Evaluation of the cost-effectiveness of pyramidal, modified pyramidal and monoscreen traps for the control of the tsetse fly, Glossina fuscipes fuscipes, in Uganda.
Several trap designs have been used for sampling and control of the tsetse fly, Glossina fuscipes fuscipes, Newstead (Diptera: Glossinidae) based on preferences of individual researchers and program managers with little understanding of the comparative efficiency and cost-effectiveness of trap designs. This study was carried out to evaluate the cost-effectiveness of four commonly used trap designs: monoscreen, modified pyramidal and pyramidal, relative to the standard biconical trap. The study was performed under high tsetse challenge on Buvuma Island, Lake Victoria, Uganda, using a 4 x 4 Latin square design replicated 3 times, so as to separate the trap positions and day effects from the treatment effect. A total of 12 trap positions were tested over 4 days. The monoscreen trap caught significantly higher numbers of G. f. fuscipes (P<0.05) followed by biconical, modified pyramidal and pyramidal traps. Analysis of variance showed that treatment factor was a highly significant source of variation in the data. The index of increase in trap catches relative biconical were 0.60 (pyramidal), 0.68 (modified pyramidal) and 1.25 (monoscreen). The monoscreen trap was cheaper (US$ 2.61) and required less material to construct than pyramidal trap (US$ 3.48), biconical and the modified pyramidal traps (US$ 4.06 each). Based on the number of flies caught per meter of material, the monoscreen trap proved to be the most cost-effective (232 flies/m) followed by the biconical trap (185 flies/m). The modified pyramidal and the pyramidal traps caught 112 and 125 flies/m, respectively.


Is vasospasm related to platelet deposition? Relationship in a porcine preparation of arterial injury in vivo.
Although aggregating platelets can release potent vasoactive substances in vitro, the importance of platelets in mediating naturally occurring or provoked spasm in vivo is not clear. To investigate the possible role of platelets in arterial spasm following arterial injury induced by angioplasty, quantitative platelet deposition of the dilated arterial segment and the degree of vasoconstriction (average percent diameter narrowing just proximal and distal to the dilated segment) produced during angioplasty of the common carotid arteries were studied in 42 heparinized normal pigs that were killed immediately after the angioplasty procedure. Angiographic films of the carotid arteries were taken before and after the dilatation to assess the vasoconstriction. Vasoconstriction was greater (40% vs 19%, p less than .002) when platelet deposition (X 10(6)/cm2) was in excess of 10, and the severity of vasoconstriction in vivo had a close positive exponential correlation (r = .77, p less than .001) with extent of platelet deposition in 24 untreated pigs. Platelet deposition and vasoconstriction were greater with severe arterial wall injury than with mild injury (58.8 versus 6.9, p less than .0001; 37% vs 21%, p less than .001, respectively). After severe injury in 18 pigs pretreated with 1 mg/kg/day aspirin, platelet deposition decreased (from 58.8 to 19.6, p less than .02) and vasoconstriction decreased (from 37% to 21%, p less than .003) relative to control. After mild injury, platelet deposition and vasoconstriction were mild and unchanged by aspirin. Thus, local vasoconstriction is influenced by the degree of platelet deposition.(ABSTRACT TRUNCATED AT 250 WORDS)


A quantitative S-Matrix approach to high-order harmonic generation from multiphoton to tunneling regimes.
We present a S-matrix description of the process of high order harmonic generation during the interaction of atoms with strong electromagnetic fields. In contrast with the state-of-the-art approaches, our model does not employ the stationary phase approximation and accounts as well for the continuum-continuum transitions. Therefore we are able to reproduce quantitatively the higher frequency part of the spectrum for arbitrary pulse shapes, and for intensities corresponding to multiphoton, tunnel and soft over-the barrier ionization regimes. In addition this model can be implemented very efficiently in a Personal Computer to calculate the harmonic generation for the atom interacting with an eight-cycle pulse at lambda =800 nm in, roughly, ten minutes (a reduction of two orders of magnitude from the typical time requirements of the exact integration).


Polycystin 2 is increased in disease to protect against stress-induced cell death.
Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. Despite its ubiquitous expression throughout the body, studies of PC2 have focused primarily on its role in the kidney, as mutations in PC2 lead to the development of autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition for which there is no cure. However, the endogenous role that PC2 plays in the regulation of general cellular homeostasis remains unclear. In this study, we measure how PC2 expression changes in different pathological states, determine that its abundance is increased under conditions of cellular stress in multiple tissues including human disease, and conclude that PC2-deficient cells have increased susceptibility to cell death induced by stress. Our results offer new insight into the normal function of PC2 as a ubiquitous stress-sensitive protein whose expression is up-regulated in response to cell stress to protect against pathological cell death in multiple diseases.


Silibinin down-regulates FAT10 and modulate TNF-α/IFN-γ-induced chromosomal instability and apoptosis sensitivity.
Pleiotropic pro-inflammatory cytokines, TNF-α and IFN-γ (TI), play important yet diverse roles in cell survival, proliferation, and death. Recent evidence highlights FAT10 as a downstream molecule in the pathway of inflammation-induced tumorigenesis through mediating the effect of cytokines in causing numerical CIN and protecting cells from cytokines-induced cell death. cDNA microarray analysis of cells treated with TI revealed 493 deregulated genes with FAT10 being the most up-regulated (85.7-fold) gene and NF-κB being the key nodal hub of TI-response genes. Silibinin is reported to be a powerful antioxidant and has anti-C effects against various carcinomas by affecting various signaling molecules/pathways including MAPK, NF-κB and STATs. As NF-κB signaling pathway is a major mediator of the tumor-promoting activities of TI, we thus examine the effects of silibinin on TI-induced FAT10 expression and CIN. Our data showed that silibinin inhibited expression of FAT10, TI-induced chromosome instability (CIN) as well as sensitizes cells to TI-induced apoptosis. Significantly, silibinin suppressed intra-tumorally injected TNF-α-induced tumor growth. This represents the first report associating silibinin with FAT10 and demonstrating that silibinin can modulate TI-induced CIN, apoptosis sensitivity and suppressing TNF-α-induced tumor growth.


TLR4 as receptor for HMGB1 induced muscle dysfunction in myositis.
Polymyositis and dermatomyositis are characterised by muscle weakness and fatigue even in patients with normal muscle histology via unresolved pathogenic mechanisms. In this study, we investigated the mechanisms by which high mobility group box protein 1 (HMGB1) acts to accelerate muscle fatigue development. Intact single fibres were dissociated from flexor digitorum brevis (FDB) of wild type, receptor for advanced glycation endproduct (RAGE) knockout and toll like receptor 4 (TLR4) knockout mice and cultured in the absence or presence of recombinant HMGB1. A decrease in sarcoplasmic reticulum Ca(2+) release during a series of 300 tetanic contractions, which reflects the development of muscle fatigue, was determined by measuring myoplasmic free tetanic Ca(2+). TLR4 and major histocompatibility complex (MHC)-class I expression in mouse FDB fibres were investigated by immunofluorescence and confocal microscopy. Immunohistochemistry was used to investigate TLR4, MHC-class I and myosin heavy chain expression in muscle fibres of patients. Our results demonstrate that TLR4 is expressed in human and mouse skeletal muscle fibres, and coexpressed with MHC-class I in muscle fibres of patients with myositis. Furthermore, we show that HMGB1 acts via TLR4 but not RAGE to accelerate muscle fatigue and to induce MHC-class I expression in vitro. In order to bind and signal via TLR4, HMGB1 must have a reduced cysteine 106 and a disulphide linkage between cysteine 23 and 45. The HMGB1-TLR4 pathway may play an important role in causing muscle fatigue in patients with polymyositis or dermatomyositis and thus is a potential novel target for future therapy.


Gene profiling of canine B-cell lymphoma reveals germinal center and postgerminal center subtypes with different survival times, modeling human DLBCL.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, and fewer than half of patients are cured with standard first-line therapy. To improve therapeutic options, better animal models that accurately mimic human DLBCL (hDLBCL) are needed. Canine DLBCL, one of the most common cancers in veterinary oncology, is morphologically similar to hDLBCL and is treated using similar chemotherapeutic protocols. With genomic technologies, it is now possible to molecularly evaluate dogs as a potential large-animal model for hDLBCL. We evaluated canine B-cell lymphomas (cBCL) using immunohistochemistry (IHC) and gene expression profiling. cBCL expression profiles were similar in many ways to hDLBCLs. For instance, a subset had increased expression of NF-κB pathway genes, mirroring human activated B-cell (ABC)-type DLBCL. Furthermore, immunoglobulin heavy chain ongoing mutation status, which is correlated with ABC/germinal center B-cell cell of origin in hDLBCL, separated cBCL into two groups with statistically different progression-free and overall survival times. In contrast with hDLBCL, cBCL rarely expressed BCL6 and MUM1/IRF4 by IHC. Collectively, these studies identify molecular similarities to hDLBCL that introduce pet dogs as a representative model of hDLBCL for future studies, including therapeutic clinical trials.


Evaluation of the efficacy of Olyset® Plus in a village-based cohort study in the Cukurova Plain, Turkey, in an area of hyperendemic cutaneous leishmaniasis.
The aim of this study was to measure the protective efficacy of Olyset(®) Plus, a new long-lasting factory-treated insecticidal net (LLIN) incorporated with 2% permethrin and 1% of the synergist piperonyl butoxide (PBO), against cutaneous leishmaniasis (CL) transmission under field conditions. A village-scale trial, promoting the use of LLIN by the local inhabitants of the study area was conducted as a pilot study in a new hyperendemic focus of CL caused by a Leishmania infantum/L. donovani hybrid parasite transmitted by proven vector species Phlebotomus tobbi in Cukurova Plain, Adana, Turkey, between May, 2013 and May, 2014. The study area comprised eight villages; two of them were selected as an intervention village with Olyset(®) Plus net (Kizillar) and a control village without net application (Malihidirli). Six villages with surrounding allopatric barriers were utilized as a buffer zone cluster between intervention and control villages. Monthly entomological surveys were performed in the intervention and control villages and Damyeri, representing the other six villages, to collect adults of Phlebotomus tobbi. Results showed a significant reduction in cutaneous leishmaniasis incidence in the intervention village from 4.78% to 0.37%. The protective efficacy rate of LLIN was 92.2%. In contrast, incidence rates increased in the control village from 3.67% to 4.69%. We also evaluated residual insecticide levels of used nets after six and 12 months of usage. It was determined that the nets had retained full insecticidal strength. These results highlight the value of real-world data on bed net effectiveness and longevity to guide decisions regarding sand fly control strategies. To the best of our knowledge, this is the first field study to evaluate Olyset(®) Plus efficacy in a hyperendemic cutaneous leishmaniasis area.


