
Clinical, radiographic and scintigraphic signs associated with spondylosis of the equine thoracolumbar spine have been poorly documented. To establish an objective radiographic and scintigraphic grading system for spondylosis lesions; to estimate the prevalence of spondylosis in a population of horses with back pain; and to compare the results of radiography and scintigraphy. Radiographic images of the thoracolumbar spine from 670 horses with clinical signs of back pain were graded. Scintigraphic images from horses with spondylosis lesions underwent subjective and objective analysis. Sensitivity and specificity of scintigraphy for detection of spondylosis relative to radiography for identification of spondylosis were calculated, and Chi-squared analysis was performed to test for an association between location and severity of lesions. Twenty-three of 670 horses (3.4%) with back pain had radiographic evidence of spondylosis. Of these horses, 14 (61%) had more than one lesion and 44% (n=22) of lesions occurred between T11-T13 vertebral bodies. Only 33% (n=28) of locations with radiographic changes had increased radiopharmaceutical uptake. Spondylosis occurs at a low prevalence in horses with back pain. It may be present alone or in association with other osseous abnormalities. The clinical significance of spondylosis needs further investigation. Spondylosis is uncommon but may be a contributor to back pain in the horse.


Phase Equilibria of Solid and Fluid Phases from Molecular Dynamics Simulations with Equilibrium and Nonequilibrium Free Energy Methods.
In this work, we present a methodology to determine phase coexistence lines for atomic and rigid molecular systems with an emphasis on solid-fluid and on solid-solid equilibria. Phase coexistence points are found by computing the absolute free energy for each candidate phase separately. For solid phases, a combination of the extended Einstein crystal and the Einstein molecule method is presented which constitutes a convenient way to compute the absolute free energy with fixed center of mass. We compare results from equilibrium methods-thermodynamic integration and reweighting using the multistate Bennett acceptance ratio estimator (MBAR)-with simulations using a nonequilibrium method and discuss their advantages and disadvantages. Once absolute free energies of different phases are available, they are combined with simulations performed in the isothermal isobaric ensemble and MBAR, which enables efficient, iterative tracing of coexistence lines. The method is applicable to both liquid-solid as well as solid-solid transitions and is comparably simple and convenient to apply since the same method (MBAR) is used to compute free energies and to trace the coexistence line. Furthermore, statistical uncertainties can readily be computed in a transparent manner. We apply the method to an atomic solid (fcc argon) as well as small molecular systems (methanol and water) using the LAMMPS simulation package. Our study shows that all methods can be used to reliably compute the absolute free energy of solid phases, while MBAR is the most flexible method with high statistical efficiency. We find the nonequilibrium method is an attractive choice since it is simple to set up and to postprocess and is, hence, less prone to errors. The presented workflow provides a flexible, efficient, and robust way to compute phase diagrams using openly available software.


APOE-epsilon4 predicts dementia but not other psychiatric disorders after traumatic brain injury.
The authors studied the association between APOE-epsilon4 genotype and axis I and II psychiatric disorders an average of 30 years after traumatic brain injury. Sixty patients were dichotomized into subjects with and without APOE-epsilon4 allele. Dementia and subclinical dementia were significantly more common with the presence of APOE-epsilon4. The occurrence of other psychiatric disorders did not differ between patients with and without APOE-epsilon4 allele.


Depression in romanian patients with type 2 diabetes: prevalence and risk factors.
Co-existing major depression was found to have a negative impact on the diabetes outcome and the quality of life. The aim of the present study was to assess the prevalence of depressive symptoms in Romanian diabetes patients and to identify the risk factors associated with depression. A total of 144 type 2 diabetes patients were included in the study. Five models of presumed predictors were used to assess the risk factors for depressive symptoms, using hierarchical regression analysis. Together with demographics, disease, lifestyle predictors, previous depressive symptoms and diabetes distress were taken into account. In our sample the prevalence of depression was 12.6%. Main risk factors for depressive symptoms were previous depressive symptoms which were associated with depression in both Model 4 (β=0.297, p=0.013) and Model 5 (β=0.239, p=0.017) and diabetes distress in Model 5 (β=0.540, p≤0.001). Employment (β =-0.276, p=0.029) and increased number of diabetes complications (β=0.236, p=0.017) became significant when diabetes distress was added to the analysis. The overall prevalence of depressive symptoms was found to be in range with the prevalence identified in the literature. Previous depression and diabetes distress were both independently associated with depression, confirming the bidirectional relationship between depression and diabetes distress. Due to the consequences for daily living, screening for diabetes distress and depression should be done in primary care units both by physicians and trained nurses.


