Recent evaluation by nephrologists is associated with fewer tunneled dialysis catheter being used at the time of first arteriovenous access creation.
Late primary care provider (PCP) or nephrologist evaluation of patients with progressive kidney disease may be associated with increased morbidity and mortality. Among patients undergoing initial arteriovenous (AV) access creation, we aimed to study the relationship of recent PCP and nephrologist evaluations with perioperative morbidity and mortality. We performed a retrospective review of patients from 2014 to 2022 who underwent initial AV access creation at an urban, safety-net hospital. Univariable and multivariable analyses identified associations of PCP and nephrologist evaluations <1 year and <3 months before surgery, respectively, with hemodialysis initiation via tunneled dialysis catheters (TDCs), 90-day readmission, and 90-day mortality. Among 558 patients receiving initial AV access, mean age was 59.7 ± 14 years, 59% were female gender, and 60.6% were Black race. Recent PCP and nephrology evaluations occurred in 386 (69%) and 362 (65%) patients, respectively. On multivariable analysis, unemployed and uninsured statuses were associated with decreased likelihood of PCP evaluation (unemployment: odds ratio [OR], 0.51; 95% confidence interval [CI], 0.34-0.77; uninsured status: OR, 0.05; 95% CI, 0.01-0.45) and nephrologist evaluation (unemployment: OR, 0.63; 95% CI, 0.43-0.91; uninsured status: OR, 0.22; 95% CI, 0.06-0.83) (all P < .05). Social support was associated with increased likelihood of PCP evaluation (OR, 1.81; 95% CI, 1.07-3.08) (all P < .05). Hemodialysis was initiated with TDCs in 304 patients (55%). Older age (OR, 0.98; 95% CI, 0.96-0.99), obesity (OR, 0.38; 95% CI, 0.25-0.58), and nephrologist evaluation (OR, 0.12; 95% CI, 0.08-0.19) were independently associated with decreased hemodialysis initiation with TDCs in patients receiving an initial AV access (all P < .05). Ninety-day readmission occurred in 270 cases (48%). Cirrhosis (OR, 2.5; 95% CI, 1.03-6.03; P = .04), coronary artery disease (OR, 2.31; 95% CI, 1.5-3.57), prosthetic AV access (OR, 1.84; 95% CI, 1.04-3.26), and impaired ambulation (OR, 1.75; 95% CI, 1.15-2.66) were independently associated with increased readmission (all P < .05). Older age (OR, 0.98; 95% CI, 0.97-0.99), prior TDC (OR, 0.65; 95% CI, 0.45-0.94), and unemployment (OR, 0.58; 95% CI, 0.39-0.86) were associated with decreased readmission (all P < .05). Ninety-day mortality occurred in 1.6% of patients. Neither PCP nor nephrologist evaluation was associated with readmission or mortality. Recent nephrology evaluation was associated with reduced hemodialysis initiation with TDCs among patients undergoing initial AV access creation. Unemployed and uninsured statuses posed barriers to accessing nephrology care.


Improving the size selectivity and exploitation pattern of cocktail shrimp (Trachypenaeus curvirostris) in shrimp trawl fishery of the South China Sea.
In order to improve the size selectivity and exploitation pattern for cocktail shrimp (Trachypenaeus curvirostris) in shrimp trawl fishery of the South China Sea (SCS), selective properties of four codends were tested and compared. These experimental codends involved two mesh sizes, 30 and 35 mm, and two mesh shapes, diamond-mesh (T0) and diamond-mesh turned by 90 degree (T90), respectively. Our results demonstrated that increasing the mesh sizes in T0 codends or/and applying T90 codends would improve the selective properties for cocktail shrimp in the SCS. By comparing selectivity parameters, delta selectivity and exploitation pattern indicators, the T90 codend with 35-mm mesh size (T90_35) presented the best selective properties for cocktail shrimp in the studied areas. It will be a potential choice to substitute the currently legal codend in fisheries management to mitigate the bycatch of undersized cocktail shrimp in shrimp trawl fisheries of the SCS.


Characterisation of aerobically grown non-spore-forming bacteria from paper mill pulps containing recycled fibres.
A total of 179 non-spore-forming bacteria aerobically growing on Nutrient Agar, Plate Count Agar or in specific enrichment conditions for salmonella, campylobacteria, listeria, yersinia or staphylococci, were isolated from 16 untreated paper mill pulps. After phenotypical screening the isolates were characterised by automated ribotyping and partial sequencing of the 16S rRNA gene. They could be divided into seven taxonomical classes representing 63 taxa (species): actinobacteria (11 species), bacilli (7), flavobacteria (3) alphaproteobacteria (10), betaproteobacteria (5), gammaproteobacteria (25) and sphingobacteria (2). Most of the gammaproteobacteria were enterobacteria, mainly species of the genera Enterobacter (7 species, 7 samples/3 mills) and Klebsiella (5 species, 6 samples/3 mills). Other commonly occurring bacteria were most closely related to Microbacterium barkeri (7 samples/3 mills), Cloacibacterium normanense (6 samples/2 mills), Pseudoxanthomonas taiwanensis (5 samples/2 mills) and Sphingobacterium composti (5 samples/1 mill). Sporadic isolates of Listeria innocua, L. monocytogenes, Enterococcus casseliflavus and Staphylococcus warneri were detected, from which only L. monocytogenes is considered to be a food pathogen. No isolates of the genera Campylobacter, Salmonella or Yersinia were detected. The detected bacteria may be harmful in process control, but the load of food pathogens with recycled fibres to paper machines is insignificant. Faecal contamination of the pulp samples was not indicated.


Mutant analysis and cellular localization of the AlgI, AlgJ, and AlgF proteins required for O acetylation of alginate in Pseudomonas aeruginosa.
Alginate is an extracellular polysaccharide produced by mucoid strains of Pseudomonas aeruginosa that are typically isolated from the pulmonary tracts of chronically infected cystic fibrosis patients. Alginate is a linear polymer of D-mannuronate and L-guluronate with O-acetyl ester linkages on the O-2 and/or O-3 position of the mannuronate residues. The presence of O-acetyl groups plays an important role in the ability of the polymer to act as a virulence factor, and the algF, algJ, and algI genes are known to be essential for the addition of O-acetyl groups to alginate. To better understand the mechanism of O acetylation of alginate, the cellular locations of the AlgI, AlgJ, and AlgF proteins were determined. For these studies, defined nonpolar algI, algJ, and algF deletion mutants of P. aeruginosa strain FRD1 were constructed, and each mutant produced alginate lacking O-acetyl groups. Expression of algI, algJ, or algF in trans in the corresponding mutant complemented each O acetylation defect. Random phoA (alkaline phosphatase [AP] gene) fusions to algF, algJ, and algI were constructed. All in-frame fusions to algF and algJ had AP activity, indicating that both AlgF and AlgJ were exported to the periplasm. Immunoblot analysis of spheroplasts and periplasmic fractions showed that AlgF was released with the periplasmic contents but that AlgJ remained with the spheroplast fraction. An N-terminal sequence analysis of AlgJ showed that its putative AlgJ signal peptide was not cleaved, suggesting that AlgJ is anchored to the cytoplasmic membrane by its uncleaved signal peptide. AP gene fusions were also used to map the membrane topology of AlgI, and the results suggest that it is an integral membrane protein with seven transmembrane domains. These results suggest that AlgI-AlgJ-AlgF may form a complex in the membrane that is the reaction center for O acetylation of alginate.


[Acute liver failure due to human herpesvirus 6 in an infant].
We report a case of a 4-months infant with fever in the absence of other specific symptoms that has rapidly and unexpectedly developed acute liver failure (ALF) with coagulopathy and complicated with bone marrow failure without encephalopathy. The main viral infection agents (hepatitis virus A, B, C, Citomegalovirus, Ebstain Barr virus, Parvovirus B19, Adenovirus), drug-induced hepatotoxicity and metabolic disorders associated to ALF were excluded. Quantitative determination of Human Herpesvirus 6 (HHV6) genome was positive with a significant number of copies for mL. A favorable evolution of the clinical symptoms and a progressive hematochemical resolution were obtained. Plasma and Vitamin K were administrated as a support therapy for treating coagulopathy. The present case report and the cases' review from the literature, evidence the importance of always including screening for HHV6 infection in the diagnostic approach to acute onset of liver failure. HHV6 is a common virus in the pediatric population with a greater number of cases of fulminant viral non-A, non-B, non-C hepatitis in immunocompetent patients due to this virus: these forms have often a high mortality rate and maybe necessitate liver transplantation; for this reason correct etiological agent identification is mandatory for the prognosis and it has to be based on the quantitative search of the virus's genome. Pathogenesis of liver-induced damage associated to HHV6 remains unclear; however in vitro studies demonstrate the potential hepatotoxicity effects of this virus.


A self-assembled delivery platform with post-production tunable release rate.
Self-assembly of three molecular components results in a delivery platform, the release rate of which can be tuned after its production. A fluorophore-conjugated gelator can be hydrolyzed by an enzyme, resulting in the release of a fluorescent small molecule. To allow the release to be tunable, the enzyme is entrapped in liposomes and can be liberated by heating the system for a short period. Crucially, the heating time determines the amount of enzyme liberated; with that, the release rate can be tuned by the time of heating.


Impact of inoculation protocols, salinity, and pH on the degradation of polycyclic aromatic hydrocarbons (PAHs) and survival of PAH-degrading bacteria introduced into soil.
Degradation of polycyclic aromatic hydrocarbons (PAHs) and survival of bacteria in soil was investigated by applying different inoculation protocols. The soil was inoculated with Sphingomonas paucimobilis BA 2 and strain BP 9, which are able to degrade anthracene and pyrene, respectively. CFU of soil bacteria and of the introduced bacteria were monitored in native and sterilized soil at different pHs. Introduction with mineral medium inhibited PAH degradation by the autochthonous microflora and by the strains tested. After introduction with water (without increase of the pore water salinity), no inhibition of the autochthonous microflora was observed and both strains exhibited PAH degradation.


