Identification, Phylogeny, and Comparative Expression of the Lipoxygenase Gene Family of the Aquatic Duckweed, Spirodela polyrhiza, during Growth and in Response to Methyl Jasmonate and Salt.
Lipoxygenases (LOXs) (EC 18.104.22.168) catalyze the oxygenation of fatty acids and produce oxylipins, including the plant hormone jasmonic acid (JA) and its methyl ester, methyl jasmonate (MeJA). Little information is available about the LOX gene family in aquatic plants. We identified a novel LOX gene family comprising nine LOX genes in the aquatic plant Spirodela polyrhiza (greater duckweed). The reduced anatomy of S. polyrhiza did not lead to a reduction in LOX family genes. The 13-LOX subfamily, with seven genes, predominates, while the 9-LOX subfamily is reduced to two genes, an opposite trend from known LOX families of other plant species. As the 13-LOX subfamily is associated with the synthesis of JA/MeJA, its predominance in the Spirodela genome raises the possibility of a higher requirement for the hormone in the aquatic plant. JA-/MeJA-based feedback regulation during culture aging as well as the induction of LOX gene family members within 6 h of salt exposure are demonstrated.


Pretreatment with wortmannin alleviates lipopolysaccharide/d-galactosamine-induced acute liver injury.
Intestinal endotoxemia-induced liver injury is a common clinical disease which leads to liver failure and death. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, could be used for suppressing autophagy in vitro and in vivo. Autophagy is an evolutionarily conserved and lysosome dependent protein degradation pathway, which participates in various physiological and pathological processes. The present study aims to explore the effect of pretreatment with wortmannin on acute liver injury and the autophagy in acute liver injury. We demonstrated that wortmannin could downregulate the expression of phosphorylated extracellular regulated protein kinase and p65, decrease the production and release of hepatic inflammatory cytokines, and then reduce hepatocytes apoptosis and necrosis. More importantly, we found that autophagy was induced to increase in LPS/D-GalN-induced acute liver injury, and pretreatment with wortmannin could effectively inhibit increased autophagy in acute liver injury. In conclusion, these results indicate that wortmannin plays a protective role in LPS/D-GalN induced hepatocytotoxity maybe by inhibiting autophagy and could be acted as a target for the treatment of acute liver injury.


Intraguild Interactions of Three Biological Control Agents of the Fall Armyworm Spodoptera frugiperda (JE Smith) in Florida.
The fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), is a maize pest worldwide. Its host range comprises more than 350 reported plant species, and it is the primary insect pest attacking maize in Florida. Global trade has not only assisted but accelerated its invasion into the Eastern Hemisphere. Regular pesticide use promotes resistance in the species; therefore, there is an urgent need for alternative pest management strategies. This study evaluated the interactions of biological control agents within a similar guild. Some of the reported interactions could potentially lead to the integration of these agents within the same niche to increase biological control efficiency against the fall armyworm. We evaluated three biocontrol agents that are natural enemies of Lepidopteran pests, the true bugs Podisus maculiventris and Euthyrhynchus floridanus (Hemiptera: Pentatomidae) and a parasitoid, Cotesia marginiventris (Hymenoptera: Braconidae). Depending on their intraguild interactions, these agents could potentially be useful for biological control of the fall armyworm. The study investigated these three biocontrol agents and concluded that integrating these agents to control the fall armyworm is a possibility; however, only under certain conditions. Investigations were focused on evaluating the predator-parasitoid and devised pairing interactions. Predator response to prey in a choice or no-choice scenario and choices based on olfaction or other bodily cues were studied under experimental laboratory conditions.