[Structural and histochemical changes in the rat cerebellum Purkinje cells after cholestasis].
The aim of the study was the estimation of structural and metabolic changes in the rat cerebellum Purkinje cells (PC) in the dynamics of subhepatic cholestasis. Histological, histochemical and electron microscopic methods were used. It was found that the cholestasis induced the progressive intensification of the structural and metabolic disturbances in the cerebellar PC reaching their maximum on days 10-20 and resulting in PC death and PC number reduction. In the cytoplasm of these cells the reduction of the activities of succinate dehydrogenase, NADH-diaphorase, glucose-6-dehydrogenase was recorded together with the decrease of RNA content and the activation of lactate dehydrogenase and acid phosphatase. The disturbances of PC at the ultrastructural level included the destruction of the nucleus and organelles (especially, of the mitochondria), associated with the increase of phagosome size and number, augmentation of relative free ribosome number, appearance of close contacts between mitichondria and cell nucleus and organelles. After 45-90 days in survived animals gradual normalization of PC structure and metabolism took place apparently as a result of spontaneous cholestasis elimination due to the development of new bile ducts.


Pregnant woman infected by Coronavirus disease (COVID-19) and calcifications of the fetal bowel and gallbladder.
COVID-19 was declared to be a pandemic due to the rapid increase of cases around the world, including the number of pregnant women. Data about vertical transmission of COVID-19 are still limited and controversial: in most cases, although a positive mother, the virus could not be isolated in amniotic fluid, cord blood, breast milk or neonatal throat swab in these patients. No data have been published about possible intrauterine sonographic signs of infection. A pregnant woman was diagnosed with SARS-CoV-2 at 35+5 weeks of gestation and managed conservatively at home. At transabdominal ultrasound at 38+3 weeks, fetal bowel and gallbladder calcifications were noted. CMV and other infectious agents were ruled out; an iterative caesarean section was performed at 38+5 weeks without complications. Placenta resulted negative for SARS-CoV-2; the umbilical cord blood sample was IgG positive and IgM negative as per maternal infection. The baby developed respiratory distress syndrome requiring endotracheal surfactant administration and nasal-CPAP for one day but nasopharyngeal swabs at birth and after 48 hours were SARS-CoV-2 negative. Neonatal abdominal ultrasound showed normal liver, acalculous gallbladder with mild parietal thickening. The baby was discharged in good conditions. Although gallbladder calcifications and echogenic bowel are highly suspicious of viral infection and were thought to be due to the vertical transmission of SARS-CoV-2, these findings were not corroborated by the results of our diagnostic tests; these sonographic findings might represent a false positive of fetal infection in mother affected by COVID-19 since vertical transmission appears to be rare.


Utilizing the Ambulatory Glucose Profile to Standardize and Implement Continuous Glucose Monitoring in Clinical Practice.
Use of continuous glucose monitoring (CGM) is recognized as a valuable component of diabetes self-management and is increasingly considered a standard of care for individuals with diabetes who are treated with intensive insulin therapy. As the clinical use of CGM technology expands, consistent and standardized glycemic metrics and glucose profile visualization have become increasingly important. A common set of CGM metrics has been proposed by an international expert panel in 2017, including standard definitions of time in ranges, glucose variability, and adequacy of data collection. We describe the core CGM metrics, as well as the standardized glucose profile format consolidating 2 weeks of CGM measurements, referred to as the ambulatory glucose profile (AGP), which was also recommended by the CGM expert panel. We present an updated AGP report featuring the core CGM metrics and a visualization of glucose patterns that need clinical attention. New tools for use by clinicians and patients to interpret AGP data are reviewed. Strategies based on the authors' experience in implementing CGM technology across the clinical care spectrum are highlighted.