Virtual screening and discovery of novel aurora kinase inhibitors.
Cancer remains one of the major contributors to human mortality and a hazard to human growth. The search for a new treatment continues unabated. Aurora kinases play an important role in cell cycle, and thus a potential target for the treatment of cancer. In the present work, we aim to discover potential leads against aurora kinase using various rational methods of drug discovery. The available crystal complexes of AKs were analyzed for their interactions and quantified with glide-extra precision (XP) docking. About 20 crystal pdb were selected from the protein databank based on the resolution factor, R-factor and R-value. And after docking with the native ligands, the RMSD value was calculated, wherein the protein with the least RMSD was found to be 3UOK which was further used for our screening of small molecules from the in-house database by molecular docking. Fragments which were found to possess the best interactions were considered for the synthesis with characterization, and biological activity was carried out against breast cancer and colorectal cancer cell lines to assess the inhibitory capability of synthesized compounds. Molecule with the molecular id IS2 i.e. (3E)-3-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2H chromene-2,4(3H)-dione was found to possess inhibitory activity with an IC50 of 1.324 nM and 5.785 µM for breast cell line and colorectal cell line studies, respectively.


Population growth lags in introduced species.
When introduced to new ecosystems, species' populations often grow immediately postrelease. Some introduced species, however, maintain a low population size for years or decades before sudden, rapid population growth is observed. Because exponential population growth always starts slowly, it can be difficult to distinguish species experiencing the early phases of slow exponential population growth (inherent lags) from those with actively delayed growth rates (prolonged lags). Introduced ungulates provide an excellent system in which to examine lags, because some introduced ungulate populations have demonstrated rapid population growth immediately postintroduction, while others have not. Using studies from the literature, we investigated which exotic ungulate species and populations (n = 36) showed prolonged population growth lags by comparing the doubling time of real ungulate populations to those predicted from exponential growth models for theoretical populations. Having identified the specific populations that displayed prolonged lags, we examined the impacts of several environmental and biological variables likely to influence the length of lag period. We found that seventeen populations (47%) showed significant prolonged population growth lags. We could not, however, determine the specific factors that contributed to the length of these lag phases, suggesting that these ungulate populations' growth is idiosyncratic and difficult to predict. Introduced species that exhibit delayed growth should be closely monitored by managers, who must be proactive in controlling their growth to minimize the impact such populations may have on their environment.


A multicenter quasi-experimental study: impact of a central line infection control program using auditing and performance feedback in five Belgian intensive care units.
We analyzed the impact associated with an intervention based on process control and performance feedback to decrease central line-associated bloodstream infection (CLABSI) rates.This study was conducted from March 2011 to September 2012 in five adult intensive care units (ICU) located in two Belgian tertiary hospitals A and B, with a total of 53 beds. This study was divided in three phases: P1 (baseline), P2 (intervention) and P3 (post intervention).During P2, external monitoring of five central venous catheters (CVC) care critical processes and monthly reporting (meetings and feedbacks reports posted) of performance indicators (CLABSI rate, CVC utilization ratio, compliance rate with each care process, and insertion site) to ICU workers were performed. The external monitoring of process measures was assessed by the same trained research nurse.A Poisson regression analysis was used to compare CLABSI incidence density rate per phase. Statistical significance was achieved with 2-sided p-value of <0.05. For the analysis, we separated the five ICU in hospital A and B when appropriate. Significantly improved total mean compliance was achieved for hand hygiene, CVC handling and CVC dressing. CLABSI rate declined from 4.00 (95% confidence interval (CI): 1.94-6.06) to 1.81 (0.46-3.17) per 1,000 CVC-days in P2 with an incidence rate ratio (IRR) of 0.49 (0.24-0.98, p = 0.043). A better response was observed in hospital A where the nurse participation at the monthly meeting was significantly higher than in hospital B (p < 0.001) as the percentage of feedbacks reports posted in ICU (p < 0.001). The decline in the CLABSI rate observed during P2 in comparison with P1 was independent of the insertion site (femoral or non-femoral; p = 0.054). The overall CLABSI rate increased to 2.73 (1.17-4.29) per 1,000 CVC-days with IRR of 0.67 (0.36-1.26, p = 0.212) in P3 compared to P1, but a high nursing turnover was observed in both hospitals. Our intervention focused on external auditing and performance feedback resulted in significant reduction in rates of CLABSI. Investigation continues regarding the most effective way to sustain CLABSI prevention practices and to improve the culture of safety in healthcare.


Capillary isoelectric focusing and isoelectric buffers: an evolving scenario.
The present review offers a new look at capillary isoelectric focusing (cIEF) by centering on the most troublesome aspects of the technique, namely: 1) how to modulate the slope of the pH gradient, for increasing resolution (equivalent to pH gradient engineering, as easily available in immobilized pH gradients); and 2) how to keep proteins in solution at (and in the proximity of) the pl value. A simple solution is offered in the first case: addition, to the standard 2-pH-units interval, of separators or spacers, i.e., of amphoteric molecules (either single or in combination) able to locally flatten the pH and increment resolution. Examples of the separation of fetal and glycated hemoglobins are provided. In the second case, a unique solubilization power (while maintaining full protein integrity and enzyme activity) is obtained if class I solubilizers are used. They consist of mixtures of sugars (e.g., sucrose and sorbitol) at ca. 1 M concentration, with zwitterions (up to 1 M) such as the class of nondetergent sulfobetaines, but also taurine and some of the Good's buffers (e.g., CAPS). In these solvents, the protein exists in a state of superhydration and its solubility is greatly augmented. The review ends with an excursus on the use of isoelectric buffers in zone electrophoretic separations. Such isoelectric buffers offer unique advantages: They permit very-high-voltage gradients (up to 1000 V/cm) and thus minimize analysis times (down to a few min in 30-35 cm long capillaries). This results in a marked increase in resolution, due to minimal diffusion-driven peak spreading. Such buffers are finding unique applications for generating peptide maps of tryptic digests of proteins and also in the analysis of oligonucleotides.


Human Factors in Sensory Feedback for Haptic Gloves.
Manual therapy training requires close proximity between the clinical teacher and students, which limits the training of people in remote and rural regions. Video-based online training can provide visual but not tactile information, which is also essential for manual therapies. This project describes the development and testing of an inexpensive sensor glove developed using commercially available sensors, suitable for monitoring the shape and force applied by the hand of a person delivering a spinal manipulation. Its focus was the development of software to provide the human user with tactile information that is usually acquired intuitively in face-to-face teaching. Though rigorous assessment of the glove's application showed errors at low levels of force in actual force measurement and interpretation by users, these errors were reduced at higher levels of force. Trainers of spinal manipulation reported the device to be very useful and suitable for the purpose. We conclude that this glove has the potential for being used for online training of students.Clinical Impact: The outcome of this study shows the feasibility of developing an inexpensive haptic glove using proprietary software for online training of students of manual therapy.


Relative validity of the food frequency questionnaire used to assess dietary intake in the Leiden Longevity Study.
Invalid information on dietary intake may lead to false diet-disease associations. This study was conducted to examine the relative validity of the food frequency questionnaire (FFQ) used to assess dietary intake in the Leiden Longevity Study. A total of 128 men and women participating in the Leiden Longevity Study were included in the present validation study. The performance of the FFQ was evaluated using the mean of three 24-hour recalls as the reference method. Evaluation in estimating dietary intake at the group level was done by paired t-tests. The relative validity of the individual energy adjusted level of intake was assessed with correlation analyses (Pearson's), with correction for measurement error. On group level, the FFQ overestimated as well as underestimated absolute intake of various nutrients and foods. The Bland and Altman plot for total energy intake showed that the agreement between the FFQ and the 24-hour recalls was dependent of intake level. Pearson correlation coefficients ranged from 0.21 (alpha linolenic acid) to 0.78 (ethanol) for nutrients and from -0.02 (legumes, non-significant) to 0.78 (alcoholic beverages) for foods. Adjustment for energy intake slightly lowered the correlation coefficients for nutrients (mean coefficient: 0.48 versus 0.50), while adjustment for within-subject variation in the 24-h recalls resulted in higher correlation coefficients for both nutrients and foods (mean coefficient: 0.69 for nutrients and 0.65 for foods). For most nutrients and foods, the ability of the FFQ to rank subjects was acceptable to good.


Sequencing and curation strategies for identifying candidate glioblastoma treatments.
Prompted by the revolution in high-throughput sequencing and its potential impact for treating cancer patients, we initiated a clinical research study to compare the ability of different sequencing assays and analysis methods to analyze glioblastoma tumors and generate real-time potential treatment options for physicians. A consortium of seven institutions in New York City enrolled 30 patients with glioblastoma and performed tumor whole genome sequencing (WGS) and RNA sequencing (RNA-seq; collectively WGS/RNA-seq); 20 of these patients were also analyzed with independent targeted panel sequencing. We also compared results of expert manual annotations with those from an automated annotation system, Watson Genomic Analysis (WGA), to assess the reliability and time required to identify potentially relevant pharmacologic interventions. WGS/RNAseq identified more potentially actionable clinical results than targeted panels in 90% of cases, with an average of 16-fold more unique potentially actionable variants identified per individual; 84 clinically actionable calls were made using WGS/RNA-seq that were not identified by panels. Expert annotation and WGA had good agreement on identifying variants [mean sensitivity = 0.71, SD = 0.18 and positive predictive value (PPV) = 0.80, SD = 0.20] and drug targets when the same variants were called (mean sensitivity = 0.74, SD = 0.34 and PPV = 0.79, SD = 0.23) across patients. Clinicians used the information to modify their treatment plan 10% of the time. These results present the first comprehensive comparison of technical and machine augmented analysis of targeted panel and WGS/RNA-seq to identify potential cancer treatments.


PPARγ in head and neck cancer prevention.
Head and neck cancer is a major source of morbidity and mortality worldwide. Intervention during the early phases of carcinogenesis represents a promising new strategy for curbing the devastating effects of this disease and its primary treatment modalities, surgery and radiation with or without concomitant chemotherapy. This review focuses on the peroxisome proliferator-activated receptor gamma (PPARγ) as a target for chemoprevention of oral cancer. Accumulating data suggest that ligands of PPARγ, which include the thiazolidinedione class of agents approved for the treatment of diabetes, inhibit cancer cell growth in vitro and in animal carcinogenesis models, providing the rationale for testing this approach in populations at risk for head and neck cancer.