Anti-biofilm and anti-virulence effects of zerumbone against Acinetobacter baumannii.
Acinetobacter baumannii is a multidrug-resistant opportunistic pathogen that affects patients with a compromised immune system and is becoming increasingly important as a hospital-derived infection. This pathogen is difficult to treat owing to its intrinsic multidrug resistance and ability to form antimicrobial-tolerant biofilms. In the present study, we aimed to assess the potential use of zerumbone as a novel anti-biofilm and/or anti-virulence agent against A. baumannii. The results showed that zerumbone at sub-inhibitory doses decreased biofilm formation and disrupted established A. baumannii biofilms. The zerumbone-induced decrease in biofilm formation was dose-dependent based on the results of microtitre plate biofilm assays and confocal laser scanning microscopy. In addition, our data validated the anti-virulence efficacy of zerumbone, wherein it significantly interfered with the motility of A. baumannii. To support these phenotypic results, transcriptional analysis revealed that zerumbone downregulated the expression of biofilm- and virulence-associated genes (adeA, adeB, adeC and bap) in A. baumannii. Overall, our findings suggested that zerumbone might be a promising bioactive agent for the treatment of biofilm- and virulence-related infections caused by multidrug-resistant A. baumannii.


The repeatability of the abbreviated (4-h) Oral Fat Tolerance Test and influence of prior acute aerobic exercise.
The Oral Fat Tolerance Test (OFTT) is regarded as a repeatable measure used to assess postprandial triglyceride (TAG) levels, with higher levels observed in cardio-metabolic disorders. Acute aerobic exercise intervention before OFTT reduces the TAG response, but the repeatability of this effect is unknown. The aim of this study was to determine the repeatability of the abbreviated 4-h OFTT with and without immediate prior aerobic exercise. On four separate days, healthy adult male participants underwent two 4-h OFTT (n = 10) and another two 4-h OFTT with 1-h of standardised moderate intensity aerobic exercise performed immediately before meal ingestion (n = 11). The OFTT meal composition included 75.4 g total fat, 21.7 g carbohydrate and 13.7 g protein. Venous blood was sampled at baseline and hourly up to 4 h after the OFTT meal ingestion, and TAG area under the curve (AUC) was calculated. Nonparametric Bland-Altman analysis of 4-h TAG AUC revealed that 9 of 10 repeat measurements fell within ±15 % of the median TAG AUC for the OFTT. By contrast, two of 11 repeat measurements fell within ±15 % of the median TAG AUC for the OFTT undertaken with 1-h prior aerobic exercise. The 4-h OFTT is a repeatable test of postprandial TAG responses in healthy men. However, aerobic exercise performed immediately before OFTT considerably increases the variability of TAG AUC. These findings have implications for interpretation of research studies investigating exercise intervention performed immediately before OFTT. Future studies should also investigate the repeatability of exercise performed 8-24 h before OFTT.


Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality.
Cytokines have been associated with the development of sepsis and diffuse tissue injury following septic or endotoxic challenges in humans. Furthermore, relative organ-system dysfunction, not specific organ dysfunction, appears to predict outcome from critical illness. We hypothesized that persistence of inflammatory cytokines within the circulation, reflecting a generalized systemic inflammatory response, is associated with multiple-system organ failure (MSOF) and death from critical illness. In addition, since hepatic function is central to host-defense homeostasis, we further reasoned that critically ill patients with hepatic cirrhosis would have an increased incidence of MSOF and death following sepsis associated with a persistence of cytokines in the blood. We measured serum levels of tumor necrosis factor (TNF), interleukin (IL) 1, IL-2, IL-6, and interferon gamma (IFG) serially for the first 48 h following the onset of hypotension (systolic blood pressure < 90 mm Hg) thought likely to be due to sepsis in all patients presenting to one ICU. These data were correlated with initial severity of shock and retrospective determination of septic or nonseptic origin, preexistent hepatic cirrhosis, subsequent development of MSOF, and outcome. Fifty-three specific episodes of shock in 52 patients were recorded (35 septic and 18 nonseptic episodes). Mortality was higher in septic patients (41 vs 17 percent, p < 0.01), as was the development of MSOF (29 vs 6 percent, p < 0.001), incidence of cirrhosis (21 vs 0 percent, p < 0.01), and TNF levels over the study interval (p < 0.01). Nonseptic patients also had an initial elevation in TNF over 48-h levels (p < 0.05) that were higher than serum levels reported for normal subjects (chi 2, p < 0.05). There was no relation between peak TNF level and outcome. Sixty-seven percent of the cirrhotic patients had development of MSOF and died, while only 30 percent of the noncirrhotic patients had development of MSOF or died (p < 0.05). The TNF and IL-6 levels in patients who had MSOF or who died were both elevated and did not decrease over time independent of presence or absence of sepsis (p < 0.01). Similarly, IL-6 levels after 12 h were higher in cirrhotic patients than in noncirrhotic septic patients (p < 0.05). No elevation in IL-1, IL-2, or IFG was seen in any patient subpopulation. TNF and IL-6 serum levels are higher in septic than in nonseptic shock, but the persistence of TNF and IL-6 in the serum rather than peak levels of cytokines predicts a poor outcome in patients with shock.


Biowep: a workflow enactment portal for bioinformatics applications.
The huge amount of biological information, its distribution over the Internet and the heterogeneity of available software tools makes the adoption of new data integration and analysis network tools a necessity in bioinformatics. ICT standards and tools, like Web Services and Workflow Management Systems (WMS), can support the creation and deployment of such systems. Many Web Services are already available and some WMS have been proposed. They assume that researchers know which bioinformatics resources can be reached through a programmatic interface and that they are skilled in programming and building workflows. Therefore, they are not viable to the majority of unskilled researchers. A portal enabling these to take profit from new technologies is still missing. We designed biowep, a web based client application that allows for the selection and execution of a set of predefined workflows. The system is available on-line. Biowep architecture includes a Workflow Manager, a User Interface and a Workflow Executor. The task of the Workflow Manager is the creation and annotation of workflows. These can be created by using either the Taverna Workbench or BioWMS. Enactment of workflows is carried out by FreeFluo for Taverna workflows and by BioAgent/Hermes, a mobile agent-based middleware, for BioWMS ones. Main workflows' processing steps are annotated on the basis of their input and output, elaboration type and application domain by using a classification of bioinformatics data and tasks. The interface supports users authentication and profiling. Workflows can be selected on the basis of users' profiles and can be searched through their annotations. Results can be saved. We developed a web system that support the selection and execution of predefined workflows, thus simplifying access for all researchers. The implementation of Web Services allowing specialized software to interact with an exhaustive set of biomedical databases and analysis software and the creation of effective workflows can significantly improve automation of in-silico analysis. Biowep is available for interested researchers as a reference portal. They are invited to submit their workflows to the workflow repository. Biowep is further being developed in the sphere of the Laboratory of Interdisciplinary Technologies in Bioinformatics - LITBIO.


Evidence for genetic differentiation and divergent selection in an autotetraploid forage grass (Arrhenatherum elatius).
The use of local provenances in restoration, agriculture and forestry has been identified as measure to sustain biological diversity and to improve local productivity. However, the delineation of regional provenances is challenging because it requires the identification of well-defined groups based on spatiogenetic differentiation and/or the evidence of local adaptation. In this study, we investigate genetic variation at 186 AFLP loci in 46 European accessions of the important grassland species Arrhenatherum elatius and ask (1) whether genetic variation within accessions differs between European geographical regions; (2) at which spatial scale populations are structured across Europe and (3) whether putatively adaptive markers contribute to this pattern and whether these markers can be related to climatic site conditions. Basic expectations of population genetics are likely to be altered in autotetraploid species, thus, we adopted a band-based approach to estimate genetic diversity and structuring. Compared to other grasses A. elatius showed high genetic diversity and considerable differentiation among accessions (Phi(ST) = 0.24). Accessions separated in a Western European and a Central/Eastern European group, without further structure within groups. A genome scan approach identified four potentially adaptive loci, whose band frequencies correlated significantly with climatic parameters, suggesting that genetic differentiation in A. elatius is also the result of adaptive processes. Knowledge on adaptive loci might in the long run also help to adapt ecosystems to adverse climate change effects through assisted migration of ecotypes rather than introduction of new species.