Detection of acute renal ischemia in swine using blood oxygen level-dependent magnetic resonance imaging.
To determine the feasibility and sensitivity of blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) to detect acute renal ischemia, using a swine model, and to present the causes of variability and assess techniques that minimize variability introduced during data analysis. BOLD MRI was performed in axial and coronal planes of the kidneys of five swine. Color R2* maps were calculated and mean R2* values and 95% confidence intervals (CIs) for the cortex and medulla were determined for baseline, renal artery occlusion and reperfusion conditions. Paired Student's t-tests were used to determine significance. Mean R2* measurements increased from baseline during renal artery occlusion in the cortex (axial, 13.8-24.6 second(-1); coronal, 14.4-24.7 second(-1)) and medulla (axial, 19.3-32.2 second(-1); coronal, 20.1-30.7 second(-1)). These differences were significant for both the cortex (axial, P < 0.04; coronal, P < 0.005) and medulla (axial, P < 0.02; coronal, P < 0.0005). No significant change was observed in the contralateral kidney. R2* values were significantly higher than baseline for medulla and cortex during renal artery occlusion. More variability exists in R2* measurements in the medulla than the cortex and in the axial than the coronal plane.


Validation of instantaneous pressure gradients measured by continuous-wave Doppler in experimentally induced aortic stenosis.
The relation between catheter-measured and Doppler-derived aortic pressure gradients was examined in 8 open-chest dogs. A snare was placed around the proximal ascending aorta and adjusted to provide a wide range of gradient to left ventricular (LV) outflow. A continuous-wave Doppler transducer was placed above the level of the obstruction and angled to optimize the audio and spectral signals. Pressure tip transducer catheters recorded LV and ascending aortic pressures simultaneously with the Doppler signal. In 120 randomly selected sinus beats, Doppler-derived maximal gradient correlated well with maximal instantaneous catheter gradient from 4 to 179 mm Hg (r = 0.99). Mean gradients also were closely related (r = 0.98). For gradients above 100 mm Hg, the correlation remained good (r = 0.98), but for gradients below 50 mm Hg, the correlation was not as precise (r = 0.81). All 120 cycles were digitized at 10-ms intervals to examine the correspondence between the Doppler and catheter data throughout systole. For the 2,742 pairs of points so obtained, the correlation was excellent (r = 0.95). The close relation between Doppler-derived pressure gradient and that measured simultaneously by catheterization provides further validation of the use of continuous-wave Doppler in the assessment of aortic stenosis, not only at maximal gradient, but throughout the period of LV ejection.


Having fun! The role of workplace fun in enhancing employees' creative behaviors in Chinese work settings.
Digital platforms and tech giants have led to a rapid shift in values and traditional ways of working. Although "diligence" has long been essential for work success and promotion, employees in modern companies are reluctant to blindly follow this attitude. Many well-known Western companies, such as Facebook and Google, see fun in the workplace as conducive to productivity and creative behavior. We investigated the associations of fun at work with experienced fun, employees' creative behavior, managers' support for fun, and trust in a Chinese context using different scales. Discriminant validity was confirmed by confirmatory factor analysis. A total of 508 workers from Taiwan and mainland China participated in the study and completed questionnaires. A key finding was that fun at work was positively related to employees' creative behavior. In addition, moderators of managerial support for fun and trust between the workplace and experienced fun were confirmed. These results can serve as a reference for Chinese managers who want to encourage creative behaviors and prevent negative behaviors in the workplace. In practice, results suggest that fun should be allowed more in the workplace because it could contribute to positive outcomes. However, managers should create a workplace that is fun, allows for creativity, and at the same time leads to high productivity.


Unusual tumor in the left ventricular outflow tract.
We report an unusual case of a pseudocyst in the left ventricular outflow tract in a 58-year-old woman. The cyst was successfully resected by a transatrial approach.


Peliosis of the spleen. Report of a case associated with chronic myelomonocytic leukemia, presenting with spontaneous splenic rupture.
A 62-year-old man had chronic myelomonocytic leukemia (untreated) for a period of 8 years. He developed a sudden, spontaneous rupture of the spleen and a splenectomy was performed. Grossly and microscopically the spleen showed peliosis. The blood-filled cavities were similar to the pseudosinuses described in the spleen of hairy-cell leukemia. The lesion common to these disorders apparently is a progressive disappearance of lining cells and of ring fibers.