New highlights on effects of rapid palatal expansion on the skull base: a finite element analysis study.
The objective of this study was to evaluate the effect of the rapid palatal expansion (RPE) on the pterygoid process (PP), spheno-occipital synchondrosis (SOS) and sella turcica (ST) in the skull of a patient with transversal maxillary collapse, and identify the distribution of mechanical stresses and displacement, by finite element analysis (FEA). Cone-beam computed tomography (CBCT) was employed to examine the skull of a patient in this study. The patient was a 13-year-old boy, with Class II skeletal relationship due to transverse atresia and maxillary protrusion. The computer-aided design (CAD) geometry of skull was imported into the SimLab v. 13.1 software, to build the finite element mesh. For the simulation, a displacement of 1 mm, 3 mm and 5 mm in a transverse direction was defined at the midpalatal suture, thereby representing the RPE. For the analysis of results, maximum principal stress (MPS) and displacements were evaluated by identifying different nodes, which were represented by the points as per the areas of interest in the study. In MPS, the maximum tensile stress was found at point 2 (366.50 MPa) and point 3 (271.50 Mpa). The maximum compressive stress was found at point 8 (-5.84 Mpa). The higher displacements in the transversal plane and the lateral segment were located at point 1 (2.212 mm), point 2 (0.903 mm) and point 3 (0.238 mm). RPE has a direct effect on PP, SOS and ST in the Class II model skeletal relationship with a transversal maxillary collapse. PP supported a higher tensile stress and displacement.


Solid-Solid Phase Transitions and tert-Butyl and Methyl Group Rotation in an Organic Solid: X-ray Diffractometry, Differential Scanning Calorimetry, and Solid-State 1H Nuclear Spin Relaxation.
Using solid-state 1H nuclear magnetic resonance (NMR) spin-lattice relaxation experiments, we have investigated the effects of several solid-solid phase transitions on tert-butyl and methyl group rotation in solid 1,3,5-tri-tert-butylbenzene. The goal is to relate the dynamics of the tert-butyl groups and their constituent methyl groups to properties of the solid determined using single-crystal X-ray diffraction and differential scanning calorimetry (DSC). On cooling, the DSC experiments see a first-order, solid-solid phase transition at either 268 or 155 K (but not both) depending on thermal history. The 155 K transition (on cooling) is identified by single-crystal X-ray diffraction to be one from a monoclinic phase (above 155 K), where the tert-butyl groups are disordered (that is, with a rotational 6-fold intermolecular potential dominating), to a triclinic phase (below 155 K), where the tert-butyl groups are ordered (that is, with a rotational 3-fold intermolecular potential dominating). This transition shows very different DSC scans when both a 4.7 mg polycrystalline sample and a 19 mg powder sample are used. The 1H spin-lattice relaxation experiments with a much larger 0.7 g sample are very complicated and, depending on thermal history, can show hysteresis effects over many hours and over very large temperature ranges. In the high-temperature monoclinic phase, the tert-butyl groups rotate with NMR activation energies (closely related to rotational barriers) in the 17-23 kJ mol-1 range, and the constituent methyl groups rotate with NMR activation energies in the 7-12 kJ mol-1 range. In the low-temperature triclinic phase, the rotations of the tert-butyl groups and their methyl groups in the aromatic plane are quenched (on the NMR time scale). The two out-of-plane methyl groups in the tert-butyl groups are rotating with activation energies in the 5-11 kJ mol-1 range.


Direct Detection of Emergent Fungal Pathogen Candida auris in Clinical Skin Swabs by SYBR Green-Based Quantitative PCR Assay.
The recent emergence of the multidrug-resistant and pathogenic yeast Candida auris continues to cause public health concern worldwide. C. auris is alarming because it causes health care-associated outbreaks and can establish invasive infections with high mortality rates. Transmission between patients is facilitated by the ability of C. auris to persistently colonize multiple body sites, including the skin, and survive for weeks on surfaces in health care settings. Rapid identification of colonized patients is needed to implement timely infection control measures. Currently, CDC laboratories use an enrichment culture-based approach that can take up to 2 weeks to identify C. auris from composite swabs from the bilateral axillae and groin. A rapid SYBR green quantitative PCR (qPCR) assay that can identify C. auris in a single day was recently described. In this study, we developed the SYBR green qPCR assay further by incorporating a DNA extraction procedure for skin swabs and by including an internal amplification control based on the distinguishable melt curve of a lambda DNA amplicon. The assay was conducted using 103 clinical axilla/groin skin swab samples. Using the enrichment culture-based approach as a gold standard, we determined that the SYBR green C. auris qPCR has a sensitivity of 0.93 and specificity of 0.96. Overall, we found that the SYBR green C. auris qPCR assay can be successfully applied for rapid and accurate detection of C. auris in patient skin swabs, thereby increasing diagnostic options for this emerging pathogen.


[Comparative efficacy of choline antagonists in chronic obstructive lung disease].
The efficacy of thiotropium bromide, 18 microg/day, versus ipratropium bromide, 160 microg/day, was studied in 20 patients with chronic obstructive lung disease (COLD) treated with a drug for 4 weeks. Clinical and spirographic parameters and arterial blood gas composition were determined. According to clinical and spirographic data, thiotropium bromide has some advantage over ipratropium. Both test drugs improved blood gas composition.


NADPH oxidases as novel pharmacologic targets against influenza A virus infection.
Influenza A viruses represent a major global health care challenge, with imminent pandemics, emerging antiviral resistance, and long lag times for vaccine development, raising a pressing need for novel pharmacologic strategies that ideally target the pathology irrespective of the infecting strain. Reactive oxygen species (ROS) pervade all facets of cell biology with both detrimental and protective properties. Indeed, there is compelling evidence that activation of the NADPH oxidase 2 (NOX2) isoform of the NADPH oxidase family of ROS-producing enzymes promotes lung oxidative stress, inflammation, injury, and dysfunction resulting from influenza A viruses of low to high pathogenicity, as well as impeding virus clearance. By contrast, the dual oxidase isoforms produce ROS that provide vital protective antiviral effects for the host. In this review, we propose that inhibitors of NOX2 are better alternatives than broad-spectrum antioxidant approaches for treatment of influenza pathologies, for which clinical efficacy may have been limited owing to poor bioavailability and inadvertent removal of beneficial ROS. Finally, we briefly describe the current suite of NADPH oxidase inhibitors and the molecular features of the NADPH oxidase enzymes that could be exploited by drug discovery for development of more specific and novel inhibitors to prevent or treat disease caused by influenza.


Shock Wave Physics as Related to Primary Non-Impact Blast-Induced Traumatic Brain Injury.
Blast overpressure exposure, an important cause of traumatic brain injury (TBI), may occur during combat or military training. TBI, most commonly mild TBI, is considered a signature injury of recent combat in Iraq and Afghanistan. Low intensity primary blast-induced TBI (bTBI), caused by exposure to an explosive shock wave, commonly leaves no obvious physical external signs. Numerous studies have been conducted to understand its biological effects; however, the role of shock wave energy as related to bTBI remains poorly understood. This report combines shock wave analysis with established biological effects on the mouse brain to provide insights into the effects of shock wave physics as related to low intensity bTBI outcomes from both open-air and shock tube environments. Shock wave peak pressure, rise time, positive phase duration, impulse, shock velocity, and particle velocity were measured using the Missouri open-air blast model from 16 blast experiments totaling 122 mice to quantify physical shock wave properties. Open-air shock waves were generated by detonating 350-g 1-m suspended Composition C-4 charges with targets on 1-m elevated stands at 2.15, 3, 4, and 7 m from the source. All mice sustained brain injury with no observable head movement, because of mice experiencing lower dynamic pressures than calculated in shock tubes. Impulse, pressure loading over time, was found to be directly related to bTBI severity and is a primary shock physics variable that relates to bTBI. The physical blast properties including shock wave peak pressure, rise time, positive phase duration, impulse, shock velocity, and particle velocity were examined using the Missouri open-air blast model in mice with associated neurobehavioral deficits. The blast-exposed mice sustained ultrastructural abnormalities in mitochondria, myelinated axons, and synapses, implicating that primary low intensity blast leads to nanoscale brain damage by providing the link to its pathogenesis. The velocity of the shock wave reflected back from the target stand was calculated from high-speed video and compared with that of the incident shock wave velocity. Peak incident pressure measured from high sample rate sensors was found to be within 1% of the velocity recorded by the high-speed camera, concluding that using sensors in or close to an animal brain can provide useful information regarding shock velocity within the brain, leading to more advanced knowledge between shock wave physics and tissue damage that leads to bTBIs.


Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies.
In recent years, increasing evidence has suggested a strong association between diabetes mellitus (DM) and hepatocellular carcinoma (HCC). To provide a quantitative assessment of this association, we performed a systematic review and meta-analysis of cohort studies. We collected studies through a literature search of Medline from January 1, 1966 and EMBASE from January 1, 1974, through July 31, 2010. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. A total of 25 cohort studies that met our inclusion and exclusion criteria were included in our analysis. Among these, 18 studies showed that DM was associated with an increased incidence of HCC (SRRs = 2.01, 95% CI: 1.61-2.51), compared with individuals without DM. There was a statistically significant heterogeneity among these studies (Q = 136.68, p < 0.001, I(2) = 87.6%). Analyses subgrouped by controlling confounders revealed that the increased incidence of HCC was independent of geographic location, alcohol consumption, history of cirrhosis, or infections with hepatitis B (HBV) or hepatitis C virus (HCV). In addition, DM was also positively associated with HCC mortality (SRR = 1.56; 95% CI: 1.30-1.87), with no significant evidence of heterogeneity among studies (Q = 1.16, p = 0.56, I(2) =0%). There were no significant publication bias (p = 0.79 for Egger's regression asymmetry test). These findings strongly support a positive association between DM and increased risk of HCC in both males and females.


Hubble Space Telescope Imaging of Neptune's Cloud Structure in 1994.
Images of Neptune taken at six wavelengths with the Hubble Space Telescope in October and November 1994 revealed several atmospheric features not present at the time of the Voyager spacecraft encounter in 1989. Furthermore, the largest feature seen in 1989, the Great Dark Spot, was gone. A dark spot of comparable size had appeared in the northern hemisphere, accompanied by discrete bright features at methane-band wavelengths. At visible wavelengths, Neptune's banded structure appeared similar to that seen in 1989.