LV Mass as a Predictor of CVD Events in Older Adults With and Without Metabolic Syndrome and Diabetes.
The purpose of this study was to examine the prognostic significance of left ventricular (LV) mass for cardiovascular disease (CVD) events in older adults with and without metabolic syndrome (MetS) and diabetes mellitus (DM). MetS and DM are associated with increased CVD risk, but it is unclear in these groups whether subclinical CVD as shown by increased LV mass improves risk prediction compared to standard risk factors in older individuals. We studied 3,724 adults (mean 72.4 ± 5.4 years of age, 61.0% female, 4.4% African-American) from the Cardiovascular Health Study who had MetS but not DM or had DM alone or had neither condition. Cox regression was used to examine the association of LV mass, (alone and indexed by height and body surface area [BSA]) as determined by echocardiography, with CVD events, including coronary heart disease (CHD), stroke, heart failure (HF), and CVD death, as well as total mortality. We also assessed the added prediction, discriminative value, and net reclassification improvement (NRI) for clinical utility of LV mass compared to standard risk factors. Over a mean follow-up of 14.2 ± 6.3 years, 2,180 subjects experienced CVD events, including 986 CVD deaths. After adjustment for age, sex and standard risk factors, LV mass was positively associated with CVD events in those with MetS (hazard ratio [HR]: 1.4, p < 0.001) and without MetS (HR: 1.4, p < 0.001), but not DM (HR: 1.0, p = 0.62), with similar findings for LV mass indexed for height or BSA. Adding LV mass to standard risk factors moderately improved the prediction accuracy in the overall sample and MetS group from changes in C-statistics (p < 0.05). Categorical-free net reclassification improvement increased significantly by 17% to 19% in those with MetS. Findings were comparable for CHD, CVD mortality, and total mortality. LV mass is associated with increased CVD risk and provides modest added prediction and clinical utility compared to standard risk factors in older persons with and without MetS but not with DM.


Electrocatalysis in proteins, nucleic acids and carbohydrates.
The ability of proteins to catalyze hydrogen evolution has been known for more than 80 years, but the poorly developed d.c. polarographic "pre-sodium wave" was of little analytical use. Recently, we have shown that by using constant current chronopotentiometric stripping analysis, proteins produce a well-developed peak H at hanging mercury drop and solid amalgam electrodes. Peak H sensitively reflects changes in protein structures due to protein denaturation, single amino acid exchange, etc. at the picomole level. Unmodified DNA and RNA do not yield such a peak, but they produce electrocatalytic voltammetric signals after modification with osmium tetroxide complexes with nitrogen ligands [Os(VIII)L], binding covalently to pyrimidine bases in nucleic acids. Recently, it has been shown that six-valent [Os(VI)L] complexes bind to 1,2-diols in polysaccharides and oligosaccharides, producing voltammetric responses similar to those of DNA-Os(VIII)L adducts. Electrocatalytic peaks produced by Os-modified nucleic acids, proteins (reaction with tryptophan residues) and carbohydrates are due to the catalytic hydrogen evolution, allowing determination of oligomers at the picomolar level.


1, 8-Cineol Protect Against Influenza-Virus-Induced Pneumonia in Mice.
1,8-Cineol is a major monoterpene principally from eucalyptus essential oils and has been shown to exert anti-inflammatory, antiviral, and inhibitory of nuclear factor (NF)-kB effect. In the present study, we evaluated the effect of 1,8-cineol on mice infected with influenza A virus. We found that 1,8-cineol protects against influenza viral infection in mice. Moreover, 1,8-cineol efficiently decreased the level of IL-4, IL-5, IL-10, and MCP-1 in nasal lavage fluids and the level of IL-1β, IL-6, TNF-α, and IFN-γ in lung tissues of mice infected with influenza virus. The results also showed that 1,8-cineol reduced the expression of NF-kB p65, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 in lung tissues. Thus, 1,8-cineol appears to be able to augment protection against IFV infection in mice via attenuation of pulmonary inflammatory responses.


Reproduction of consistent pulse-waveform changes using a computational model of the cerebral circulatory system.
Due to the inaccessibility of the cranial vault, it is difficult to study cerebral blood flow dynamics directly. A mathematical model can be useful to study these dynamics. The model presented here is a novel combination of a one-dimensional fluid flow model representing the major vessels of the circle of Willis (CoW), with six individually parameterized auto-regulatory models of the distal vascular beds. This model has the unique ability to simulate high temporal resolution flow and velocity waveforms, amenable to pulse-waveform analysis, as well as sophisticated phenomena such as auto-regulation. Previous work with human patients has shown that vasodilation induced by CO2 inhalation causes 12 consistent pulse-waveform changes as measured by the morphological clustering and analysis of intracranial pressure algorithm. To validate this model, we simulated vasodilation and successfully reproduced 9 out of the 12 pulse-waveform changes. A subsequent sensitivity analysis found that these 12 pulse-waveform changes were most affected by the parameters associated with the shape of the smooth muscle tension response and vessel elasticity, providing insight into the physiological mechanisms responsible for observed changes in the pulse-waveform shape.


Serum amyloid A protein concentration in bone marrow transplantation for beta thalassaemia.
To investigate whether serum amyloid A protein (SAA) and C-reactive protein (CRP) concentrations could be used in the management of beta thalassaemic patients undergoing bone marrow transplantation (BMT). Serum SAA and CRP concentrations were determined in paired samples from 66 patients with beta thalassaemia before and after BMT. Serum SAA concentrations were determined by an enzyme linked immunoassay (EIA); serum CRP concentrations were determined by a nephelometric assay. Serum SAA concentrations before transplantation were significantly higher in the group that subsequently rejected the transplant than the group without complications. SAA concentrations increased after BMT in acute graft versus host disease (GvHD) and rejection. No significant increase in SAA or CRP was found in chronic GvHD. Increases in serum in SAA and CRP concentrations were not related to concomitant infection episodes. The different acute phase response in acute GvHD and rejection compared with chronic GvHD suggests that different immunopathogenic mechanisms are responsible.


A Framework for Outpatient Infusion of Antispike Monoclonal Antibodies to High-Risk Patients with Mild-to-Moderate Coronavirus Disease-19: The Mayo Clinic Model.
The administration of spike monoclonal antibody treatment to patients with mild to moderate COVID-19 is very challenging. This article summarizes essential components and processes in establishing an effective spike monoclonal antibody infusion program. Rapid identification of a dedicated physical infrastructure was essential to circumvent the logistical challenges of caring for infectious patients while maintaining compliance with regulations and ensuring the safety of our personnel and other patients. Our partnerships and collaborations among multiple different specialties and disciplines enabled contributions from personnel with specific expertise in medicine, nursing, pharmacy, infection prevention and control, electronic health record (EHR) informatics, compliance, legal, medical ethics, engineering, administration, and other critical areas. Clear communication and a culture in which all roles are welcomed at the planning and operational tables are critical to the rapid development and refinement needed to adapt and thrive in providing this time-sensitive beneficial therapy. Our partnerships with leaders and providers outside our institutions, including those who care for underserved populations, have promoted equity in the access of monoclonal antibodies in our regions. Strong support from institutional leadership facilitated expedited action when needed, from a physical, personnel, and system infrastructure standpoint. Our ongoing real-time assessment and monitoring of our clinical program allowed us to improve and optimize our processes to ensure that the needs of our patients with COVID-19 in the outpatient setting are met.


Preliminary results of colour Doppler-guided intratendinous glucocorticoid injection for Achilles tendonitis in five patients.
It is debated as to whether Achilles tendonitis (AT) has an inflammatory component. The intratendinous hyperaemia demonstrated with colour Doppler has been interpreted as neovascularisation. Glucocorticoid injection around the tendon is a common therapeutic procedure. The intratendinous hyperaemia seen with ultrasound (US) colour Doppler represents an inflammatory background. Glucocorticoid injections will be effective if administered inside the tendon where the inflammation seems to be. An uncontrolled, prospective study with a minimum follow-up of 3 months. Six tendons in five patients were evaluated with grey-scale US and colour Doppler before and after US-guided intratendinous glucocorticoid injection. Pain at rest and at activity was evaluated on a visual analogue scale. With colour Doppler all tendons had intratendinous flow. Pain and colour Doppler activity decreased during a mean follow-up of 182 days (range 92-309 days). One tendon relapsed after 199 days. Intratendinous glucocorticoid injections seem to have a marked effect on both symptoms and colour Doppler findings, which may be taken as an indication of an inflammatory component in the disease. Colour Doppler adds significant information to grey-scale US with regard to diagnosis, location and follow-up of AT.


Leu-M1 antigen expression in advanced (tumor) stage mycosis fungoides.
The authors describe two patients with clinically and histopathologically documented advanced (tumor) stage mycosis fungoides. In each case the large, pleomorphic neoplastic cells lacked the monoclonal antibody-defined cell surface antigens commonly associated with immature and mature T-cells, i.e., T11, Leu-1, T3, T4, T6, T8, and T10, but expressed various T-cell-associated activation antigens, such as HLA-DR, Tac, and T21. Leu-M1, a monocyte-associated antigen, was not expressed by the small, cerebriform neoplastic cells in the plaque stage lesions of either patient. However, Leu-M1 was expressed by most of the large, pleomorphic neoplastic cells present in the nodular lesions of both patients. The pattern of Leu-M1 antigen expression was identical to that previously reported in the Reed-Sternberg cells of Hodgkin's disease. Identification of these two patients suggests using caution in the interpretation of the results of immunophenotypic analysis of cutaneous lymphoid neoplasms and that Leu-M1 should not be used as a diagnostic indicator of Hodgkin's disease or a histiocytic-derived neoplasm. These studies also suggest that Leu-M1 may be preferentially expressed on a subpopulation of activated, rapidly proliferating, and/or dedifferentiated neoplastic T-cells that proliferate in the advanced (tumor) stages of mycosis fungoides.


A broken, O-shaped catheter during coronary angiography: Percutaneous retrieval via femoral approach using a wire-balloon technique.
Entrapment of equipment during coronary angiography is an uncommon but serious complication of invasive coronary procedures. Percutaneous extraction of trapped material is the accepted method of treatment. This case report is a description of the extraction of a diagnostic catheter retained as a result of collapsing into an O-shape in the right common iliac artery while trying to engage the tip of the catheter with the right coronary ostium. This rationale and unique wire-balloon method, requiring no specifically designed device, can be simply and safely performed in similar cases.