Genome-wide association replicates the association of Duffy antigen receptor for chemokines (DARC) polymorphisms with serum monocyte chemoattractant protein-1 (MCP-1) levels in Hispanic children.
Obesity is associated with a chronic low inflammatory state characterized by elevated levels of chemokines. Monocyte chemoattractant protein-1 (MCP-1) is a member of the cysteine-cysteine (CC) chemokine family and is increased in obesity. The purpose of this study was to identify loci regulating serum MCP-1 in obese Hispanic children from the Viva La Familia Study. A genome-wide association (GWA) analysis was performed in 815 children, ages 4-19 years, using genotypes assayed with the Illumina HumanOmni1-Quad v1.0 BeadChips. All analyses were performed in SOLAR using a linear regression-based test under an additive model of allelic effect, while accounting for the relatedness of family members via a kinship variance component. The strongest association for MCP-1 levels was found with a non-synonymous single nucleotide polymorphism (SNP), rs12075, resulting in an amino acid substitution (Asp42Gly) in the Duffy antigen receptor for chemokines (DARC) gene product (minor allele frequency=43.6%, p=1.3 × 10(-21)) on chromosome 1. Four other DARC SNPs were also significantly associated with MCP-1 levels (p<10(-16)-10(-6)). The Asp42Gly variant was associated with higher levels of MCP-1 and accounted for approximately 10% of its variability. In addition, MCP-1 levels were significantly associated with SNPs in chemokine receptor 3 (CCR3) and caspase recruitment domain family, member 9 (CARD9). In summary, the association of the DARC Asp42Gly variant with MCP-1 levels replicates previous GWA results substantiating a potential role for DARC in the regulation of pro-inflammatory cytokines.


GC-MS, FT-IR analysis of black fungus polysaccharides and its inhibition against skin aging in mice.
The monosaccharide compositions, molecular weights, structure were investigated for the black fungus polysaccharides. Analysis of sugar components by gas chromatograph-mass spectrometer (GC-MS) showed that component ratios of neutral sugars in the polysaccharides were Glc:Man=82.97:12.93. Fourier transform infrared (FT-IR) analysis showed that the band at about 1649cm(-1) can indicate the presence of CO groups or CC groups vibration in structures. Pharmacological experiment showed that black fungus polysaccharides administration could significantly reduce malondialchehyche (MDA), lipofuscin (LF) contents and enhance superoxide dismutase (SOD) activities in skin. This indicated that black fungus polysaccharides may slow down skin aging.


Visual assessment of causality in the Poisson effect.
When a material is stretched along a spatial axis, it is causally compressed along the orthogonal axis, as quantified in the Poisson effect. The present study examined how human observers assess this causality. Stimuli were video clips of a white rectangular region that was horizontally stretched while it was vertically compressed, with spatially sinusoidal modulation of the magnitude of vertical compressions. It was found that the Poisson's ratio-a well-defined index of the Poisson effect-was not an explanatory factor for the degree of reported causality. Instead, reported causality was explained by image features related to deformation magnitudes. Comparing a material's shape before and after deformation was not always required for the causality assessment. This suggests that human observers determine causality in the Poisson effect by using heuristics based on image features not necessarily related to the physical properties of the material.


Sensitivity of percutaneous endoscopy compared with ultrasonography in the detection of residue or mucosal lesions after topical gallbladder stone dissolution.
Early gallstone recurrence in some patients after "successful" percutaneous topical dissolution may be due to residual debris. An endoscope small enough to be introduced without dilating the existing percutaneous track was used for gallbladder examination after stone dissolution. The sensitivity of gallbladder endoscopy was compared with ultrasonography and double-contrast cholecystography for the detection of residual debris or mucosal lesions in 18 patients who underwent percutaneous topical dissolution. All examinations were performed before catheter removal and after the gallbladder was deemed stone-free by the traditionally employed technique of single-contrast cholecystography. Residual debris was detected in only one patient by ultrasonography and in none of the 18 patients by double-contrast cholecystography, yet endoscopy showed stone fragments ranging from 1 to 3 mm in 13 of the 18 patients. In all these patients, catheter repositioning and additional solvent perfusion resulted in elimination of the debris as assessed endoscopically. Two patients had endoscopically detected erosions. Double-contrast fluoroscopy found only one of these, whereas ultrasonography detected neither. Percutaneous gallbladder endoscopy is a more sensitive imaging modality for the detection of residual stone debris or mucosal lesions after gallstone dissolution.