Analysis of Distribution and Localization of Proteins of the Reelin Signalling Pathway in Mesial Temporal Lobe Epilepsy.
Granule cell dispersion (GCD) is pathognomonic of hippocampal sclerosis seen in the mesial temporal lobe epilepsy (MTLE). Current animal studies indicate deficiency of Reelin is associated with abnormal granule cell migration leading to GCD. The present study aimed to evaluate complete Reelin signalling pathway to assess whether Reelin deficiency is related to MTLE. Hippocampal sclerosis was confirmed by H&E stain. To explore the amount and cellular location of the Reelin cascade molecules, the hippocampal tissues from MTLE surgery and controls (n = 15 each) were studied using Immuno-histochemistry (IHC). Additionally, confocal imaging was used to validate the IHC findings by co-localization of different proteins. Quantification of IHC images was performed using histo-score and confocal images by Image J software. Immune-expression of active Reelin was significantly reduced in patients. Reelin receptors were deranged, apolipoprotein E receptor 2 was increased while very low-density lipoprotein receptor was reduced. Disabled-1, a downstream molecule was significantly reduced in MTLE. Its ultimate target, cofilin was thus disinhibited & expressed more in MTLE. Reelin cleaving protease, matrix metalloprotease-9 (MMP-9) and MMP-9 inhibitor, tissue inhibitor of matrix protease-1, showed reduced expression in extracellular matrix. Semi-quantification of immunohistochemistry was done using Histo (H) score. H score of Reelin in diseased patients was 15 against 125 for control patients. These results were validated by confocal fluorescence microscopy. Reelin signalling cascade was deranged in chronic MTLE. Pharmacological manipulation of Reelin cascade can be done at various levels and it may provide novel treatment options for MTLE.


Novel immunohistochemical markers in the diagnosis of nonglial tumors of nervous system.
Immunohistochemistry (IHC) has become an important adjunct tool in diagnostic neuro-oncology practice enabling immunophenotypic characterization of tumor cells. There have been several recent publications regarding new IHC markers that are useful for diagnosis of brain tumors. To introduce the latest advances in IHC in this field, we review the features of novel IHC marker antibodies applicable to selected nonglial tumors in the nervous system, based on recently published reports and our own experiences. We discuss (1) aquaporin-1 and alpha-inhibin for hemangioblastoma, (2) beta-catenin for craniopharyngioma, (3) brachyury for chordoma, and (4) INI-1 for hereditary schwannomas. All the markers presented here are used primarily for supporting or confirming the histologic diagnosis, with the exception of (4), which may be of help in identification of inherited forms in schwannomas. As with other surgical pathology practices, the judicious use of a panel of IHC antibodies selected on the basis of the histologic findings is important for an accurate diagnosis of brain tumors. Of note is that IHC results should be always interpreted in the histopathologic context.


Purification of two calcium/calmodulin-dependent forms of cyclic nucleotide phosphodiesterase by using conformation-specific monoclonal antibody chromatography.
A procedure for nondenaturing immunopurification of bovine calmodulin-dependent 3',5'-cyclic-nucleotide phosphodiesterase (3',5'-cyclic-nucleotide 5'-nucleotidohydrolase, EC 126.96.36.199) is described that utilizes chromatography on a conformation-specific monoclonal antibody column. Hybridomas derived from spleen cells of mice immunized with Ca(2+)/calmodulin/phosphodiesterase were screened for antiphosphodiesterase antibody production. A stable cell line was established that secretes a monoclonal antibody that binds to the Ca(2+)/calmodulin/enzyme complex with an approximate K(d) of 10(-9) M. The dissociation constant was increased by two orders of magnitude when calmodulin interaction with the enzyme was inhibited by Ca(2+) chelation. This differential reactivity was utilized for affinity chromatography of heart and brain phosphodiesterases on monoclonal antibody columns. Highly purified phosphodiesterases were eluted in good yield with buffer containing EGTA. The immunopurified enzymes from heart and brain exhibited specific activities of approximately 300 units/mg when assayed at millimolar concentrations of cGMP or cAMP. Calmodulin stimulated both enzymes 10- to 15-fold over basal activity under these conditions. However, analysis of the two preparations by NaDodSO(4)/polyacrylamide gel electrophoresis revealed an apparent subunit of M(r) 61,000 for the brain enzyme, in contrast to the M(r) 59,000 cardiac subunit. The observed difference was not an artifact of tissue homogenization because both forms were detected after purification from mixed-tissue homogenates. These results suggest that mild, biospecific elution from a conformation-specific monoclonal antibody column may be a general technique applicable to the rapid isolation of proteins whose antigenic determinants can be altered with specific ligands.


Prevalence of Asymptomatic Mpox among Men Who Have Sex with Men, Japan, January-March 2023.
We prospectively assessed asymptomatic monkeypox virus infections among men who have sex with men in Tokyo, Japan, during the initial phase of the mpox epidemic. Our findings suggest that asymptomatic infections were likely underestimated and were comparable in magnitude to symptomatic infections, highlighting the need to improve testing accessibility among high-risk populations.


Toxoplasmic retinochoroiditis--a historical review and current concepts.
Toxoplasmic retinochoroiditis usually presents during the first three decades of life as a consequence of intra-uterine infection by Toxoplasma gondii. The ingestion of infected undercooked meat, or foodstuffs contaminated by infected cat faeces, constitute the primary sources of infection for the non-immune mother. It is thought that following congenital infection, Toxoplasma cysts remain dormant in otherwise normal retina and that acute retinochoroiditis is the result of reactivation of the parasite, perhaps by cyst rupture. Treatment is indicated for sight threatening disease and comprises anti-Toxoplasma agents. The addition of steroids may be required to diminish the inflammatory response. Photocoagulation of normal retina around focal lesions probably decreases the incidence of recurrent inflammation. Women should be advised not to eat undercooked meat and to avoid contact with cat excrement during pregnancy. These measures will decrease the incidence of both eye disease and the more severe manifestations of congenital toxoplasmosis, which include congenital abnormalities, mental retardation, hydrocephalus and blindness.


Application of visible-light photosensitization to form alkyl-radical-derived thin films on gold.
Visible-light irradiation of phthalimide esters in the presence of the photosensitizer [Ru(bpy)3]2+ and the stoichiometric reducing agent benzyl nicotinamide results in the formation of alkyl radicals under mild conditions. This approach to radical generation has proven useful for the synthesis of small organic molecules. Herein, we demonstrate for the first time the visible-light photosensitized deposition of robust alkyl thin films on Au surfaces using phthalimide esters as the alkyl radical precursors. In particular, we combine visible-light photosensitization with particle lithography to produce nanostructured thin films, the thickness of which can be measured easily using AFM cursor profiles. Analysis with AFM demonstrated that the films are robust and resistant to mechanical force while contact angle goniometry suggests a multilayered and disordered film structure. Analysis with IRRAS, XPS, and TOF SIMS provides further insights.


Uniform resampling of digitized contours.
This paper addresses the problem of the nonuniform intersample distance of digital curves obtained as a result of quantization of continuous contours on a square lattice. A resampling algorithm based on variable-factor interpolation and decimation is presented, and its performance is evaluated analytically and by computer simulations assuming the grid-intersect quantization. It is shown that the output of the resampling algorithm outperforms the original digital curve in terms of the average and maximum error in the measurement of length by 50 and 73 percent, respectively. The resampling algorithm can be used as a preprocessing stage in shape analysis systems to enhance their performance by increasing the accuracy and consistency of both local and global features such as curvature and the Fourier shape descriptors.


Prospects for new leprosy diagnostic tools, a narrative review considering ELISA and PCR assays.
Slit skin smear and histopathological examinations are currently the main laboratory tools used to aid the diagnosis of leprosy. However, their sensitivity is low, and many cases are not detected. New methodologies have been studied to develop more accurate tests. This narrative review aims to raise attention to the results of molecular (polymerase chain reaction) and serological (Enzyme-Linked Immunosorbent Assay) tests applied to the diagnosis of leprosy, and to summarize the available information about the former. Original scientific articles published in indexed international journals, whose study involved aspects of the diagnosis and classification of leprosy cases or home contacts, were selected. The data were extracted independently using a standardized method that dictated the inclusion of the following information: diagnosis in Paucibacillary and Multibacillary cases and in household contacts; sample number; sample type; study design; studied variables; statistical analysis employed; main results; and limitations identified. In clinical practice, the results from molecular and serological tests are assessed separately, with moderate sensitivity and specificity. However, an integrated study of these methodologies has been suggested for greater accuracy in diagnosis.


Accelerating the Pace of Cancer Prevention- Right Now.
As a nation, we underinvest in prevention and fail to implement strategies that ensure all population groups equitably share in the return on investment in prevention research and the benefits of prevention effectiveness. There is significant evidence indicating that by applying knowledge that we already have to reduce tobacco, inactivity, and obesity (known modifiable causes of cancer), we can prevent more than 50% of cancers. Vaccination against HPV, aspirin and selective estrogen receptor modulators, and screening programs further reduce risk. Evidence-based prevention strategies are inconsistently implemented across the United States. Substantial variation across States indicates that there is much room for improvement in implementation of prevention. Implementation science applies innovative approaches to identifying, understanding, and developing strategies for overcoming barriers to the adoption, adaptation, integration, scale-up, and sustainability of evidence-based interventions, tools, policies, and guidelines that will prevent cancer through application of evidence-based interventions. When we get implementation of prevention programs right and at scale, we achieve substantial population benefits. Although many efforts are underway to maximize our knowledge about the causes and treatments of cancer, we can achieve reductions in the cancer burden right now by doing what we already know. The time to start is now. Cancer Prev Res; 11(4); 171-84. ©2018 AACR.


Characterisation of sugar beet (Beta vulgaris L. ssp. vulgaris) varieties using microsatellite markers.
Sugar beet is an obligate outcrossing species. Varieties consist of mixtures of plants from various parental combinations. As the number of informative morphological characteristics is limited, this leads to some problems in variety registration research. We have developed 25 new microsatellite markers for sugar beet. A selection of 12 markers with high quality patterns was used to characterise 40 diploid and triploid varieties. For each variety 30 individual plants were genotyped. The markers amplified 3-21 different alleles. Varieties had up to 7 different alleles at one marker locus. All varieties could be distinguished. For the diploid varieties, the expected heterozygosity ranged from 0.458 to 0.744. The average inbreeding coefficient F(is) was 0.282 +/- 0.124, but it varied widely among marker loci, from F(is) = +0.876 (heterozygote deficiency) to F(is) = -0.350 (excess of heterozygotes). The genetic differentiation among diploid varieties was relatively constant among markers (F(st) = 0.232 +/- 0.027). Among triploid varieties the genetic differentiation was much lower (F(st) = 0.100 +/- 0.010). The overall genetic differentiation between diploid and triploid varieties was F(st) = 0.133 across all loci. Part of this differentiation may coincide with the differentiation among breeders' gene pools, which was Fst = 0.063. Based on a combination of scores for individual plants all varieties can be distinguished using the 12 markers developed here. The markers may also be used for mapping and in molecular breeding. In addition, they may be employed in studying gene flow from crop to wild populations.