Spatio-temporal dynamics of impulse responses to figure motion in optic flow neurons.
White noise techniques have been used widely to investigate sensory systems in both vertebrates and invertebrates. White noise stimuli are powerful in their ability to rapidly generate data that help the experimenter decipher the spatio-temporal dynamics of neural and behavioral responses. One type of white noise stimuli, maximal length shift register sequences (m-sequences), have recently become particularly popular for extracting response kernels in insect motion vision. We here use such m-sequences to extract the impulse responses to figure motion in hoverfly lobula plate tangential cells (LPTCs). Figure motion is behaviorally important and many visually guided animals orient towards salient features in the surround. We show that LPTCs respond robustly to figure motion in the receptive field. The impulse response is scaled down in amplitude when the figure size is reduced, but its time course remains unaltered. However, a low contrast stimulus generates a slower response with a significantly longer time-to-peak and half-width. Impulse responses in females have a slower time-to-peak than males, but are otherwise similar. Finally we show that the shapes of the impulse response to a figure and a widefield stimulus are very similar, suggesting that the figure response could be coded by the same input as the widefield response.


Androidal fat dominates in predicting cardiometabolic risk in postmenopausal women.
We hypothesized that soy isoflavones would attenuate the anticipated increase in androidal fat mass in postmenopausal women during the 36-month treatment, and thereby favorably modify the circulating cardiometabolic risk factors: triacylglycerol, LDL-C, HDL-C, glucose, insulin, uric acid, C-reactive protein, fibrinogen, and homocysteine. We collected data on 224 healthy postmenopausal women at risk for osteoporosis (45.8-65 y, median BMI 24.5) who consumed placebo or soy isoflavones (80 or 120 mg/d) for 36 months and used longitudinal analysis to examine the contribution of isoflavone treatment, androidal fat mass, other biologic factors, and dietary quality to cardiometabolic outcomes. Except for homocysteine, each cardiometabolic outcome model was significant (overall P-values from ≤.0001 to .0028). Androidal fat mass was typically the strongest covariate in each model. Isoflavone treatment did not influence any of the outcomes. Thus, androidal fat mass, but not isoflavonetreatment, is likely to alter the cardiometabolic profile in healthy postmenopausal women.


Seasonal and biogeographical patterns of gastrointestinal parasites in large carnivores: wolves in a coastal archipelago.
Parasites are increasingly recognized for their profound influences on individual, population and ecosystem health. We provide the first report of gastrointestinal parasites in gray wolves from the central and north coasts of British Columbia, Canada. Across 60 000 km(2), wolf feces were collected from 34 packs in 2005-2008. At a smaller spatial scale (3300 km(2)), 8 packs were sampled in spring and autumn. Parasite eggs, larvae, and cysts were identified using standard flotation techniques and morphology. A subset of samples was analysed by PCR and sequencing to identify tapeworm eggs (n=9) and Giardia cysts (n=14). We detected ≥14 parasite taxa in 1558 fecal samples. Sarcocystis sporocysts occurred most frequently in feces (43·7%), followed by taeniid eggs (23·9%), Diphyllobothrium eggs (9·1%), Giardia cysts (6·8%), Toxocara canis eggs (2·1%), and Cryptosporidium oocysts (1·7%). Other parasites occurred in ≤1% of feces. Genetic analyses revealed Echinococcus canadensis strains G8 and G10, Taenia ovis krabbei, Diphyllobothrium nehonkaiense, and Giardia duodenalis assemblages A and B. Parasite prevalence differed between seasons and island/mainland sites. Patterns in parasite prevalence reflect seasonal and spatial resource use by wolves and wolf-salmon associations. These data provide a unique, extensive and solid baseline for monitoring parasite community structure in relation to environmental change.


PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells.
Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression.


Linked Mutations in the Ebola Virus Polymerase Are Associated with Organ Specific Phenotypes.
Ebola virus (EBOV) causes a severe infection called Ebola virus disease (EVD). The pathogenesis of EBOV infection is complex, and outcome has been associated with a variety of immunological and cellular factors. Disease can result from several mechanisms, including direct organ and endothelial cell damage as a result of viral replication. During the2013 to 2016 Western Africa EBOV outbreak, several mutants emerged, with changes in the genes of nucleoprotein (NP), glycoprotein (GP), and the large (L) protein. Reverse genetic analysis has been used to investigate whether these mutations played any role in pathogenesis with mixed results depending on the experimental system used. Previous studies investigated the impact of three single nonsynonymous mutations (GP-A82V, NP-R111C, and L-D759G) on the fatality rate of mouse and ferret models and suggested that the L-D759G mutation decreased the virulence of EBOV. In this study, the effect of these three mutations was further evaluated by deep sequencing to determine viral population genetics and the host response in longitudinal samples of blood, liver, kidney, spleen, and lung tissues taken from the previous ferret model. The data indicated that the mutations were maintained in the different tissues, but the frequency of minor genomic mutations were different. In addition, compared to wild-type virus, the recombinant mutants had different within host effects, where the D759G (and accompanying Q986H) substitution in the L protein resulted in an upregulation of the immune response in the kidney, liver, spleen, and lungs. Together these studies provide insights into the biology of EBOV mutants both between and within hosts. IMPORTANCE Ebola virus infection can have dramatic effects on the human body which manifest in Ebola virus disease. The outcome of infection is either survival or death and in the former group with the potential of longer-term health consequences and persistent infection. Disease severity is undoubtedly associated with the host response, often with overt inflammatory responses correlated with poorer outcomes. The scale of the2013 to 2016 Western African Ebola virus outbreak revealed new aspects of viral biology. This included the emergence of mutants with potentially altered virulence. Biobanked tissue from ferret models of EBOV infected with different mutants that emerged in the Western Africa outbreak was used to investigate the effect of EBOV genomic variation in different tissues. Overall, the work provided insights into the population genetics of EBOV and showed that different organs in an animal model can respond differently to variants of EBOV.


Postnatal corticosteroids for prevention and treatment of chronic lung disease in the preterm newborn.
Despite significant progress in the treatment of preterm neonates, bronchopulmonary dysplasia (BPD) continues to be a major cause of neonatal morbidity. Affected infants suffered from long-term pulmonary and nonpulmonary sequel. The pulmonary sequels include reactive airway disease and asthma during childhood and adolescence. Nonpulmonary sequels include poor coordination and muscle tone, difficulty in walking, vision and hearing problems, delayed cognitive development, and poor academic achievement. As inflammation seems to be a primary mediator of injury in pathogenesis of BPD, role of steroids as antiinflammatory agent has been extensively studied and proven to be efficacious in management. However, evidence is insufficient to make a recommendation regarding other glucocorticoid doses and preparations. Numerous studies have been performed to investigate the effects of steroid. The purpose of this paper is to evaluate these studies in order to elucidate the beneficial and harmful effects of steroid on the prevention and treatment of BPD.


Food switching by two specialized algae-scraping cichlid fishes in Lake Malawi, Africa.
Two cichlid species morphological specialized for scraping algae were observed in Lake Malawi also to feed extensively upon zooplankton, phytoplankton, detritus, fish fry and fish eggs. These field observations confirm laboratory studies that cichlids are facultative in their feeding repertoire. Such an ability contributes to the success of the family Cichlidae. We hypothesize that the morphological specializations become critically important when food resources are low and effective cropping is required.


Hordeum chilense genome, a useful tool to investigate the endosperm yellow pigment content in the Triticeae.
The wild barley Hordeum chilense fulfills some requirements for being a useful tool to investigate the endosperm yellow pigment content (YPC) in the Triticeae including its diploid constitution, the availability of genetic resources (addition and deletion stocks and a high density genetic map) and, especially, its high seed YPC not silenced in tritordeums (amphiploids derived from H. chilense and wheat). Thus, the aim of this work was to test the utility of the H. chilense genome for investigating the YPC in the Triticeae. Twelve genes related to endosperm carotenoid content and/or YPC in grasses (Dxr, Hdr [synonym ispH], Ggpps1, Psy2, Psy3, Pds, Zds, e-Lcy, b-Lcy, Hyd3, Ccd1 and Ppo1) were identified, and mapped in H. chilense using rice genes to identify orthologs from barley, wheat, sorghum and maize. Macrocolinearity studies revealed that gene positions were in agreement in H. vulgare and H. chilense. Additionally, three main regions associated with YPC were identified in chromosomes 2Hch, 3Hch and 7Hch in H. chilense, the former being the most significant one. The results obtained are consistent with previous findings in wheat and suggest that Ggpps1, Zds and Hyd3 on chromosome 2Hch may be considered candidate genes in wheat for further studies in YPC improvement. Considering the syntenic location of carotenoid genes in H. chilense, we have concluded that the Hch genome may constitute a valuable tool for YPC studies in the Triticeae.


"Pictures don't lie, seeing is believing": exploring attitudes to the introduction of pictorial warnings on cigarette packs in Ghana.
To compare perceptions of text and pictorial warning labels on cigarette packs among Ghanaian smokers and nonsmokers and to explore their views on the introduction of pictorial warnings in Ghana. Qualitative study involving 12 focus group discussions with 50 smokers and 35 nonsmokers aged 15 years and older in Kumasi, Ghana. Semistructured discussion guides along with visual discussant aids were used to explore the perception, acceptance, and potential use of pictorial warning labels in Ghana. Health warnings combining text and a picture were perceived by both smokers and nonsmokers to communicate health messages more effectively than text-only or picture-only warnings. The effect of text-only warnings was considered limited by low levels of literacy and by the common practice of single stick sales rather than sales of packs. Of the 6 health warnings tested, lung cancer, blindness, stroke, and throat/mouth cancer messages were perceived to have the most impact on smoking behavior, including uptake and quit attempts. Warning labels combining pictures and text have the potential to reduce smoking uptake, increase quit attempts, and reduce smoking appeal among smokers and nonsmokers in Ghana. Measures to prevent single stick sales, or to promote health messages to purchasers of single sticks, are required.