Reactive oxygen species-mediated DNA damage and apoptosis in human skin epidermal cells after exposure to nickel nanoparticles.
Nickel nanoparticles (NiNPs) are increasingly used in various applications due to their unique properties. However, there is little information concerning the toxicity of NiNPs in the human skin cell (A431). The present study was designed to investigate the cytotoxicity, apoptosis, and DNA damage due to NiNPs in A431 cells. A cellular proliferative capacity test showed that NiNPs induce significant cytotoxicity in a dose- and time-dependent manner. NiNPs were also found to induce oxidative stress evidenced by the generation of reactive oxygen species (ROS) and depletion of glutathione (GSH). Further, co-treatment with the antioxidant N-acetylcysteine (NAC) mitigated the ROS generation due to NiNPs, suggesting the potential mechanism of oxidative stress. NiNPs also induced significant elevation of lipid peroxidation, catalase, and superoxide dismutase and caspase-3 activity in A431 cells. In addition, NAC suppressed NiNP-induced caspase-3 activity. DNA fragmentation analysis using the comet assay showed that the NiNPs cause genotoxicity in a dose- and time-dependent manner. Therefore, the study points out the capability of the NiNPs to induce oxidative stress resulting in apoptosis and genotoxicity. This study warrants more careful assessment of NiNPs before their industrial applications.


Pictorial Essay: Understanding of Persistent Left Superior Vena Cava and Its Differential Diagnosis.
Persistent left superior vena cava (PLSVC) is a rare congenital, thoracic, and vascular anomaly. Although PLSVCs generally do not have a hemodynamic effect, several types of PLSVC and some cardiac anomalies may manifest with clinical symptoms. The presence of PLSVC can render catheterization via left subclavian access difficult when placing a pacemaker or central venous catheter. As such, recognizing a PLSVC that is typically incidentally discovered can prevent complications such as vascular injury. Differentiating vessels found in a similar location as PLSVC is necessary when performing thoracic vascular procedures. This pictorial essay explains the multi-detector CT findings of a PLSVC, and provides a summary of other blood vessels that require differentiation during thoracic vascular procedures.


Analysis of transcriptional and epigenetic changes in hybrid vigor of allopolyploid Brassica napus uncovers key roles for small RNAs.
Heterosis is a fundamental biological phenomenon characterized by the superior performance of a hybrid compared with its parents. The underlying molecular basis for heterosis, particularly for allopolyploids, remains elusive. In this study we analyzed the transcriptomes of Brassica napus parental lines and their F1 hybrids at three stages of early flower development. Phenotypically, the F1 hybrids show remarkable heterosis in silique number and grain yield. Transcriptome analysis revealed that various phytohormone (auxin and salicylic acid) response genes are significantly altered in the F1 hybrids relative to the parental lines. We also found evidence for decreased expression divergence of the homoeologous gene pairs in the allopolyploid F1 hybrids and suggest that high-parental expression-level dominance plays an important role in heterosis. Small RNA and methylation studies aimed at examining the epigenetic effect of the changes in gene expression level in the F1 hybrids showed that the majority of the small interfering RNA (siRNA) clusters had a higher expression level in the F1 hybrids than in the parents, and that there was an increase in genome-wide DNA methylation in the F1 hybrid. Transposable elements associated with siRNA clusters had a higher level of methylation and a lower expression level in the F1 hybrid, implying that the non-additively expressed siRNA clusters resulted in lower activity of the transposable elements through DNA methylation in the hybrid. Our data provide insights into the role that changes in gene expression pattern and epigenetic mechanisms contribute to heterosis during early flower development in allopolyploid B. napus.