Trial-based cost-effectiveness analysis of ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) versus DSAEK.
To evaluate the cost-effectiveness of ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) versus standard DSAEK. A cost-effectiveness analysis using data from a multicentre randomized clinical trial was performed. The time horizon was 12 months postoperatively. Sixty-four eyes of 64 patients with Fuchs' endothelial dystrophy were included and randomized to UT-DSAEK (n = 33) or DSAEK (n = 31). Relevant resources from healthcare and societal perspectives were included in the cost analysis. Quality-adjusted life years (QALYs) were determined using the Health Utilities Index Mark 3 questionnaire. The main outcome was the incremental cost-effectiveness ratio (ICER; incremental societal costs per QALY). Societal costs were €9431 (US$11 586) for UT-DSAEK and €9110 (US$11 192) for DSAEK. Quality-adjusted life years (QALYs) were 0.74 in both groups. The ICER indicated inferiority of UT-DSAEK. The cost-effectiveness probability ranged from 37% to 42%, assuming the maximum acceptable ICER ranged from €2500-€80 000 (US$3071-US$98 280) per QALY. Additional analyses were performed omitting one UT-DSAEK patient who required a regraft [ICER €9057 (US$11 127) per QALY, cost-effectiveness probability: 44-62%] and correcting QALYs for an imbalance in baseline utilities [ICER €23 827 (US$29 271) per QALY, cost-effectiveness probability: 36-59%]. Furthermore, the ICER was €2101 (US$2581) per patient with clinical improvement in best spectacle-corrected visual acuity (≥0.2 logMAR) and €3274 (US$4022) per patient with clinical improvement in National Eye Institute Visual Functioning Questionnaire-25 composite score (≥10 points). The base case analysis favoured DSAEK, since costs of UT-DSAEK were higher while QALYs were comparable. However, additional analyses revealed no preference for UT-DSAEK or DSAEK. Further cost-effectiveness studies are required to reduce uncertainty.


The declining demand for hospital care as a rationale for duty hour reform.
The regulation of duty hours of physicians in training remains among the most hotly debated subjects in medical education. Although recent duty hour reforms have been chiefly motivated by concerns about resident well-being and medical errors attributable to resident fatigue, the debate surrounding duty hour reform has infrequently involved discussion of one of the most important secular changes in hospital care that has affected nearly all developed countries over the last 3 decades: the declining demand for hospital care. For example, in 1980, we show that resident physicians in US teaching hospitals provided, on average, 1,302 inpatient days of care per resident physician compared to 593 inpatient days in 2011, a decline of 54%. This decline in the demand for hospital care by residents provides an under-recognized economic rationale for reducing residency duty hours, a rationale based solely on supply and demand considerations. Work hour reductions and growing requirements for outpatient training can be seen as an appropriate response to the shrinking demand for hospital care across the health-care sector.


Impact of Extent of Lymphadenectomy on Survival in Patients With Endometrial Cancer: A Matched Cohort Study.
This study aimed to determine whether a pelvic and para-aortic lymphadenectomy (PPAL) improves survival compared with a pelvic lymphadenectomy (PL) in patients with endometrial cancer. Data from all women operated for endometrial cancer between 1998 and 2013 were extracted from the Surveillance, Epidemiology and End Results database. Women treated with PL were matched with those treated with PPAL according to age and risk of recurrence. The primary endpoint was disease-specific survival (DSS). A total of 1015 patients who underwent PL were matched with 1015 patients who underwent PPAL. The 3-year DSS probabilities for patients at intermediate- and high-risk (IHR) of recurrence were similar in the PPAL group and the PL group. Multivariate analysis of prognostic factors indicated that in patients with an IHR of recurrence, PPAL did not reduce the risk of death compared with PL. For patients with an IHR of recurrence, the extent of lymphadenectomy does not impact DSS.


Final efficacy and safety results of pemetrexed continuation maintenance therapy in the elderly from the PARAMOUNT phase III study.
The PARAMOUNT Phase III trial showed that maintenance pemetrexed after pemetrexed plus cisplatin induction was well tolerated and effective for patients with advanced nonsquamous non-small-cell lung cancer. Approximately 17% of patients receiving maintenance therapy in this study were 70 years of age or older. Here we report efficacy and safety results from the PARAMOUNT study for elderly (≥70 years) and non-elderly (<70 years) patients. Final efficacy and safety data from the PARAMOUNT study were analyzed post hoc using subgroup analyses for elderly and non-elderly patients. The median age was 73 years in the elderly subgroup (n = 92) and 60 years in the non-elderly subgroup (n = 447). Subgroups had similar baseline characteristics, except for a higher percentage of males and patients with a performance status of one in the elderly subgroup. For elderly patients, the median PFS was 6.4 months for pemetrexed and 3.0 months for placebo; the median OS was 13.7 months for pemetrexed and 12.1 months for placebo. For non-elderly patients, the median PFS was 4.0 months for pemetrexed and 2.8 months for placebo; the median OS was 13.9 months for pemetrexed and 10.8 months for placebo. Elderly patients experienced similar levels of low-grade toxicities, but had a higher percentage of grade 3/4 anemia and neutropenia than non-elderly patients, although importantly, this did not translate into increased febrile neutropenia. Continuation maintenance pemetrexed had comparable survival and toxicity profiles in the elderly and non-elderly subgroups. However, grade 3/4 anemia and neutropenia were numerically higher for elderly patients.


Adsorption of bovine serum albumin on Zr co-sputtered a-C(:H) films: Implication on wear behaviour.
The use of protective coatings in biomedical field is an ongoing scientific challenge. Among different materials, carbon-based coatings are considered a potential surface treatment for orthopaedic implants. In this study, the effect of Zr incorporation in amorphous carbon coatings on the wear behaviour under protein containing lubrication was investigated. The coatings were deposited by dc unbalanced magnetron sputtering in Ar (non-hydrogenated) and Ar+CH4 (hydrogenated) discharges onto Ti based biomedical substrate. To improve the adhesion between the film and substrate a functional gradient Ti based layer was deposited (~550 nm). The surface wettability was evaluated to assess the effect of the Zr and hydrogen content. The films with Zr were found to be hydrophobic enhancing the protein adsorption onto the surface; no significant differences were found when H was incorporated in the films. The adsorption layer characterized by X-ray photoelectron spectroscopy showed a well defined nitrogen peak originating from the organic layer. The tribological properties of the film were evaluated by unidirectional pin-on-disc testing with diluted bovine serum lubrication and physiological solution at 37 ± 3C°. The friction and the wear of the coatings were very low compared to uncoated substrates in both lubrication conditions. The ability of the surfaces to adsorb proteins was considered as the driving force for wear resistance acting as a protecting layer. In addition, the incorporation of Zr decreased the wear of the counterbody (Ti alloy) due to higher albumin adsorption.


Recent mountain pine beetle outbreaks, wildfire severity, and postfire tree regeneration in the US Northern Rockies.
Widespread tree mortality caused by outbreaks of native bark beetles (Circulionidae: Scolytinae) in recent decades has raised concern among scientists and forest managers about whether beetle outbreaks fuel more ecologically severe forest fires and impair postfire resilience. To investigate this question, we collected extensive field data following multiple fires that burned subalpine forests in 2011 throughout the Northern Rocky Mountains across a spectrum of prefire beetle outbreak severity, primarily from mountain pine beetle (Dendroctonus ponderosae). We found that recent (2001-2010) beetle outbreak severity was unrelated to most field measures of subsequent fire severity, which was instead driven primarily by extreme burning conditions (weather) and topography. In the red stage (0-2 y following beetle outbreak), fire severity was largely unaffected by prefire outbreak severity with few effects detected only under extreme burning conditions. In the gray stage (3-10 y following beetle outbreak), fire severity was largely unaffected by prefire outbreak severity under moderate conditions, but several measures related to surface fire severity increased with outbreak severity under extreme conditions. Initial postfire tree regeneration of the primary beetle host tree [lodgepole pine (Pinus contorta var. latifolia)] was not directly affected by prefire outbreak severity but was instead driven by the presence of a canopy seedbank and by fire severity. Recent beetle outbreaks in subalpine forests affected few measures of wildfire severity and did not hinder the ability of lodgepole pine forests to regenerate after fire, suggesting that resilience in subalpine forests is not necessarily impaired by recent mountain pine beetle outbreaks.


Controls on Dissolved Organic Carbon Bioreactivity in River Systems.
Inland waters transport, transform and retain significant amounts of dissolved organic carbon (DOC) that may be biologically reactive (bioreactive) and thus potentially degraded into atmospheric CO2. Despite its global importance, relatively little is known about environmental controls on bioreactivity of DOC as it moves through river systems with varying water residence time (WRT). Here we determined the influence of WRT and landscape properties on DOC bioreactivity in 15 Swedish catchments spanning a large geographical and environmental gradient. We found that the short-term bioreactive pools (0-6 d of decay experiments) were linked to high aquatic primary productivity that, in turn, was stimulated by phosphorus loading from forested, agricultural and urban areas. Unexpectedly, the percentage of long-term bioreactive DOC (determined in 1-year experiments) increased with WRT, possibly due to photo-transformation of recalcitrant DOC from terrestrial sources into long-term bioreactive DOC with relatively lower aromaticity. Thus, despite overall decreases in DOC during water transit through the inland water continuum, DOC becomes relatively more bioreactive on a long time-scale. This increase in DOC bioreactivity with increasing WRT along the freshwater continuum has previously been overlooked. Further studies are needed to explain the processes and mechanisms behind this pattern on a molecular level.


Toxic impact of phosphamidon on acid phosphatase of prawn, Metapenaeus monoceros (Fabricius).
Activity levels of acid phosphatase (ACPase) in midgut gland and muscle tissues of penaeid prawn, Metapenaeus monoceros were studied after exposure to selected sublethal concentrations of phosphamidon after acute and chronic exposure. Phosphamidon was found to elevate the activity levels of ACPase in the selected tissues. The rate of elevation of ACPase is dose-dependant and is more at higher concentrations. Acute and chronic exposure to phosphamidon creates disturbances in the normal functioning at the cellular level in the tissues of prawn, M. monoceros.