Comprehension of prosody in Huntington's disease.
Patients with Huntington's Disease (HD) who were without dementia were compared to unilateral stroke patients and controls as previously reported in 1983, to discover if they had a prosodic defect. Subjects were presented tape-recorded speech filtered sentences and asked to indicate the tone of voice as happy, sad or angry (affective prosody), or as a question, command or statement (propositional prosody). HD patients were impaired in comprehension of both types of prosody compared to controls but were not different from stroke patients. A second study compared early HD patients with at-risk siblings and spouse controls on comprehension of affective and propositional prosody, discrimination of both types of prosody, rhythm discrimination and tonal memory (Seashore tests). HD patients were impaired in both comprehension and discrimination of all types of prosody. HD patients were less accurate than at-risk patients on the tonal memory task but not on the rhythm discrimination task. These findings suggest compromise in ability to understand the more subtle prosodic aspects of communication which may contribute to social impairment of HD patients very early in the course of the disease.


Duality of liver and kidney lesions after systemic infection of immunosuppressed and immunocompetent mice with Aspergillus fumigatus.
Invasive aspergillosis is a life-threatening disease mainly caused by Aspergillus fumigatus. Patients at risk are generally immunocompromised and lungs are assumed to provide the primary site for infection and invasive disease manifestation. Contrarily, visceral organ involvement appears to result from a subsequent hematogenous spread. To compare the kinetics of dissemination within deep organs in immunosuppressed vs. immunocompetent mice, we used a bioluminescent A. fumigatus strain in an intravenous infection model. By applying an immunosuppressive regimen with corticosteroids, dissemination to the liver and kidneys was observed already 24 h after inoculation accompanied by a marked inflammatory response within the liver. In contrast, in the immunocompetent condition, fungal growth and inflammation were mainly restricted to the kidneys and only small amounts of fungal biomass and a weak inflammatory response were detected in the liver. Additionally, disease progressed much slower compared with the immunosuppressed condition. This is the first study underlying the duality between liver and renal tropism of A. fumigatus in relation to the immune status of the host.


Subcellular localization of the coat protein in tobacco cells infected by cucumber mosaic virus isolated from Catharanthus roseus.
Electron microscopy and immunolabelling with antiserum specific to cucumber mosaic virus coat protein were used to examine tobacco leaf cells infected by cucumber mosaic virus isolated from Catharanthus roseus (CMV-Cr). Crystalline and amorphous inclusions in the vacuoles were the most obvious cytological modifications seen. Immunogold labelling indicated that the crystalline inclusion was made up of virus particles and amorphous inclusions contained coat protein. Rows of CMV-Cr particles were found between membranes of dictyosomes, but membranous bodies and tonoplast-associated vesicles were not evident. Virus particles and/or free coat protein were easily detected in the cytoplasm by immunolabelling. No gold labelling was found within nuclei, chloroplasts and mitochondria.


TBCRC 032 IB/II Multicenter Study: Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients with AR+ Metastatic Triple-Negative Breast Cancer.
Preclinical data demonstrating androgen receptor (AR)-positive (AR+) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR+ (≥10%) breast cancer. Phase Ib patients [estrogen receptor positive (ER+) or TNBC] with AR+ breast cancer received 160 mg enzalutamide in combination with taselisib to determine dose-limiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clinical benefit rate (CBR) at 16 weeks. The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, P = 0.06), and increased PFS (4.6 vs. 2.0 months, P = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel FGFR2 fusions and AR splice variants. The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR+ tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists.


Plant extracellular matrix metalloproteinases.
The plant extracellular matrix (ECM) includes a variety of proteins with critical roles in the regulation of plant growth, development, and responses to pests and pathogens. Several studies have shown that various ECM proteins undergo proteolytic modification. In mammals, the extracellular matrix metalloproteinases (MMPs) are known modifiers of the ECM, implicated in tissue architecture changes and the release of biologically active and/or signalling molecules. Although plant MMPs have been identified, little is known about their activity and function. Plant MMPs show structural similarity to mammalian MMPs, including the presence of an auto-regulatory cysteine switch domain and a zinc-binding catalytic domain. Plant MMPs are differentially expressed in cells and tissues during plant growth and development, as well as in response to several biotic and abiotic stresses. The few gene expression and mutant analyses to date indicate their involvement in plant growth, morphogenesis, senescence and adaptation and response to stress. In order to gain a further understanding of their function, an analysis and characterisation of MMP proteins, their activity and their substrates during plant growth and development are still required. This review describes plant MMP work to date, as well as the variety of genomic and proteomic methodologies available to characterise plant MMP activity, function and potential substrates.


Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR.
Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC. We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B. Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform.


Lateralization of event-related beta desynchronization in the EEG during pre-cued reaction time tasks.
Here, we investigate whether the event-related desynchronization (ERD) of spectral components of the cortical EEG in the beta (13-30 Hz) frequency range may, in part, index motor selection processes. Specifically, we sought evidence for a contralaterally dominant component of the beta ERD that is limited to trials in which motor selection is possible prior to any imperative cue to move, with attendant behavioural advantage. We measured reaction time and assessed the lateralization of beta ERD in 12 healthy volunteers as they performed pre-cued choice reaction time tasks, in which warning S1 cues were either fully predictive about the laterality of a subsequent imperative S2 signal or provided no laterality information. We calculated 'lateralized ERD index' (LERDI), a parallel measure to the lateralized readiness potential in the time domain. Trials with 100% S1-S2 congruency produced significantly shorter reaction times than trials with 50% S1-S2 congruency, where laterality information was unreliable. Beta LERDI indicated significantly greater lateralisation of the ERD in the warning-go interval and of event-related synchronization (ERS) following movement in the 100% condition than in the 50% condition. The lateralization of the beta ERD with respect to hand persisted, even when subjects were instructed to make movements of opposite laterality to those prompted. Lateralized EEG changes occur in the beta band in the S1-S2 interval prior to movement, but only when informative warning cues allow early motor selection, as suggested by the shortening of reaction time. Furthermore, the enhanced contralateral ERS with 100% S1-S2 congruency suggests that this phenomenon is at least partly independent of afferent feedback, as the same movement was made in the 100 and 50% conditions. Lateralized suppression of beta power prior to externally generated movements is associated with motor selection.


Characterization of damage mechanisms associated with reference point indentation in human bone.
Measurement of bone mineral density (BMD) is the clinical gold standard in cases of compromised skeletal integrity, such as with osteoporosis. While BMD is a useful measurement to index skeletal health, it is also limited since it cannot directly assess any mechanical properties. The ability to directly assess mechanical properties of bone tissue would be clinically important. Reference point indentation (RPI) is a technology that has been designed to try and achieve this goal. While RPI has been shown to detect altered bone tissue properties, the underlying physical mechanism of these measurements has not been characterized. Thus, we designed a study whereby the contribution of (1) test cycle number and (2) test load level to RPI test-induced sub-surface damage was characterized and quantified. Standardized specimens were prepared from cadaveric human tibiae (n=6), such that 12 replicates of each testing condition could be carried out. A custom rig was fabricated to accurately position and map indentation sites. One set of tests was carried out with 1, 5, 10, 15 and 20 cycles (Max Load: 8 N, Freq: 2 Hz), and a second set of tests was carried out with Load levels of 2, 4, 6, 8 or 10 N (Cycle number: 20, Freq: 2 Hz). The RPI parameter Loading Slope (LS) was cycle dependent at 5, 10, 15 and 20 cycles (p<0.05). First Cycle Indentation Distance (ID 1st), Total Indentation Distance (TID), Mean Energy Dissipation (ED), First Cycle Unloading Slope (US 1st), Mean Unloading Slope (US) and LS were significantly different at 6, 8 and 10 N compared to 2 N (p<0.05). From the histomorphometric measurements, damage zone span was significantly different after 5, 10, 15 and 20 cycles compared with 1 cycle while indent profile width and indent profile depth were significantly different at 10, 15 and 20 cycles (p<0.05). With the load varying protocol, each of these parameters differed significantly at each increased load level (4, 6, 8, 10 N) compared with the basal level of 2 N (p<0.05). The damage area parameter in both protocols was significantly different from baseline at the three upper levels tested (i.e. 10, 15, 20 cycles and 6, 8, 10 N, in cycle and load variant protocols, respectively). Specimens were scanned by micro-computed tomography, which showed no material or microstructural differences between samples, and processed for histological analyses and damage quantification. Consistent microdamage patterns were present with evidence of damage via compaction at the indented regions. While damage in the direction of loading was established early, the damage area then increased radially with cycle number. These data help to further understand the physical manifestations of RPI parameters and will help to further facilitate its use as a clinical diagnostic tool.


Drug-loaded nanobubbles for ultrasound-mediated antitumor treatment.
Polylactic acid (PLA) bubbles that can act both as ultrasound contrast agents and drug carriers have the disadvantage of low encapsulation efficiency and do not allow effective extravasation into the tumor tissue. In this regard, PLA and lecithin are considered drug carriers. The present study used a modified ultrasonic double emulsion-solvent evaporation technology in order to prepare paclitaxel-loaded PLA-lecithin nanobubbles. X-ray diffraction analysis (XRD) was used to investigate the state of the drug in the bubbles, whereas the tumor weight and the inhibition rate of tumor bearing mice in the ultrasound-mediated function were further examined. The results indicated that the nanobubbles prepared with a mass ratio of PLA and lecithin at 50:250 were characterized as inner hollow. The size of these particles was approximately 615 nm, and the drug loading and encapsulation reached 8.34±0.67% and 91.42±5.48%, respectively. Paclitaxel was distributed in the shell of the bubbles in an amorphous state, and the in vitro drug release was characterized by sustained release, zero release and ultrasound mediated drug release. The injection of H22 hematoma-bearing mice with ultrasound-mediated drug-loaded PLA-lecithin nano-scaled bubbles could reduce the toxicity and increase the antitumor efficacy compared with paclitaxel.