Morphostructural data and phylogenetic relationships of a new cnidarian myxosporean infecting spleen of an economic and ecological important bryconid fish from Brazil.
A new cnidarian myxosporean infecting the spleen of an economic and ecological important bryconid fish (Salminus franciscanus) is described based on integrative taxonomic approach including morphological, ultrastructural, biological traits, geography, molecular data and phylogenetic analysis. In a total of thirty specimens examined, nineteen (63.3%) were infected by an undescribed parasite species belonging to the genus Myxobolus. Plasmodial development was asynchronous, with young development in the periphery and mature myxospores in the central area and without projections and microvilli in the plasmodial wall. Mature myxospores were ovoid in shape and measured 7.9 ± 0.2 μm (7.6-8.1 μm) in length and 5.4 ± 0.1 μm (5.0-5.6 μm) in width. The two polar capsules were equal in size, occupying a little more than half of the myxospore body, measuring 4.0 ± 0.2 μm (3.9-4.1 μm) in length and 1.7 ± 0.1 μm (1.5-1.8 μm) in width. The polar tubules coiled in six turns, perpendicular to the long axis of polar capsule. Phylogenetic analysis placed the new species within a clade containing nine myxobolid species from South American characiforms fish and appears as a close species of Myxobolus pantanalis. Nevertheless, the sequences of the new species and M. pantanalis have a large genetic divergence of 13.5% in their SSU rDNA. In light of the differences observed from the integrative taxonomy, we confidently considered that this isolate is a new species of cnidarian myxosporean, M. douradae n. sp., increasing the knowledge of diversity of this enigmatic group of cnidarians.


Synthesis and tubulin-binding properties of new allocolchicinoids.
Allocolchicinoids with B- and C-ring variations were synthesized using sequential enyne-metathesis/ Diels-Alder reactions (A-->AB-->ABC approach) and evaluated for their inhibitory effect on tubulin assembly in vitro. (-)-Allocolchicine 11 with methyl ester at C10 and (+/-)-cyclopropyl allocolchicinoid 32 exhibit similar activity than (-)-colchicine (1), probably derived from a similar flexibility in the biphenyl system. The presence of methyl ester at C10 led to a little loss in potency in comparison with the series with methyl ester at C9. A complete loss of activity was observed for allocolchicine 9 with methyl ester at C11.


Sex Differences in Animal Models of Sodium-Valproate-Induced Autism in Postnatal BALB/c Mice: Whole-Brain Histoarchitecture and 5-HT2A Receptor Biomarker Evidence.
Autism spectrum disorder (ASD) is characterised by problems with social interaction, verbal and nonverbal communication and repetitive behaviour. In mice, the 14th postnatal day is believed to correspond to the third trimester of human embryonic development and is considered a vital period for central nervous system development. It has been shown that ASD affects 2 to 3 times more male than female individuals. In the present study, ASD was induced in 14 postnatal day (PND) BALB/c mice using valproic acid (VPA). VPA administration brought about substantial differences in the histoarchitecture of the brain in both male and female mice, linked to behavioural deficits. We observed that both male and female mice showed similar morphological changes in the prefrontal cortex, hippocampus and Purkinje cells. We also observed hair loss from PND 17 to 25, which was again similar between male and female mice. However, there were higher rates of change in the cerebral cortex, frontal cortex and temporal lobe and hippocampus in VPA-treated male animals. With respect to the cerebellum, we did not observe any alterations by haematoxylin and eosin (H&E) staining, but detailed morphological observation using scanning electron microscopy (SEM) showed a higher rate of phenotype changes in VPA-treated male animals. Moreover, 5-HT2A receptor protein levels were upregulated in the cerebral cortex, hippocampus and Purkinje cells in VPA-treated male mice compared with control animals and VPA-treated female mice, as shown by immunohistochemical analysis. Based on all these findings, we conclude that male animals are more susceptible to VPA-induced ASD than females.