SCRIB controls apical contractility during epithelial differentiation.
Although mutations in the SCRIB gene lead to multiple morphological organ defects in vertebrates, the molecular pathway linking SCRIB to organ shape anomalies remains elusive. Here, we study the impact of SCRIB-targeted gene mutations during the formation of the gut epithelium in an organ-on-chip model. We show that SCRIB KO gut-like epithelia are flatter with reduced exposed surface area. Cell differentiation on filters further shows that SCRIB plays a critical role in the control of apical cell shape, as well as in the basoapical polarization of myosin light chain localization and activity. Finally, we show that SCRIB serves as a molecular scaffold for SHROOM2/4 and ROCK1 and identify an evolutionary conserved SHROOM binding site in the SCRIB carboxy-terminal that is required for SCRIB function in the control of apical cell shape. Our results demonstrate that SCRIB plays a key role in epithelial morphogenesis by controlling the epithelial apical contractility during cell differentiation.


Protective effect of S-adenosyl-L-methionine on bromobenzene- and D-galactosamine-induced toxicity to isolated rat hepatocytes.
The protective effect of S-adenosyl-L-methionine (SAMe) on bromobenzene (BB)- or D-galactosamine (GalN)-induced damage to isolated rat hepatocytes and its effect on cellular glutathione (GSH) levels were investigated. SAMe at concentrations of 0.5 to 3.0 mmol/L significantly reduced lactate dehydrogenase leakage from cells exposed to 1.6 mmol/L BB (P < .05 to .001) during 2 hours' incubation. GalN at 25 to 50 mmol/L induced a marked increase of LDH leakage from the cells during the later stage of 24 hours' incubation and SAMe at 1.0 mmol/L clearly attenuated the LDH leakage in GalN (25 mmol/L)-exposed cells. The GSH content in the cells exposed to 2.4 mmol/L BB for 150 minutes was markedly decreased, and further decreased during 24 hours' incubation. SAMe (1.5 mmol/L) both reduced LDH leakage and corrected GSH depletion in cells exposed to 2.4 mmol/L BB. The GSH content in 25 and 50 mmol/L GalN-exposed cells was strikingly diminished to 51.2% and 32.8% of the controls, respectively, during 24 hours' of exposure. SAMe at 1.5 mmol/L significantly reduced the loss in GSH content in 25 mmol/L GalN-exposed cells. The findings show that SAMe has beneficial effects on both BB- and GalN-induced toxicity to rat hepatocytes. The main mechanism behind the protective effect of SAMe on BB and GalN toxicity seems to be associated with enhancement of GSH synthesis in the cells.


Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies.
Neurotropic viral infections continue to pose a serious threat to human and animal wellbeing. Host responses combatting the invading virus in these infections often cause irreversible damage to the nervous system, resulting in poor prognosis. Rabies is the most lethal neurotropic virus, which specifically infects neurons and spreads through the host nervous system by retrograde axonal transport. The key pathogenic mechanisms associated with rabies infection and axonal transmission in neurons remains unclear. Here we studied the pathogenesis of different field isolates of lyssavirus including rabies using ex-vivo model systems generated with mouse primary neurons derived from the peripheral and central nervous systems. In this study, we show that neurons activate selective and compartmentalized degeneration of their axons and dendrites in response to infection with different field strains of lyssavirus. We further show that this axonal degeneration is mediated by the loss of NAD and calpain-mediated digestion of key structural proteins such as MAP2 and neurofilament. We then analysed the role of SARM1 gene in rabies infection, which has been shown to mediate axonal self-destruction during injury. We show that SARM1 is required for the accelerated execution of rabies induced axonal degeneration and the deletion of SARM1 gene significantly delayed axonal degeneration in rabies infected neurons. Using a microfluidic-based ex-vivo neuronal model, we show that SARM1-mediated axonal degeneration impedes the spread of rabies virus among interconnected neurons. However, this neuronal defense mechanism also results in the pathological loss of axons and dendrites. This study therefore identifies a potential host-directed mechanism behind neurological dysfunction in rabies infection. This study also implicates a novel role of SARM1 mediated axonal degeneration in neurotropic viral infection.


The Fgfr2(S252W/+) mutation in mice retards mandible formation and reduces bone mass as in human Apert syndrome.
Apert syndrome is a common craniosynostosis caused by gain-of-function missense mutations of fibroblast growth factor receptor 2 (FGFR2). Mice with the FGFR2 S252W mutation can elucidate the mechanism by which the human Apert syndrome phenotypes arise. However, many studies have focused on mutant skull and long bone malformation, only few studies have focused on mandible changes. Bone formation and micro-architecture between 28- and 56-day-old mutant mice and controls were compared to investigate the changes in the mandibular micro-architecture caused by the Fgfr2(S252W/+) mutation to provide a basis for exploring the pathogenesis and therapeutic measures of human Apert syndrome. Fgfr2(S252W/+) mutant mice were established, and their general characteristics, including weight, naso-anal length, and calcium and phosphate content in serum and bone were tested. Calcein labeling, tartrate-resistant acid phosphatase staining and toluidine blue staining were used to detect osteoblast and osteoclast activities. H&E staining and micro-CT detection were used to test micro-architecture changes. The changes in mineral apposition rate and micro-architecture of the Fgfr2(S252W/+) mice were statistically significant; however, the magnitude of the micro-architecture became less with age. The Fgfr2(S252W/+) mutation may retard mandibular bone formation, decreased bone volume, and compromised skeletal architecture by regulating both osteoblastogenesis and osteoclastogenesis.


Innovations in anesthesia pre-screening through data systems and telecommunications.
In summary, the anesthesia pre-screening concept along with the supporting computer systems allow for fingertip nursing informatics, data collection, and retrievability, providing the continuity of care so emphasized in health care today. Departmental efficiency is maximized in both processing and communicating the patient information for the caregivers through the up-to-the-minute accuracy and safety built into the data system. At this point in APS implementation, the scope of cost-savings has yet to be fully identified, yet the perception is that it is quite substantial. At the same time, recent research results confirm our hypothesis that the personal touch provided by APS phone screening and individual case management has improved patient safety, convenience, and satisfaction along with overall effectiveness. Since the CAPS system will grow in scope and complexity over the next few years, the system will be migrated to a clientserver configuration. Although "client-server" may be an overused term, its potential for improved data accessibility, integrity, and raw processing throughput is great once the field solidifies in this area. The addition of graphical user interfaces and natural language facilities will further enhance the ease of use of the system. In the near term, an on-line version of the Physician's Desk Reference will be added for use during patient calls. This computerized version offers speed as well as a more comprehensive searching ability as opposed to its tree-based cousin.


Ornithine decarboxylase activity in embryos depends on temperature of development rather than on the stage of development. Molecular adaptation to temperature changes in poikilothermic animals.
The activity of ornithine decarboxylase (ODC) (the key enzyme of polyamine synthesis) in different poikilothermic animals depends on the temperatures at which they were kept just before the enzyme assay. With an increase in temperature (within physiological limits) ODC activity rises 5-25-fold within several hours. With a decrease in temperature it falls at the same rate. This effect, studied on loach (Misgurnus fossilis) embryos in detail, was also shown for embryos, larvae and some adult tissues of many species. It is not, however, observed in homoiothermic animals (chick embryos and mammalian cells), nor in bacteria and plants. Changes in polyamine concentrations follow those in ODC activity, but more slowly and to a lesser extent. It is assumed that modulation of ODC activity changes as a result of its synthesis and degradation. We suggest that the temperature-dependence of ODC activity is a mechanism of adaptation which maintains the optimal cellular concentration of polyamines for each temperature.


Mineral content of culinary and medicinal plants cultivated by Hmong refugees living in Sacramento, California.
Since the end of the American-Vietnamese War in 1975, more than 1.5 million refugees from Southeast Asia have resettled in the United States. Included among these displaced persons were the Hmong from Laos, a subsistence-based, shifting-cultivation, agricultural society. Hmong who resettled in urban areas have viewed vacant lots adjacent to urban dwellings as potential garden sites for production of familiar herbs and vegetables. In the present study exotic culinary and medicinal herbs grown by Hmong refugees in Sacramento, California were identified and analyzed for mineral composition. The herbs grown in these urban gardens were significant ingredients of Hmong recipes, and herb leaves, or infusions of steamed herb leaves were widely consumed as a component of pregnancy and post-partum diets. Six common species, Acorus gramineus, aff. Angelica, Dendranthema indicum, Eupatorium lindleyana, Sedum aff. sarmentosum, and Sedum aff. spectabile, were used in combination to season chicken. Polygonum odoratum, also widely cultivated, was used to season fish. Exotic culinary-medicinal species with highest mineral profiles included: Basella alba (Ca, Mg, Mn, Zn); Houttuynia cordata (Fe, Mg, Mn); Justica gendarussa (Ca, Mg, Zn); and Polygonum odoratum (Ca, Mg, Mn). While vacant lots sometimes are heavy metal contamination sites, we found no detectable levels of arsenic, cadmium, chromium, or lead in the samples analyzed.


Evaluation of the protective effect of Myrtus communis in scopolamine-induced Alzheimer model through cholinergic receptors.
Alzheimer's disease is a progressive neurodegenerative disorder causing common health problem with increasing age. Evidences show that the key symptoms of AD are mainly caused by cholinergic system dysfunction which has a role in cognitive disorders. Cholinergic pathways especially muscarinic receptors like M1 subtype also have a major role in learning, memory, cognitive functions and emotional state. There is no available permanent treatment currently to cure AD or to change its progression. This study was designed to investigate the factors that play important role in pathogenesis of AD and to compare the effects of Galantamine treatment with effects of Myrtus communis treatment. The expression level of M1, ACh, BDNF; AChE activity, GSH level, MDA and MPO activity and AChE gene expression were investigated in scopolamine-induced rat model. Results showed that, administration of MC significantly improves the SCOP-induced reduction of latency and object recognition time; increasing BDNF, M1 and ACh receptor expression levels in the different brain regions. Additionally, MC showed an increased in AChE by enhancing GSH activity and reducing MDA level and MPO activity. In conclusion MC considered as a possible novel therapeutic approach that can be a valuable alternative way in the prevention and treatment of AD.


Iron deficiency in heart failure: diagnosis and clinical implications.
Iron deficiency is a widely prevalent finding in patients with heart failure, observed on average in 50% of outpatients and up to 80% of acute patients, regardless of the ejection fraction and the presence of anaemia, being an independent predictor of worst functional capacity and reduced survival. The definition of iron deficiency in heart failure considers the state of chronic inflammation that characterizes the pathology, recognizing a discriminating role for transferrin saturation. The studies conducted so far, which focused on the patient with heart failure with at least moderately reduced ejection fraction, have shown clinical benefit with intravenous supplementation of ferric carboxymaltose in terms of functional capacity, quality of life, laboratory markers of disease and inflammation, and possible reduction of re-hospitalizations, but not in terms of mortality. Based on this evidence, guidelines recommend intravenous ferric carboxymaltose in decompensated and iron-deficient patients, while research is at work to investigate the clinical impact of supplementation in contexts not yet examined, such as that of decompensation in patients with heart failure and preserved ejection fraction.