Effect of oilseed type on milk fatty acid composition of individual cows, and also bulk tank milk fatty acid composition from commercial farms.
Supplementing dairy cow diets with oilseed preparations has been shown to replace milk saturated fatty acids (SFA) with mono- and/or polyunsaturated fatty acids (MUFA, PUFA), which may reduce risk factors associated with cardio-metabolic diseases in humans consuming milk and dairy products. Previous studies demonstrating this are largely detailed, highly controlled experiments involving small numbers of animals, but in order to transfer this feeding strategy to commercial situations further studies are required involving whole herds varying in management practices. In experiment 1, three oilseed supplements (extruded linseed (EL), calcium salts of palm and linseed oil (CPLO) and milled rapeseed (MR)) were included in grass silage-based diets formulated to provide cows with ~350 g oil/day, and compared with a negative control (Control) diet containing no supplemental fat, and a positive control diet containing 350 g/cow per day oil as calcium salt of palm oil distillate (CPO). Diets were fed for 28-day periods in a 5×4 Latin Square design, and milk production, composition and fatty acid (FA) profile were analysed at the end of each period. Compared with Control, all lipid supplemented diets decreased milk fat SFA concentration by an average of 3.5 g/100 g FA, by replacement with both cis- and trans-MUFA/PUFA. Compared with CPO, only CPLO and MR resulted in lower milk SFA concentrations. In experiment 2, 24 commercial dairy farms (average herd size±SEM 191±19.3) from the south west of the United Kingdom were recruited and for a 1 month period asked to supplement their herd diets with either CPO, EL, CPLO or MR at the same inclusion level as the first study. Bulk tank milk was analysed weekly to determine FA concentration by Fourier Transform mid-IR spectroscopy prediction. After 4 weeks, EL, CPLO and MR all decreased herd milk SFA and increased MUFA to a similar extent (average -3.4 and +2.4 g/100 g FA, respectively) when compared with CPO. Differing responses observed between experiments 1 and 2 may be due in part to variations in farm management conditions (including basal diet) in experiment 2. This study demonstrates the importance of applying experimental research into commercial practice where variations in background conditions can augment different effects to those obtained under controlled conditions.


Mathematical modelling in tobacco control research: protocol for a systematic review.
Tobacco control researchers have recently become more interested in systems science methods and mathematical modelling techniques as a means to understand how complex inter-relationships among various factors translate into population-level summaries of tobacco use prevalence and its associated medical and social costs. However, there is currently no resource that provides an overview of how mathematical modelling has been used in tobacco control research. This review will provide a summary of studies that employ modelling techniques to predict tobacco-related outcomes. It will also propose a conceptual framework for grouping existing modelling studies by their objectives. We will conduct a systematic review that is informed by Cochrane procedures, as well as guidelines developed for reviews that are specifically intended to inform policy and programme decision-making. We will search 5 electronic databases to identify studies that use a mathematical model to project a tobacco-related outcome. An online data extraction form will be developed based on the ISPOR-SMDM Modeling Good Research Practices. We will perform a qualitative synthesis of included studies. Ethical approval is not required for this study. An initial paper, published in a peer-reviewed journal, will provide an overview of our findings. Subsequent papers will provide greater detail on results within each study objective category and an assessment of the risk of bias of these grouped studies.


Maintained deep brain stimulation for severe dystonia despite infection by using externalized electrodes and an extracorporeal pulse generator.
Infection in the context of implant surgery is a dreaded complication, usually necessitating the removal of all affected hardware. Severe dystonia is a debilitating condition that can present as an emergency and can occasionally be life threatening. The authors present 2 cases of severe dystonia in which deep brain stimulation was maintained despite the presence of infection, using ongoing stimulation by externalization of electrode wires and an extracorporeal pulse generator. This allowed the infection to clear and wounds to heal while maintaining stimulation. This strategy is similar to that used in the management of infected cardiac pacemakers. The authors suggest that this prolonged extracorporeal stimulation should be considered by neurosurgeons in the face of this difficult clinical situation.


Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials.
Highly emetogenic chemotherapy induces emesis in almost all patients in the absence of prophylaxis. Guidelines recommend use of a neurokinin-1 (NK-1) receptor antagonist in conjunction with a 5-HT3 receptor antagonist and corticosteroid in patients receiving highly emetogenic chemotherapy. We aimed to assess rolapitant, an NK-1 receptor antagonist, for prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of cisplatin-based highly emetogenic chemotherapy. We conducted two global, randomised, double-blind, active-controlled, phase 3 trials (HEC-1 and HEC-2) at 155 cancer centres (76 in HEC-1 and 79 in HEC-2) in 26 countries (17 in HEC-1 and 14 in HEC-2). We enrolled patients with cancer aged 18 years or older, who had not previously been treated with cisplatin, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly assign patients to treatment. Patients were stratified by sex and randomly allocated to either oral rolapitant (180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) about 1-2 h before administration of highly emetogenic chemotherapy. All patients received granisetron (10 μg/kg intravenously) and dexamethasone (20 mg orally) on day 1, and dexamethasone (8 mg orally) twice daily on days 2-4. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients were allowed to receive the same study drug they were assigned in cycle 1, unless removed at the clinician's discretion. Patients could also choose to leave the study at any point. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a cancer centre compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (no emesis or use of rescue medication) in the delayed phase (>24-120 h after initiation of chemotherapy) in cycle 1. These studies are registered with ClinicalTrials.gov, numbers NCT01499849 and NCT01500213. Both studies have been completed. Between Feb 21, 2012, and March 12, 2014, 532 patients in HEC-1 and 555 patients in HEC-2 were randomly assigned to treatment. 526 patients in HEC-1 (264 rolapitant and 262 active control) and 544 in HEC-2 (271 rolapitant and 273 active control) received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients in the rolapitant group had complete responses in the delayed phase than did patients in the active control group (HEC-1: 192 [73%] vs 153 [58%]; odds ratio 1·9, 95% CI 1·3-2·7; p=0·0006; HEC-2: 190 [70%] vs 169 [62%]; 1·4, 1·0-2·1; p=0·0426; pooled studies: 382 [71%] vs 322 [60%]; 1·6, 1·3-2·1; p=0·0001). The incidence of adverse events was similar across treatment groups. The most commonly reported treatment-related treatment-emergent adverse events in the rolapitant versus active control groups were headache (three [<1%] vs two [<1%]), hiccups (three [<1%] vs four [<1%]), constipation (two [<1%] vs three [<1%]), and dyspepsia (two [<1%] vs three [<1%]). For cycle 1, the most common grade 3-5 adverse events in patients allocated rolapitant versus active control were neutropenia (HEC-1: nine [3%] vs 14 [5%]; HEC-2: 16 [6%] vs 14 [5%]), anaemia (HEC-1: one [<1%] vs one [<1%]; HEC-2: seven [3%] vs two [<1%]), and leucopenia (HEC-1: six [2%] vs two [<1%]; HEC-2: two [<1%] vs two [<1%]). No serious treatment-emergent adverse events were treatment related, and no treatment-related treatment-emergent adverse events resulted in death. Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well-tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the at-risk period (120 h) after administration of highly emetogenic cisplatin-based chemotherapy. TESARO, Inc.


Comparing the effectiveness of small-particle versus large-particle inhaled corticosteroid in COPD.
Small airway changes and dysfunction contribute importantly to airway obstruction in chronic obstructive pulmonary disease (COPD), which is currently treated with inhaled corticosteroids (ICS) and long-acting bronchodilators at Global initiative for Obstructive Lung Disease (GOLD) grades 2-4. This retrospective matched cohort analysis compared effectiveness of a representative small-particle ICS (extrafine beclomethasone) and larger-particle ICS (fluticasone) in primary care patients with COPD. Smokers and ex-smokers with COPD ≥ 40 years old initiating or stepping-up their dose of extrafine beclomethasone or fluticasone were matched 1:1 for demographic characteristics, index prescription year, concomitant therapies, and disease severity during 1 baseline year. During 2 subsequent years, we evaluated treatment change and COPD exacerbations, defined as emergency care/hospitalization for COPD, acute oral corticosteroids, or antibiotics for lower respiratory tract infection. Mean patient age was 67 years, 57%-60% being male. For both initiation (n=334:334) and step-up (n=189:189) patients, exacerbation rates were comparable between extrafine beclomethasone and fluticasone cohorts during the 2 year outcome period. Odds of treatment stability (no exacerbation or treatment change) were significantly greater for patients initiating extrafine beclomethasone compared with fluticasone (adjusted odds ratio 2.50; 95% confidence interval, 1.32-4.73). Median ICS dose exposure during 2 outcome years was significantly lower (P<0.001) for extrafine beclomethasone than fluticasone cohorts (315 μg/day versus 436 μg/day for initiation, 438 μg/day versus 534 μg/day for step-up patients). We observed that small-particle ICS at significantly lower doses had comparable effects on exacerbation rates as larger-particle ICS at higher doses, whereas initiation of small-particle ICS was associated with better odds of treatment stability during 2-years' follow-up.


Longevity and developmental stability in the dung fly Sepsis cynipsea, as affected by the ectoparasitic mite, Pediculoides mesembrinae.
Fluctuating asymmetry (FA) is a widely employed measure of developmental stability. It has been found to increase with many stressors including parasite infection. Associations between parasites and FA may exist for several reasons in addition to parasites being the direct cause of increased FA. Developmentally stable individuals may have superior immune systems, and be less susceptible to parasite infection, and/or may be less exposed to parasites than developmentally unstable ones. Mites negatively impact host fitness in a number of insects, and if FA is a reflection of general genetic quality, as has been proposed, associations between mite number and FA are predicted. Potential relationships were investigated between an ectoparasitic mite, Pediculoides mesembrinae (Canestrini) (Phthiraptera: Menoponidae) and FA in the common dung fly Sepsis cynipsea (L.) (Diptera: Sepsidae). While it was found that mite infested flies died much faster than flies without mites, indicating that mites indeed stress their hosts, counter to expectations, no associations between mites and FA were found in any analyses. Additionally, FA in mite-infected flies generally did not differ from previously published FA data from uninfected S. cynipsea. Nevertheless, parasitized males tended to be somewhat less asymmetrical than non-parasitized males, but based on our data, it does not appear that mite infestation is generally associated with developmental stability in S. cynipsea.