A microbiology study on the wounds of pediatric patients undergoing spinal fusion for scoliosis.
Surgical site infection is a significant complication in posterior spinal fusion for scoliosis in pediatric and adolescent patients. Current literature demonstrates a lack of consensus regarding best prophylactic systemic and topical antibiotic regimens for reducing infection rates. This study aims to identify which common microbes are present at particular locations in the spine, and whether these are covered by our current systemic and topical antibiotic prophylaxis regimens. A prospective observational study at a National Children's Hospital was conducted on 21 consecutive patients who underwent elective surgery for spinal deformity. Swabs were taken from four layers of the spine, including the superficial skin surface at the start of the case (after surgical site preparation with povidone-iodine), the deep dermis, and the deep surgical bed at the end of exposure and again after the corrective maneuver prior to closure. At each layer, swabs were taken from the proximal, middle, and distal portion of the wound. Swabs were sent to the laboratory for culture and susceptibility testing. Thirteen (62%) of patients had positive microbial growth. Two microbes were identified, Staphylococcus epidermidis (9.5% of patients) and Cutibacterium acnes (Propionibacterium acnes) (52% of patients). 100% of these microbes were sensitive to cefazolin and vancomycin. 3% of patients had positive growth at the skin layer, 32% positive at the dermal layer, 17% positive after exposure, and 40% positive at the conclusion of the case (p = 0.006). No difference was observed in microbial presence in the upper thoracic, lower thoracic and lumbar spine. Despite adequate surgical site preparation and sterile procedure, microbial contamination remains abundant in the dermal layer and deeper in the spinal wound throughout the case.


Localization of antigenic determinants on bovine encephalitogenic protein: disease-inducing activity of fragment 44-68 in rabbits.
Region 44-68 of the basic protein of bovine central nervous system myelin is shown to have moderate encephalitogenic activity when rabbits are used as test animals. This finding is interpreted to mean that a second disease-inducing site, different from the decapeptide region enclosing residues 65-74 described by Shapira et al. (1971a) exists within region 44-89 of the encephalitogenic protein. On the other hand, we have been unable to induce clinical disease with peptide 69-89.


Octanoylglucuronide excretion in patients with a defective oxidation of medium-chain fatty acids.
Octanoyl-beta-D-glucuronide was identified in the urine of five patients with hypoketotic hypoglycemia and dicarboxylic aciduria due to a defective beta-oxidation of medium-chain fatty acids. Two subjects who ingested large amounts of medium-chain triglycerides also excreted large amounts of the glucuronide. The substance was extracted from the urine with ethyl acetate and analyzed by: (1) gas chromatography/mass spectrometry (GC-MS) of the trimethylsilyl derivative and (2) preparative one-dimensional thin-layer chromatography followed by enzymatic hydrolysis with beta-glucuronidase and again GC-MS. A quantitative analysis was performed indirectly by measuring the urinary bound octanoate after the removal of octanoylcarnitine. Octanoylglucuronide represents an additional mechanism for the detoxification of octanoate; its formation may be of help for the maintenance of carnitine homeostasis in patients with medium-chain acyl-CoA dehydrogenase deficiency.