Evaluation of lifestyle and dietary inflammatory score and their relationship with the odds of depression, stress, and anxiety in adults living in Yazd, Iran; based on YaHS and TAMYZ cohort study.
Mental disorders such as depression, anxiety and stress are becoming more common worldwide. The aim of this study was to examine the relationship between dietary inflammations scores (DIS) and lifestyle inflammation scores (LIS) and the risk of depression, stress, and anxiety in a large sample of Iranian adults. This study was based on 5579 adults (20-70 years) who participated in the Yazd Health Study (YaHS). The DIS score was calculated from the intake of 19 food groups and the LIS score was derived from four components. Multivariable logistic regression models were used to estimate the odds ratio (ORs) and 95 % confidence interval (CI) of depression, stress, and anxiety across quartiles of DIS and LIS. 2749 of the participants (46 % male) had anxiety, depression and stress. According to the adjusted model, there was a positive association between LIS and the risk of anxiety (OR: 1.23, 95 % CI: 1.01-1.49) and depression (OR: 1.39, 95 % CI: 1.14-1.69, P for trend: 0.03). However, there was no significant association between LIS and the risk of stress. There was also no significant association between DIS and the risk of anxiety, depression and stress. This study demonstrated that higher LIS scores were associated with depression and anxiety. It is suggested that following a LIS that includes smoking status, physical activity, alcohol consumption, and body mass index as indicators of the inflammatory promoting lifestyle, may increase the risk of depression and anxiety.


[Redox properties of peptides potentially regulating animal hibernation].
Weak redox properties of peptides isolated from the brain of hibernating animals were determined in reactions with free radicals. The peptides Thr-Ser-Lys-Tyr-Arg (NKT) and Tyr-Arg diminished concentration of anion-radicals of dye excited by light, thus demonstrating electron-acceptor properties toward radicals. In contrast, the peptides Thr-Ser-Lys-Tyr (RZ-5) and Asp-Tyr acted as electron donors in the same radical reactions. The possible role of redox properties of these peptides in their regulation of Ca currents in excitable tissues is discussed.


CD133+ endothelial-like stem cells restore neovascularization and promote longevity in progeroid and naturally aged mice.
The stem cell theory of aging dictates that a decline in the number and/or function of stem cells causes tissue degeneration and aging; however, it still lacks unequivocal experimental support. Here, using lineage tracing and single-cell transcriptomics, we identify a population of CD133+ bone marrow-derived endothelial-like cells (ELCs) as potential endothelial progenitor cells, which contribute to tubular structures in vitro and neovascularization in vivo. We demonstrate that supplementation with wild-type and young ELCs respectively restores neovascularization and extends lifespan in progeric and naturally aged mice. Mechanistically, we identify an upregulation of farnesyl diphosphate synthase (FDPS) in aged CD133+ ELCs-a key enzyme in isoprenoid biosynthesis. Overexpression of FDPS compromises the neovascularization capacity of CD133+ ELCs, whereas FDPS inhibition by pamidronate enhances neovascularization, improves health measures and extends lifespan in aged mice. These findings highlight stem cell-based strategies for the treatment of progeria and age-related pathologies.


Drug-induced expansion and differentiation of V gamma 9V delta 2 T cells in vivo: the role of exogenous IL-2.
Human Vgamma9Vdelta2 T cells recognize nonpeptidic Ags generated by the 1-deoxy-d-xylulose 5-phosphate (many eubacteria, algae, plants, and Apicomplexa) and mevalonate (eukaryotes, archaebacteria, and certain eubacteria) pathways of isoprenoid synthesis. The potent Vgamma9Vdelta2 T cell reactivity 1) against certain cancer cells or 2) induced by infectious agents indicates that therapeutic augmentations of Vgamma9Vdelta2 T cell activities may be clinically beneficial. The functional characteristics of Vgamma9Vdelta2 T cells from Macaca fascicularis (cynomolgus monkey) are very similar to those from Homo sapiens. We have found that the i.v. administration of nitrogen-containing bisphosphonate or pyrophosphomonoester drugs into cynomolgus monkeys combined with s.c. low-dose (6 x 10(5) U/animal) IL-2 induces a large pool of CD27+ and CD27- effector/memory T cells in the peripheral blood of treated animals. The administration of these drugs in the absence of IL-2 is substantially less effective, indicating the importance of additional exogenous costimuli. Shortly after the costimulatory IL-2 treatment, only gammadelta (but not alphabeta) T cells expressed the CD69 activation marker, indicating that Vgamma9Vdelta2 T lymphocytes are more responsive to low-dose IL-2 than alphabeta T cells. Up to 100-fold increases in the numbers of peripheral blood Vgamma9Vdelta2 T cells were observed in animals receiving the gammadelta stimulatory drug plus IL-2. Moreover, the expanded Vgamma9Vdelta2 T cells were potent Th1 effectors capable of releasing large amounts of IFN-gamma. These results may be relevant for designing novel (or modifying current) immunotherapeutic trials with nitrogen-containing bisphosphonate or pyrophosphomonoester drugs.


Large-scale circular RNA deregulation in T-ALL: unlocking unique ectopic expression of molecular subtypes.
Circular RNAs (circRNAs) are stable RNA molecules that can drive cancer through interactions with microRNAs and proteins and by the expression of circRNA encoded peptides. The aim of the study was to define the circRNA landscape and potential impact in T-cell acute lymphoblastic leukemia (T-ALL). Analysis by CirComPara of RNA-sequencing data from 25 T-ALL patients, immature, HOXA overexpressing, TLX1, TLX3, TAL1, or LMO2 rearranged, and from thymocyte populations of human healthy donors disclosed 68 554 circRNAs. Study of the top 3447 highly expressed circRNAs identified 944 circRNAs with significant differential expression between malignant T cells and normal counterparts, with most circRNAs displaying increased expression in T-ALL. Next, we defined subtype-specific circRNA signatures in molecular genetic subgroups of human T-ALL. In particular, circZNF609, circPSEN1, circKPNA5, and circCEP70 were upregulated in immature, circTASP1, circZBTB44, and circBACH1 in TLX3, circHACD1, and circSTAM in HOXA, circCAMSAP1 in TLX1, and circCASC15 in TAL-LMO. Backsplice sequences of 14 circRNAs ectopically expressed in T-ALL were confirmed, and overexpression of circRNAs in T-ALL with specific oncogenic lesions was substantiated by quantification in a panel of 13 human cell lines. An oncogenic role of circZNF609 in T-ALL was indicated by decreased cell viability upon silencing in vitro. Furthermore, functional predictions identified circRNA-microRNA gene axes informing modes of circRNA impact in molecular subtypes of human T-ALL.


Interplay between two RND systems mediating antimicrobial resistance in Brucella suis.
The RND-type efflux pumps are responsible for the multidrug resistance phenotype observed in many clinically relevant species. Also, RND pumps have been implicated in physiological processes, with roles in the virulence mechanisms of several pathogenic bacteria. We have previously shown that the BepC outer membrane factor of Brucella suis is involved in the efflux of diverse drugs, probably as part of a tripartite complex with an inner membrane translocase. In the present work, we characterize two membrane fusion protein-RND translocases of B. suis encoded by the bepDE and bepFG loci. MIC assays showed that the B. suis DeltabepE mutant was more sensitive to deoxycholate (DOC), ethidium bromide, and crystal violet. Furthermore, multicopy bepDE increased resistance to DOC and crystal violet and also to other drugs, including ampicillin, norfloxacin, ciprofloxacin, tetracycline, and doxycycline. In contrast to the DeltabepE mutant, the resistance profile of B. suis remained unaltered when the other RND gene (bepG) was deleted. However, the DeltabepE DeltabepG double mutant showed a more severe phenotype than the DeltabepE mutant, indicating that BepFG also contributes to drug resistance. An open reading frame (bepR) coding for a putative regulatory protein of the TetR family was found upstream of the bepDE locus. BepR strongly repressed the activity of the bepDE promoter, but DOC released the repression mediated by BepR. A clear induction of the bepFG promoter activity was observed only in the BepDE-defective mutant, indicating a regulatory interplay between the two RND efflux pumps. Although only the BepFG-defective mutant showed a moderate attenuation in model cells, the activities of both bepDE and bepFG promoters were induced in the intracellular environment of HeLa cells. Our results show that B. suis harbors two functional RND efflux pumps that may contribute to virulence.


Indole-3-carbinol improves neurobehavioral symptoms in a cerebral ischemic stroke model.
Stroke is one of the most common causes of death worldwide and also responsible for permanent disability. Ischemic stroke has been found to affect 80% of stroke patients. Recombinant tissue plasminogen activator (rtPA) is the widely used drug for the ischemic stroke with narrow therapeutic window. Indole-3-carbinol (I3C) is a natural compound obtained from brassica species having antithrombotic activity. Middle cerebral artery occlusion (MCAO) model was used followed by reperfusion after 2 h of ischemia for the evaluation of the I3C against ischemic stroke. After reperfusion, I3C (12.5, 25, and 50 mg/kg) was given by oral route once daily and continued up to the 14th day. Behavioral studies including postural reflex, forelimb placing, and cylinder tests showed I3C attenuated the MCAO-induced increase in average score and asymmetry score efficiently. Mean cerebral blood flow (CBF) was improved by treatment with I3C (12.5 mg/kg) by 60% of baseline at 6 h. I3C inhibited ADP-induced platelet aggregation and reduced ischemic volume significantly. It also inhibited in vitro the ADP-induced platelet aggregation in healthy human volunteers. I3C improves behavioral scores and mean CBF after focal cerebral ischemia in rats. Furthermore, I3C showed prophylactic anti-thrombotic activity against carrageenan induced tail thrombosis. Therefore, preclinical evidence points to I3C as a potential candidate for use in cerebral ischemic stroke.