A Potential Complication of COVID-19: A Case of Non-Traumatic Rhabdomyolisis.
Rhabdomyolysis can present as a clinical challenge due to broad etiological spectrum, non-specific symptomatology and numerous systemic complications including acute kidney injury. Emerging evidence suggests that rhabdomyolysis may be an associated early or late complication of coronavirus disease 2019 (COVID-19) infection. We present a case of a 55-year-old woman with recent COVID-19 pneumonia who was later found to have non-traumatic rhabdomyolysis incidentally captured on COVID-19 screening labs.


Fuzzy rank LUM filters.
The rank information of samples is widely utilized in nonlinear signal processing algorithms. Recently developed fuzzy transformation theory introduces the concept of fuzzy ranks, which incorporates sample spread (or sample diversity) information into the sample ranking framework. Thus, the fuzzy rank reflects a sample's rank, as well as its similarity to the other sample (namely, joint rank order and spread), and can be utilized to improve the performance of the conventional rank-order-based filters. In this paper, the well-known lower-upper-middle (LUM) filters are generalized utilizing the fuzzy ranks, yielding the class of fuzzy rank LUM (F-LUM) filters. Statistical and deterministic properties of the F-LUM filters are derived, showing that the F-LUM smoothers have similar impulsive noise removal capability to the LUM smoothers, while preserving the image details better. The F-LUM sharpeners are capable of enhancing strong edges while simultaneously preserving small variations. The performance of the F-LUM filters are evaluated for the problems of image impulsive noise removal, sharpening and edge-detection preprocessing. The experimental results show that the F-LUM smoothers can achieve a better tradeoff between noise removal and detail preservation than the LUM smoothers. The F-LUM sharpeners are capable of sharpening the image edges without amplifying the noise or distorting the fine details. The joint smoothing and sharpening operation of the general F-LUM filters also showed superiority in edge detection preprocessing application. In conclusion, the simplicity and versatility of the F-LUM filters and their advantages over the conventional LUM filters are desirable in many practical applications. This also shows that utilizing fuzzy ranks in filter generalization is a promising methodology.


Enhanced Patient Involvement and the Need to Revise the Core Set - Report from the Psoriatic Arthritis Working Group at OMERACT 2014.
To discuss the need for revision of the "core set" of domains to be included for assessment in psoriatic arthritis (PsA) randomized controlled trials and longitudinal observational studies, review work undertaken since the 2012 meeting of Outcome Measures for Rheumatology 11 (OMERACT 11) to include patient perspectives in this revision, and reassess proposed composite measures in the context of new research data and the OMERACT Filter 2.0 framework. The OMERACT 12 (2014) PsA working group presented work completed over the last 2 years to incorporate patient involvement in PsA outcomes research, review the endorsed PsA core set based on the patient perspective as well as new research findings, and further develop PsA responder indices. Breakout groups then discussed 2 topics: (1) the need to revise the PsA core set, and opportunities to add, move, or merge existing domains to improve existing redundancy; and (2) how to incorporate the core set in a composite index. Breakout groups fed back to the working group before participant voting. Meeting participants endorsed the need to revise the PsA core set according to the OMERACT Filter 2.0 framework (100%), and the inclusion of disease impact (94%) and fatigue (72%) in the inner circle. Breakout group feedback suggested the core set revision was an opportunity to consolidate pathophysiologic aspects such as arthritis, enthesitis, dactylitis, spondylitis as "inflammatory musculoskeletal disease," and nail and skin psoriasis as "psoriasis activity." Future work will focus on updating the PsA core set and development of responder indices with ongoing, meaningful involvement of patient research partners.


Isokinetic strength, endurance, and subjective outcomes after biceps tenotomy versus tenodesis: a postoperative study.
Similar subjective outcomes have been reported for tenotomy or tenodesis of the long head of the biceps. Few studies have reported on postoperative strength and endurance. Biceps tenodesis results in superior subjective outcomes, strength, and endurance compared with tenotomy. Cohort study; Level of evidence, 3. Participants completed isokinetic strength and endurance testing for elbow flexion and supination on the operative and nonoperative sides a minimum of 2 years after biceps tenotomy or tenodesis. Modified American Shoulder and Elbow Surgeons (MASES) and Single Assessment Numeric Evaluation (SANE) scores were obtained. The operative/nonoperative strength and endurance scores were compared for the tenotomy and tenodesis groups, with the nonoperative shoulder serving as the control for each participant's operative shoulder. Change scores for strength and endurance were reported as percentage increase or decrease as compared with the nonoperative side. Change scores and MASES and SANE scores were compared between the 2 groups. The presence of a "popeye" deformity or pain at the tenodesis site was noted. Thirty-five patients (19 tenotomy, 16 tenodesis) were studied. No significant difference was noted in postoperative MASES and SANE scores. Operative-side peak supination torque was significantly decreased relative to the nonoperative side in the tenotomy group, which had a significantly larger decrease in supination peak torque than did the tenodesis group on comparison of change scores. No significant difference was noted for peak flexion torque or flexion/supination endurance between operative and nonoperative sides in either group or between change scores for peak flexion torque or flexion/supination endurance in the tenotomy and tenodesis groups. Four tenotomy patients had a popeye deformity, 2 of whom reported painful cramping. Two patients had pain at the tenodesis site. Subjective outcomes are similar for patients treated with tenotomy and tenodesis. Tenotomy decreases supination peak torque relative to the nonoperative side and tenodesis.


E2A basic-helix-loop-helix transcription factors are negatively regulated by serum growth factors and by the Id3 protein.
Id3, a member of the Id multigene family of dominant negative helix-loop-helix transcription factors, is induced sharply in murine fibroblasts by serum growth factors. To identify relevant targets of Id3 activity, the yeast two-hybrid system was used to identify proteins that dimerize with Id3. Four murine cDNAs were identified in the screen, all of which encode helix-loop-helix proteins: E12, E47, ALF1 and Id4. Co-immunoprecipitation assays confirm that Id3 interacts with E12, E47 and two alternative splice products of ALF1 in vitro. Id3 disrupts DNA binding by these proteins in vitro and blocks transcriptional activation by these factors in cultured murine cells. Additionally, Id3 shows evidence of interacting with the related proteins E2-2 and MyoD, but not c-Myc. These results suggest that Id3 can function as a general negative regulator of the basic-helix-loop-helix family of transcription factors exemplified by the 'E' proteins and MyoD. Although it was previously suspected that E2A is constitutively expressed, our data indicate that E2A is induced in quiescent fibroblasts, by growth factor withdrawal but not by contact inhibition of cell proliferation. These observations extend the role of Id3 in the functional antagonism of E2A-class transcription factors, and suggest that E2A proteins may mediate growth inhibition.


Maintenance of normal intestinal mucosa: function, structure, and adaptation.
Diet is of fundamental importance in the healthy functioning of alimentary epithelium, or during the disease process. Specifically, the incidence of 'non-hereditary' gastrointestinal disease varies widely throughout the world, partly because of different cultural and dietary habits. The aim of this review is to outline the mechanisms that modulate normal mucosal development and growth in the small and large intestine. In addition a brief mention will be made of morphological changes in certain pathological conditions.


Can health systems be enhanced for optimal health services through disease-specific programs? Results of field studies in Viet Nam and Cambodia.
Developing better health systems is the key to delivering optimal health services, although more evidence of effective strategies to do so is needed. Field surveys were conducted in Viet Nam and Cambodia to identify best practices in addressing health system bottlenecks to scale up disease control programs. The two countries were compared over time using a framework for analysis developed by the authors. In Viet Nam, a health system was in place for decades at the central to municipal levels, although it was fragile until the 1990s, when the government started taking measures. In Cambodia, the previous health system had been destroyed during previous internal conflict. In the post-conflict period, the health system was rebuilt with support for programs followed by centralization of health services. In different settings, different measures were taken to deal with similar bottlenecks. In Cambodia, vertical programs were dominant, so the government sought to centralize drug management to deal with shortages of essential drugs, while Viet Nam sought to mobilize resources to ensure drug distribution at all levels. This study shows there is no single successful approach to health systems, and a systemic approach needs to be taken because elimination of one bottleneck may reveal another. Efforts to enhance disease-specific programs may not always contribute to overall enhancement of the health system, and the best possible approach may not be the same in different countries. Further study is needed to explore common issues and principles for effective strategies to enhance health systems in different contexts.


Cpt1a gene expression in peripheral blood mononuclear cells as an early biomarker of diet-related metabolic alterations.
Research on biomarkers that provide early information about the development of future metabolic alterations is an emerging discipline. Gene expression analysis in peripheral blood mononuclear cells (PBMC) is a promising tool to identify subjects at risk of developing diet-related diseases. We analysed PBMC expression of key energy homeostasis-related genes in a time-course analysis in order to find out early markers of metabolic alterations due to sustained intake of high-fat (HF) and high-protein (HP) diets. We administered HF and HP diets (4 months) to adult Wistar rats in isocaloric conditions to a control diet, mainly to avoid overweight associated with the intake of hyperlipidic diets and, thus, to be able to characterise markers of metabolically obese normal-weight (MONW) syndrome. PBMC samples were collected at different time points of dietary treatment and expression of relevant energy homeostatic genes analysed by real-time reverse transcription-polymerase chain reaction. Serum parameters related with metabolic syndrome, as well as fat deposition in liver, were also analysed. The most outstanding results were those obtained for the expression of the lipolytic gene carnitine palmitoyltransferase 1a (Cpt1a). Cpt1a expression in PBMC increased after only 1 month of exposure to both unbalanced diets, and this increased expression was maintained thereafter. Interestingly, in the case of the HF diet, Cpt1a expression was altered even in the absence of increased body weight but correlated with alterations such as higher insulin resistance, alteration of serum lipid profile and, particularly, increased fat deposition in liver, a feature characteristic of metabolic syndrome, which was even observed in animals fed with HP diet. We propose Cpt1a gene expression analysis in PBMC as an early biomarker of metabolic alterations associated with MONW phenotype due to the intake of isocaloric HF diets, as well as a marker of increased risk of metabolic diseases associated with the intake of HF or HP diets.