Inhibition of acetyl-CoA carboxylase by spirotetramat causes growth arrest and lipid depletion in nematodes.
Plant-parasitic nematodes pose a significant threat to agriculture causing annual yield losses worth more than 100 billion US$. Nematode control often involves the use of nematicides, but many of them including non-selective fumigants have been phased out, particularly due to ecotoxicological concerns. Thus new control strategies are urgently needed. Spirotetramat (SPT) is used as phloem-mobile systemic insecticide targeting acetyl-CoA carboxylase (ACC) of pest insects and mites upon foliar application. However, in nematodes the mode of action of SPT and its effect on their development have not been studied so far. Our studies revealed that SPT known to be activated in planta to SPT-enol acts as a developmental inhibitor of the free-living nematode Caenorhabditis elegans and the plant-parasitic nematode Heterodera schachtii. Exposure to SPT-enol leads to larval arrest and disruption of the life cycle. Furthermore, SPT-enol inhibits nematode ACC activity, affects storage lipids and fatty acid composition. Silencing of H. schachtii ACC by RNAi induced similar phenotypes and thus mimics the effects of SPT-enol, supporting the conclusion that SPT-enol acts on nematodes by inhibiting ACC. Our studies demonstrated that the inhibition of de novo lipid biosynthesis by interfering with nematode ACC is a new nematicidal mode of action addressed by SPT, a well-known systemic insecticide for sucking pest control.


Determination of Dy substitution site in Nd2-xDyxFe14B by HAADF-STEM and illustration of magnetic anisotropy of "g" and "f" sites, before and after substitution.
Nd2Fe14B and Nd2-xDyxFe14B (x = 0.25, 0.50) particles were prepared by the modified co-precipitation followed by reduction-diffusion process. Bright field scanning transmission electron microscope (BF-STEM) image revealed the formation of Nd-Fe-B trigonal prisms in [- 101] viewing zone axis, confirming the formation of Nd2Fe14B/Nd2-xDyxFe14B. Accurate site for the Dy substitution in Nd2Fe14B crystal structure was determined as "f" site by using high-angle annular dark field scanning transmission electron microscope (HAADF-STEM). It was found that all the "g" sites are occupied by the Nd, meanwhile Dy occupied only the "f" site. Anti-ferromagnetic coupling at "f" site decreased the magnetic moment values for Nd1.75Dy0.25Fe14B (23.48 μB) and Nd1.5Dy0.5Fe14B (21.03 μB) as compared to Nd2Fe14B (25.50 μB). Reduction of magnetic moment increased the squareness ratio, coercivity and energy product. Analysis of magnetic anisotropy at constant magnetic field confirmed that "f" site substitution did not change the patterns of the anisotropy. Furthermore, magnetic moment of Nd2Fe14B, Nd2-xDyxFe14B, Nd ("f" site), Nd ("g" site) and Dy ("f" site) was recorded for all angles between 0° and 180°.


HLA-A*02:411 identified in a platelet donor from China.
HLA-A*02:411 differs from HLA-A*02:01:01:01 at nucleotides 770 and 771, where Threonine (T) replaces Isoleucine (I) at residue 233.


CTL responses to DCs stimulated with leishmania antigens detected by DCs expressing Leishmania gp63.
Leishmania is a pathogenic parasite which infects mononuclear cells in vertebrate hosts. Different strategies have been taken to develop immunity against Leishmania. DCs loaded with immunogenic antigen have resulted in different levels of Th1-type immune response and cytotoxic T lymphocytes (CTL) activity. To evaluate the potency of DCs primed with soluble Leishmania mexicana antigens (SLA) in developing CTL activity. DCs were loaded with SLA and injected to Balb/c mice. After two weeks the mice were sacrificed and their splenocytes were used as effector cells in a standard 4-hour cytotoxicity assay against DCs transfected with pcDNA3 containing L. mexicana gp63 gene. Immunization of Balb/c mice with DCs loaded with SLA resulted in high levels of CTL activity against DCs transfected with pcDNA3 containing L. mexicana gp63 gene. The results indicate a high potency for DCs primed with Leishmania antigens in inducing CTL activity, which can be used for developing an immunogenic vaccine against Leishmania.