Inattention and hyperactivity in children at risk of obesity: a community cross-sectional study.
There is a link between the symptoms of hyperactivity/inattention and overweight in children. Less is known about the factors which might influence this relationship, such as physical and sedentary activity levels or exercise self-efficacy. The aim of this study is to examine the associations between the symptoms of hyperactivity/inattention and risk factors for adult obesity in a sample of children with barriers to exercise. Children aged 9-11 years were recruited from 24 primary schools that participated in the Steps to Active Kids (STAK) physical activity intervention study. Study inclusion criteria were low exercise self-efficacy, teacher-rated overweight or asthma. Children with high levels of physical activity were excluded. Measures included parent and teacher-rated behavioural and emotional well-being using the Strengths and Difficulties Questionnaire, physical and sedentary activity levels, BMI (body mass index) and exercise self-efficacy. Of 424 participating children, 62% were girls and 39% were classified as overweight or obese. As compared with population norms, boys in this at-risk sample were more likely to receive an abnormal teacher-rated hyperactivity/inattention score (OR 1.48, 95% CI 1.01 to 2.17). Children with teacher-rated abnormal hyperactivity/inattention scores reported higher levels of sedentary activity (OR 1.13, 95% CI 1.02 to 1.17), but not physically active activity. The pattern of findings was similar for children with hyperactivity/inattention problems as rated by both parent and teacher (pervasive hyperactivity and impairment). Although BMI was not directly related to hyperactivity/inattention, children with risk factors for adult obesity have more hyperactivity/inattention problems. In particular, hyperactivity/inattention is associated with higher levels of sedentary activity. Higher rates of pervasive hyperactivity and impairment were apparent in this at-risk group.


Angiotensin II type 1 receptor blockade: high hopes sent back to reality?
Chronic activation of the renin-angiotensin system (RAS) plays a crucial role in the development of various cardiovascular diseases (CVD). Thus, effective RAS inhibition has been a major achievement to improve the treatment of patients at risk for CVDs, such as myocardial infarction, heart failure and stroke. Three substance classes that block RAS-activation are currently available, angiotensin converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockade (ARB) and renin inhibitors. Although the overall goal of these drugs remains the blockade of RAS activation, their individual targets in this system vary and may substantially influence the clinical benefit derived from the long term use of these substances. Here, we summarize the evidence available for the use of ARBs in different cardiovascular pathologies and the impact of this evidence on current treatment guidelines for patients at risk for CVD. Today, ARBs represent a good alternative in case of ACE-inhibitor intolerance due to their outstanding tolerability. ARBs in comparison to ACE-inhibitors have been proven to exert similar effective in the treatment of systolic heart failure, primary prevention of stroke, new onset of diabetes mellitus (DM) type 2 and DM type 2 dependent macroalbuminuria. ARBs should be considered as alternatives to ACE-inhibitors in subjects post-myocardial infarction. Overall however, there is no profound proof for a specific cardiovascular protection by blockade of the angiotensin II Type 1 (AT1) receptor that exceeds the impact of ACE-inhibition or synergises with ACE-blockade. In fact, combination of ARBs and ACE-inhibitor result in an increased rate of adverse effects and, therefore, this combination should not be encouraged. To summarize, the initial hope for a more specific impact on cardiovascular diseases by inhibition of the AT1-receptor in comparison to ACE-inhibition has not come true. However, ARBs have been proven to be equally effective as ACE-blockade in a large variety of clinical settings.