Potential value of major antigenic protein 2 for serological diagnosis of heartwater and related ehrlichial infections.
Cowdria ruminantium is the etiologic agent of heartwater, a disease causing major economic loss in ruminants in sub-Saharan Africa and the Caribbean. Development of a serodiagnostic test is essential for determining the carrier status of animals from regions where heartwater is endemic, but most available tests give false-positive reactions with sera against related Erhlichia species. Current approaches rely on molecular methods to define proteins and epitopes that may allow specific diagnosis. Two major antigenic proteins (MAPs), MAP1 and MAP2, have been examined for their use as antigens in the serodiagnosis of heartwater. The objectives of this study were (i) to determine if MAP2 is conserved among five geographically divergent strains of C. ruminantium and (ii) to determine if MAP2 homologs are present in Ehrlichia canis, the causative agent of canine ehrlichiosis, and Ehrlichia chaffeensis, the organism responsible for human monocytic ehrlichiosis. These two agents are closely related to C. ruminantium. The map2 gene from four strains of C. ruminantium was cloned, sequenced, and compared with the previously reported map2 gene from the Crystal Springs strain. Only 10 nucleic acid differences between the strains were identified, and they translate to only 3 amino acid changes, indicating that MAP2 is highly conserved. Genes encoding MAP2 homologs from E. canis and E. chaffeensis also were cloned and sequenced. Amino acid analysis of MAP2 homologs of E. chaffeensis and E. canis with MAP2 of C. ruminantium revealed 83.4 and 84.4% identities, respectively. Further analysis of MAP2 and its homologs revealed that the whole protein lacks specificity for heartwater diagnosis. The development of epitope-specific assays using this sequence information may produce diagnostic tests suitable for C. ruminantium and also other related rickettsiae.


Fast and accurate three-dimensional point spread function computation for fluorescence microscopy.
The point spread function (PSF) plays a fundamental role in fluorescence microscopy. A realistic and accurately calculated PSF model can significantly improve the performance in 3D deconvolution microscopy and also the localization accuracy in single-molecule microscopy. In this work, we propose a fast and accurate approximation of the Gibson-Lanni model, which has been shown to represent the PSF suitably under a variety of imaging conditions. We express the Kirchhoff's integral in this model as a linear combination of rescaled Bessel functions, thus providing an integral-free way for the calculation. The explicit approximation error in terms of parameters is given numerically. Experiments demonstrate that the proposed approach results in a significantly smaller computational time compared with current state-of-the-art techniques to achieve the same accuracy. This approach can also be extended to other microscopy PSF models.


[Migrane treatment in the Netherlands in the early twentieth century].
The treatment of migraine in the Netherlands underwent important changes in the beginning of the 20th century. Several factors played a role, including the development of analgesics (acetylsalicylic acid, phenacetin, and fampridine++) at the end of the 19th century. The introduction of phenobarbital for the treatment of epilepsy in 1912 resulted in prescription of this drug for migraine, because of the supposed similarities between both afflictions. Although ergotamine had been reported for the treatment of headache at the end of the 19th century and been recommended again during the 1920s, it appeared in the Dutch literature only at the end of the 1930s. Research abroad showed this drug to have vasoconstrictive properties in migraine, again confirming the vasogenic origin of the affliction. This is striking as vasodilating drugs had been prescribed for several years. The non-medical treatment largely remained as previously, notably the prescription of diets. The relation between migraine and anaphylaxis, based on research by the French school, was also investigated in the Netherlands and resulted in the prescription of diets to immunize against the proteins involved.


Physician-Patient Communication Course: When the Inauguration of a New Israeli Medical School Coincided with COVID-19 Pandemic.
The curriculum of the Adelson School of Medicine at Ariel University, the newly established sixth medical school in Israel, includes a simulation center-based extended course on physician-patient communication, aiming to help students master the core competency of interpersonal and communication skills. For more than a year following the emergence of the COVID-19 pandemic, the school suspended most face-to-face (F2F) encounters, transforming most teaching activities to remote platforms. The paper outlines the ways we adapted teaching of this course to these circumstances, the reactions of students and mentors to the changes and results of 1st year students' survey. During the lockdown in the first year 48 of 70 first-year students participated in a voluntary anonymous online evaluation of the course assessing motivation to become a physician; perceptions, feelings and attitudes towards the communication course, and advantages and disadvantages of online and F2F medical interviews. 46.1% of the responding students reported that the pandemic strengthened their desire to become physicians. 56.3% claimed that they were able to a relatively large extent to empathize with COVID-19 patients who were exposed to the virus; 79.1% viewed their mentors as positive role models of communication skills. The students were able to receive and offer social support to their peers. They evaluated very highly the short instructional videos produced by the faculty. During the lockdown, the respondents generally indicated positive attitudes towards the communication course, the mentors and the inclusion of physician-patient communication as a topic in medical education. The students and mentors reported many disadvantages and few advantages of remote learning. Yet inevitably remote learning including online-based simulations is a step towards preparations for future practice within virtual medical care and telemedicine. The limitations of this study include the cross-sectional design, small sample size and self-reporting.


Plasma asymmetric dimethylarginine concentrations are not related to differences in maximal oxygen uptake in endurance trained and untrained men.
What is the central question of this study? Is there an association of plasma concentration of asymmetric dimethylarginine, which is related to exercise capacity in patients with cardiovascular diseases, with oxygen delivery and subsequently exercise capacity in healthy subjects in the absence of the potentially confounding influence of inflammation and oxidative stress? What is the main finding and its importance? Plasma asymmetric dimethylarginine concentrations are not related to exercise capacity in healthy subjects, while O2 delivery in the working skeletal muscle during the maximal graded-exercise test is not associated with any of the l-arginine analogues. ADMA alone does not play a crucial role in local muscle perfusion and in maintaining exercise capacity. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis that could limit oxygen (O2 ) delivery in the working skeletal muscles by altering endothelium-dependent vasodilatation. Exercise capacity is associated with plasma ADMA concentrations in patients with cardiovascular diseases, but this issue has still not been investigated in healthy subjects. We aimed to determine whether plasma ADMA concentrations were negatively associated with exercise capacity in young healthy male subjects. Ten men with maximal oxygen uptake ( V ̇ O 2 max ) > 65 mL kg-1 min-1 were included in the high exercise capacity group (HI-FIT), and 10 men with V ̇ O 2 max < 45 mL kg-1 min-1 were included in the low exercise capacity group (LO-FIT). Plasma ADMA and other l-arginine analogue concentrations were measured before and after a maximal graded-exercise test by liquid chromatography-tandem mass spectrometry. Microvascular O2 delivery during exercise was estimated through the pattern from the sigmoid model of muscle deoxygenation in the vastus lateralis measured by near infrared spectroscopy. V ̇ O 2 max was 60% higher in the HI-FIT group (median: 70.2 mL kg-1 min-1 ; IQR: 68.0-71.9 mL kg-1 min-1 ) than in the LO-FIT group (median: 43.8 mL kg-1 min-1 ; IQR: 34.8-45.3 mL kg-1 min-1 ). Plasma ADMA concentrations did not differ between the LO-FIT and HI-FIT groups before (0.50 ± 0.06 vs. 0.54 ± 0.07 μmol L-1 , respectively) and after the maximal incremental exercise test (0.49 ± 0.08 vs. 0.55 ± 0.03 μmol L-1 , respectively). There was no significant association of plasma ADMA concentrations with the pattern of local muscle deoxygenation and exercise capacity. Exercise capacity and microvascular O2 delivery are not related to plasma ADMA concentrations in young healthy male subjects. Our findings show that ADMA does not play a crucial role in local muscle perfusion and in maintaining exercise capacity without pathological conditions.


Population screening of 75- and 76-year-old men and women for silent atrial fibrillation (STROKESTOP).
Atrial fibrillation (AF) is important because it is common and is a major cause of stroke unless treated with oral anticoagulant. The prevalence of AF increases with age as does the risk of stroke. At 75 years the risk from age alone is so high that current guidelines recommend anticoagulation even in the absence of other risk factors. Atrial fibrillation is often asymptomatic and only discovered by chance or when a stroke already has occurred. We have launched a major screening study for silent AF in which 25,000 Swedes aged 75 and 76 years are randomized to either participate in a screening programme using ambulant intermittent electrocardiogram (ECG) recording to detect silent AF, or act as a control group. Patients in whom AF is detected are offered cardiological examination and anticoagulant treatment according to current guidelines. The cohort and the controls will be followed prospectively for 5 years after the inclusion of the first participant. An interim analysis will be made after 3 years. Our hypothesis is that screening for AF will reduce stroke incidence in the screened population, and that this screening will prove to be cost effective. Secondary endpoints are: any thromboembolic event, intracranial bleeding, other major bleeding, first ever diagnosis of dementia, death from any cause, and a composite of these endpoints.


Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican.
Lumican, a prototypic leucine-rich proteoglycan with keratan sulfate side chains, is a major component of the cornea, dermal, and muscle connective tissues. Mice homozygous for a null mutation in lumican display skin laxity and fragility resembling certain types of Ehlers-Danlos syndrome. In addition, the mutant mice develop bilateral corneal opacification. The underlying connective tissue defect in the homozygous mutants is deregulated growth of collagen fibrils with a significant proportion of abnormally thick collagen fibrils in the skin and cornea as indicated by transmission electron microscopy. A highly organized and regularly spaced collagen fibril matrix typical of the normal cornea is also missing in these mutant mice. This study establishes a crucial role for lumican in the regulation of collagen assembly into fibrils in various connective tissues. Most importantly, these results provide a definitive link between a necessity for lumican in the development of a highly organized collagenous matrix and corneal transparency.


Experiences With Stress Among African American Men Living With Type 2 Diabetes: A Qualitative Inquiry.
Self-managing type 2 diabetes (T2D) is critical but often presents a challenge among African American men. Stress may exacerbate both mental and physical problems, which can lead to poor self-management; however, the evidence is sparse. The purpose of this manuscript is to examine the relationship the role of stress in type 2 diabetes management among a prospective group of African American men living in the southern United States. Nineteen African American men with T2D were recruited from barbershops and churches. Interviews were conducted using a semi structured interview guide. Transcripts were analyzed using a phenomenological approach and focused on identifying common themes describing the responses regarding any stress that the participants have pertaining to living with and managing T2D. The themes that emerged from the participant responses are: (a) experiencing less stress, (b) stress not attributed from diabetes, (c) avoid thinking about stress, and (d) some stress is prevalent. Overall, participants expressed either that diabetes was not attributing to the stress that they have or that they have less stress than they did prior to being diagnosed with T2D. In this sample of African American men, stress became a factor for some participants when considering the complications that can occur from diabetes. These findings suggest the need for key considerations to only incorporate general information about diabetes and stress management, but should be gender and culturally relevant to African American men.