Evaluation of seasonal influenza vaccines for H1N1pdm09 and type B viruses based on a replication-incompetent PB2-KO virus.
Vaccination is the first line of protection against influenza virus infection in humans. Although inactivated and live-attenuated vaccines are available, each vaccine has drawbacks in terms of immunogenicity and safety. To overcome these issues, our group has developed a replication-incompetent PB2-knockout (PB2-KO) influenza virus that replicates only in PB2-expressing cells. Here we generated PB2-KO viruses possessing the hemagglutinin (HA) and neuraminidase (NA) segments from H1N1pdm09 or type B viruses and tested their vaccine potential. The two PB2-KO viruses propagated efficiently in PB2-expressing cells, and expressed chimeric HA as expected. Virus-specific IgG and IgA antibodies were detected in mice immunized with the viruses, and the immunized mice showed milder clinical signs and/or lower virus replication levels in the respiratory tract upon virus challenge. Our results indicate that these PB2-KO viruses have potential as vaccine candidates.


The influence of redox conditions on aqueous-solid partitioning of arsenic and selenium in a closed coal ash impoundment.
A closed coal ash impoundment case study characterized the effects of field redox conditions on arsenic and selenium partitioning through monitoring of porewater and subsurface gas in conjunction with geochemical speciation modeling. When disposed coal ash materials and porewater were recovered for testing, oxidation led to lower arsenic and higher selenium concentrations in leaching test extracts compared to porewater measurements. Multiple lines of evidence suggest multiple mechanisms of arsenic retention are plausible and the concurrent presence of several redox processes and conditions (e.g., methanogenesis, sulfate reduction, and Fe(III)-reduction) controlled by spatial gradients and dis-equilibrium. Geochemical speciation modeling indicated that, under reducing field conditions, selenium was immobilized through the formation of insoluble precipitates Se(0) or FeSe while arsenic partitioning was affected by a progression of reactions including changes in arsenic speciation, reduction in adsorption due to dissolution and recrystallization of hydrous ferric oxides, and precipitation of arsenic sulfide minerals.


Racial and ethnic stratification in the relationship between homeownership and self-rated health.
Social scientists have long demonstrated that socioeconomic resources benefit health. More recently, scholars have begun to examine the potential stratification in the health returns different groups receive for a given resource. Motivated by fundamental cause theory, this paper examines homeownership as a salient health resource with potentially stratified benefits. Homeowners have significantly greater housing quality, wealth, neighborhood quality and integration, and physical and mental health than renters. However, there are compelling theoretical reasons to expect the health advantage of homeownership to be unequally distributed across racial and ethnic groups. Regression analyses of 71,874 household heads in the United States from the 2012 March Current Population Survey initially suggest all homeowners experience a significant health advantage. Further examination finds robust evidence for a homeowner health advantage among Whites, on par with the difference between the married and divorced. The advantage among minority households is considerably smaller, and not significant among Latinos or Asians. Conditioning on a broad array of observable characteristics, White homeowners emerge as exceptionally healthy compared to White renters and all minority groups. This leads to the unexpected finding that racial/ethnic differences in health are concentrated among homeowners. The findings demonstrate the interactive nature of racial/ethnic stratification in health through both access to and returns from socioeconomic resources.


Using isoform-specific inhibitors to target lipid kinases.
In this issue of Cell, Knight et al. (2006) present a detailed pharmacological analysis of the PI3 kinase (PI3-K) family using small molecule inhibitors. They conclude that p110alpha, a PI3-K isoform, has a critical role in insulin signaling. In a related Cancer Cell paper, Fan et al. (2006) show that blocking activation of both p110alpha and the kinase mTOR with a small molecule inhibitor limits the growth of gliomas.