Kinetics and mechanism of K+- and Na+-induced folding of models of human telomeric DNA into G-quadruplex structures.
Cation-induced folding into quadruplex structures for three model human telomeric oligonucleotides, d[AGGG(TTAGGG)(3)], d[TTGGG(TTAGGG)(3)A] and d[TTGGG(TTAGGG)(3)], was characterized by equilibrium titrations with KCl and NaCl and by multiwavelength stopped flow kinetics. Cation binding was cooperative with Hill coefficients of 1.5-2.2 in K(+) and 2.4-2.9 in Na(+) with half-saturation concentrations of 0.5-1 mM for K(+) and 4-13 mM for Na(+) depending on the oligonucleotide sequence. Oligonucleotide folding in 50 mM KCl at 25 degrees C consisted of single exponential processes with relaxation times tau of 20-60 ms depending on the sequence. In contrast, folding in100 mM NaCl consisted of three exponentials with tau-values of 40-85 ms, 250-950 ms and 1.5-10.5 s. The folding rate constants approached limiting values with increasing cation concentration; in addition, the rates of folding decreased with increasing temperature over the range 15-45 degrees C. Taken together, these results suggest that folding of G-rich oligonucleotides into quadruplex structures proceeds via kinetically significant intermediates. These intermediates may consist of antiparallel hairpins in rapid equilibrium with less ordered structures. The hairpins may subsequently form nascent G-quartets stabilized by H-bonding and cation binding followed by relatively slow strand rearrangements to form the final completely folded topologies. Fewer kinetic intermediates were evident with K(+) than Na(+), suggesting a simpler folding pathway in K(+) solutions.


Physiological measures tracking seasonal changes in peak running speed.
It is unclear whether physiological measures monitored in an incremental treadmill test during a training season provide useful diagnostic information about changes in distance running performance. To quantify the relationship between changes in physiological measures and performance (peak running speed) over a training season. Well-trained distance runners (34 males; VO2max 64 +/- 6 mL x kg(-1) x min(-1), mean +/- SD) completed four incremental treadmill tests over 17 wk. The tests provided values of peak running speed, VO2max, running economy, and lactate threshold (as speed and %VO2max). The physiological measures were included in simple and multiple linear regression models to quantify the relationship between changes in these measures and changes in peak speed. The typical within-subject variation in peak speed from test to test was 2.5%, whereas those for physiological measures were VO2max (mL x min(-1) x kg(-1)) 3.0%, economy (m x kg x mL(-1)) 3.6%, lactate threshold (%VO2max) 8.7%, and body mass 1.8%. In simple models these typical changes predicted the following changes in performance: VO2max 1.4%, economy 0.8%, lactate threshold -0.3%, and body mass -0.2% (90% confidence limits approximately +/-0.7%); the corresponding correlations with performance were 0.57, 0.33, -0.05, and -0.13 respectively (approximately +/-0.20). In a multiple linear regression model, the contribution of each physiological variable to performance changed little after adjustment for the other variables. Change in VO2max in an incremental test during a running season is a good predictor of change in peak running speed, change in running economy is a moderate predictor, and lactate threshold and body mass provide little additional information.


A Prospective Multicenter Registry on Feasibility, Safety, and Outcome of Endovascular Recanalization in Childhood Stroke (Save ChildS Pro).
Rationale: Early evidence for the benefit of mechanical thrombectomy (MT) in pediatric patients with intracranial large vessel occlusion has been shown in previous retrospective cohorts. Higher-level evidence is needed to overcome the limitations of these studies such as the lack of a control group and the retrospective design. Randomized trials will very likely not be feasible, and several open questions remain, for example, the impact of arteriopathic etiologies or a possible lower age limit for MT. Save ChildS Pro therefore aims to demonstrate the safety and effectiveness of MT in pediatric patients compared to the best medical management and intravenous thrombolysis. Design: Save ChildS Pro is designed as a worldwide multicenter prospective registry comparing the safety and effectiveness of MT to the best medical care alone in the treatment of pediatric arterial ischemic stroke (AIS). It will include pediatric patients (<18 years) with symptomatic acute intracranial arterial occlusion who underwent either MT or best medical treatment including intravenous thrombolysis. Outcomes: The primary endpoint of Save ChildS Pro is the modified Rankin Scale score at 90 days post-stroke. Secondary endpoints will comprise the decrease of the Pediatric National Institutes of Health Stroke Scale score from admission to discharge and rate of complications. Discussion: Save ChildS Pro aims to provide high-level evidence for MT for pediatric patients with AIS, thereby improving functional outcome and quality of life and reducing the individual, societal, and economic burden of death and disability resulting from pediatric stroke. Clinical Trial Registration: Save ChildS Pro is registered at the German Clinical Trials Registry (DRKS; identifier: DRKS00018960).