miRandb: a resource of online services for miRNA research.
Recent discovery of thousands of small and large noncoding RNAs, in parallel to technical improvements enabling scientists to study the transcriptome in much higher depth, has resulted in massive data generation. This burst of information prompts the development of easily accessible resources for storage, retrieval and analysis of raw and processed data, and hundreds of Web-based tools dedicated to these tasks have been made available. However, the increasing number and diversity of bioinformatics tools, each covering a specific and specialized area, as well as their redundancies, represent potential sources of complication for end users. To overcome these issues, we are introducing an easy-to-follow classification of microRNA (miRNA)-related bioinformatics tools for biologists interested in studying this important class of small noncoding RNAs. We also developed our miRNA database miRNA algorithmic network database (miRandb) that is a meta-database, which presents a survey of > 180 Web-based miRNA databases. These include miRNA sequence, discovery, target prediction, target validation, expression and regulation, functions and their roles in diseases, interactions in cellular pathways and networks and deep sequencing. miRandb recapitulates the diverse possibilities and facilitates that access to the different categories of miRNA resources. Researchers can easily select the category of miRNA information and desired organism, in result eligible databases with their features are presented. This database introducing an easy-to-follow classification of available resources that can facilitate selection of appropriate resources for miRNA-related bioinformatics tools. Finally, we described current shortages and future necessities that assist researchers to use these tools easily. Our database is accessible at http://mirandb.ir.


Noninvasive methods to assess pulse wave velocity: comparison with the invasive gold standard and relationship with organ damage.
To compare noninvasive methods to assess pulse wave velocity (PWV) with the invasive gold standard in terms of absolute values, age-related changes, and relationship with subclinical organ damage. Invasive aortic PWV (aoPWVinv) was measured in 915 patients undergoing cardiac catheterization (mean age 61 years, range 27-87 years). Carotid-femoral PWV (cfPWV) was measured with tonometry, using subtracted distance (cfPWVsub), body height-based estimated distance (cfPWVbh), direct distance × 0.8 (cfPWVdir0.8), and caliper-based distance (cfPWVcalip) for travel distance calculation. Aortic PWV was estimated (aoPWVestim) from single-point radial waveforms, age, and SBP. Invasive and noninvasive transit times were strikingly similar (median values 60.8 versus 61.7 ms). In the entire group, median value of aoPWVinv was 8.3 m/s, of cfPWVsub and cfPWVbh 8.1 m/s, and of aoPWVest 8.5 m/s. CfPWVsub overestimated aoPWVinv in younger patients by 0.7 m/s and underestimated aoPWVinv in older patients by 1.7 m/s, with good agreement from 50 to 70 years of age. AoPWVestim differed from aoPWVinv by no more than 0.4 m/s across all age groups. CfPWVdir0.8, measured in 632 patients, overestimated aoPWVinv by 1.7 m/s in younger patients, with good agreement in middle-aged and older patients. CfPWVcalip, measured in 336 patients, underestimated aoPWVinv in all ages. In 536 patients with preserved systolic function, aoPWVinv and aoPWVestim were superior to cfPWVs in predicting coronary atherosclerosis, renal function impairment, left atrial enlargement, and diastolic dysfunction. CfPWVsub, cfPWVdir0.8, and aoPWVestim are reasonable surrogates for aoPWVinv. AoPWVinv predicts subclinical organ damage better than cfPWVs, and as good as aoPWVestim.


Developmental Differentiation and Binding of Mental Processes with g through the Life-Span.
Integration/differentiation of mental processes is major mechanism of development. Developmental theories ascribe intellectual development to it. In psychometric theory, Spearman's law of diminishing returns postulates that increasing g allows increasing differentiation of cognitive abilities, because increased mental power allows variable investment in domain-specific learning. Empirical evidence has been inconsistent so far, with some studies supporting and others contradicting this mechanism. This state of affairs is due to a developmental phenomenon: Both differentiation and strengthening of relations between specific processes and g may happen but these changes are phase-specific and ability-specific, depending upon the developmental priorities in the formation of g in each phase. We present eight studies covering the age span from 4 to 85 years in support of this phenomenon. Using new powerful modeling methods we showed that differentiation and binding of mental processes in g occurs in cycles. Specific processes intertwine with g at the beginning of cycles when they are integrated into it; when well established, these processes may vary with increasing g, reflecting its higher flexibility. Representational knowledge, inductive inference and awareness of it, and grasp of logical constraints framing inference are the major markers of g, first intertwining with in their respective cycles and differentiating later during the periods of 2-6, 7-11, and 11-20 years, respectively. The implications of these findings for an overarching cognitive developmental/differential theory of human mind are discussed.


Brevetoxin augments NMDA receptor signaling in murine neocortical neurons.
Brevetoxins (PbTx) are potent allosteric enhancers of voltage-gated sodium channel (VGSC) function and are associated with periodic "red tide" blooms. These neurotoxins produce neuronal injury and death in cerebellar granule cells (CGC) following acute exposure. In murine neocortical neurons, brevetoxin induces Ca(2+) influx that is mediated through both glutamatergic and non-glutamatergic pathways. Inasmuch as Src kinase is capable of upregulating the NMDA subtype of glutamate receptors, we determined whether Src kinase participated in PbTx-2-induced Ca(2+) influx. Inhibition of Src kinase blocked PbTx-2-induced Ca(2+) influx. PbTx-2 treatment moreover increased tyrosine phosphorylation of the NR2B subunit. A rise in intracellular [Na(+)] and phosphorylation of NMDA receptors by Src kinase is known to increase NMDA receptor activity. We therefore explored the influence of brevetoxin on NMDA receptor function. We found that PbTx-2 augments NMDA receptor-mediated Ca(2+) influx in both spontaneously oscillating mature neurons and in non-oscillatory immature neurons. PbTx-2 also enhanced the effect of bath-applied NMDA on extracellular signal-regulated kinase 2 (ERK2) activation. These results suggest that brevetoxin augments NMDA receptor signaling in neocortical neurons, and this upregulation may be mediated by coincidence of an elevation in intracellular [Na(+)] and Src kinase activation.


Neuroendocrine and psychological assessment in a guinness 10 days scuba dive.
This study was designed to evaluate physiological and psychological stress parameters in 2 professional trained scuba divers, using a unique physiopathologic model, offered by the guinness 240 hours scuba dive. Two scuba dive masters have spent 240 hours at 6 - 8 meters depth (26.4 ft) in Ponza Island water (Italy). Blood samples were collected daily in the underwater bell; samples were carried out of water in waterproof bags. Breath samples were collected, measuring ethylene release. Psychological assessment was performed using the State and Trait Anxiety Inventory and the Zung self-rating depression scale. In the studied subjects, cortisol and prolactin showed physiological pulsatile secretion. Breath ethylene didn't exceed normal values. At the start of the study, no subjects showed high levels of state anxiety, trait anxiety and current depression. Psychometric scales scores remained steady during the diving period and no subjects showed anxiety and/or depression and/or panic symptoms during the time of observation. The present study shows that, although the long-time diving, well trained professional divers did not develop anxiety and/or depression. No subject discontinued the diving due to occurred psychological disorders or systemic events. The present report shows that the long-term diving permanence is possible, at least in well trained scuba divers.


Assessment of Driver's Drowsiness Based on Fractal Dimensional Analysis of Sitting and Back Pressure Measurements.
The most effective way of preventing motor vehicle accidents caused by drowsy driving is through a better understanding of drowsiness itself. Prior research on the detection of symptoms of drowsy driving has offered insights on providing drivers with advance warning of an elevated risk of crash. The present study measured back and sitting pressures during a simulated driving task under both high and low arousal conditions. Fluctuation of time series of center of pressure (COP) movement of back and sitting pressure was observed to possess a fractal property. The fractal dimensions were calculated to compare the high and low arousal conditions. The results showed that under low arousal (the drowsiness state) the fractal dimension was significantly lower than what was calculated with high arousal. Accumulated drowsiness thus contributed to the loss of self-similarity and unpredictability of time series of back and sitting pressure measurement. Drowsiness further reduces the complexity of the posture control system as viewed from back and sitting pressure. Thus, fractal dimension is a necessary and sufficient condition of a decreased arousal level. It further is a necessary condition for detecting the interval or point in time with high risk of crash.


Outer membrane proteins responsible for multiple drug resistance in Pseudomonas aeruginosa.
Three types of multiple-drug-resistant mutants which were phenotypically similar to previously described nalB, nfxB, and nfxC mutants were isolated from Pseudomonas aeruginosa PAO1 and two clinical isolates. Type 1 (nalB-type) mutants showed cross-resistance to meropenem, cephems, and quinolones. They overproduced an outer membrane protein with an apparent molecular mass of 50 kDa (OprM). Type 2 (nfxB-type) mutants showed cross-resistance to quinolones and new cephems, i.e., cefpirome and cefozopran, concomitant with overproduction of an outer membrane protein with an apparent molecular mass of 54 kDa (OprJ). Type 3 (nfxC-type) mutants showed cross-resistance to carbapenems and quinolones. They produced decreased amounts of OprD and increased amounts of a 50-kDa protein (OprN), which was almost the same molecular weight as that of OprM, but it was distinguishable from OprM by its heat modifiability on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In the presence of salicylate, the parent strains showed an increased level of resistance to carbapenems and quinolones and produced decreased amounts of OprD and increased amounts of OprN. Salicylate caused the repression of OprJ production and the loss of resistance to cefpirome and cefozopran in two of the three OprJ-overproducing mutants, although salicylate slightly increased the level of resistance in the parent strains. The changes in susceptibilities were transient in the presence of salicylate. These data suggest that at least three different outer membrane proteins, OprM, OprJ, and OprN, are associated with multiple drug resistance in P. aeruginosa.