A blood-assisted optical biosensor for automatic glucose determination.
A new approach for glucose determination in blood based on the spectroscopic properties of blood hemoglobin (Hb) is presented. The biosensor consists of a glucose oxidase (GOx) entrapped polyacrylamide (PAA) film placed in a flow cell. Blood is simply diluted with bidistilled water (150:1, v:v) and injected into the carrier solution. When reaching the PAA film, the blood glucose reacts with the GOx and the resulting H(2)O(2) reacts with the blood Hb. This produces an absorbance change in this compound. The GOx-PAA film can be used at least 100 times. Lateral reactions of H(2)O(2) with other blood constituents are easily blocked (by azide addition). The linear response range can be fitted between 20 and 1200 mg dL(-1) glucose (R.S.D. 4%, 77 mg dL(-1)). In addition to the use of untreated blood, two important analytical aspects of the method are: (1) the analyte concentration can be obtained by an absolute calibration method; and (2) the signal is not dependent on the oxygen concentration. A mathematical model relating the Hb absorbance variation during the reaction with the glucose concentration has been developed to provide theoretical support and to predict its application to other compounds after changing the GOx by another enzyme. The method has been applied to direct glucose determination in 10 blood samples, and a correlation coefficient higher than 0.98 was obtained after comparing the results with those determined by an automatic analyzer. As well as sharing some of the advantages of disposable amperometric biosensors, the most significant feature of this approach is its reversibility.


A paired-agent fluorescent molecular imaging strategy for quantifying antibody drug target engagement in in vivo window chamber xenograft models.
A paired-agent fluorescent molecular imaging strategy is presented as a method to measure drug target engagement in whole tumor imaging. The protocol involves dynamic imaging of a pair of targeted and control imaging agents prior to and following antibody therapy. Simulations demonstrated that antibody "drug target engagement" can be estimated within a 15%-error over a wide range of tumor physiology (blood flow, vascular permeability, target density) and antibody characteristics (affinity, binding rates). Experimental results demonstrated the first in vivo detection of binding site barrier, highlighting the potential for this methodology to provide novel insights in drug distribution/binding imaging.


The paradox of public participation in the healthcare in Poland--what citizens want, and what they think.
To assess the concept of public involvement in the decision-making process in the healthcare sector in Poland. A poll was conducted in 2011 on a representative random sample of residents of Poland. Respondents were asked about their preferences concerning the selection of the groups most appropriately representing public interests in the process of decision-making in the healthcare: Patients' Advocacy Groups (PAGs), Carers' Advocacy Groups (CAGs) and Citizens' Councils (CCs). A systematic literature review was performed to study real life examples of patients' involvement in the decision making processes in the Polish healthcare sector as well. In total, 83% of respondents would wish the participation of PAGs in decision-making concerning healthcare resources. The attitude to the engagement of CAGs and CCs was still positive but significantly lower, by 6 and 7 percentage points respectively. Some socio-demographic differences were observed. In the literature review, five examples of the Polish patients' empowerment and three cases of PAGs' engagement in decision making process were identified. Although its importance was met with a universal approval by the majority of responders, real life examples of public engagement in decision making process indicate there is still room for improvement in the Polish healthcare.


The ultraviolet absorption spectra of some chlorinated biphenyls.
The UV spectra of 29 chlorobiphenyls have been examined. With increasing chloro substitution in which there are less than two chlorine groups ortho to the Ph-Ph bond the lambdamax values for the K band (attributed to the conjugation between the two phenyl rings) are shifted to longer wavelengths and for the more highly substituted chlorobiphenyls there is also a bathochromic shift of the main band (due to the benzenoid skeleton). Introduction of two or more chlorine atoms ortho to the Ph-Ph bond results in a hipsochromic shift of K band and diminished xi value due to steric inhibition of resonance between the two phenyl rings. The sterically hindered chlorobiphenyls and the more highly chlorinated Aroclors also exhibit a series of low-intensity fine-structured absorption maxima between 268-302 nm. The UV spectra of chlor-biphenyls are particularly diagnostic with respect to the degree of substitution at the 2, 2', 6 and 6' positions and can be used in the structural analysis of separated chlorobiphenyls. The data may also aid in correlating the photochemical reactivities.


Imbalanced target prediction with pattern discovery on clinical data repositories.
Clinical data repositories (CDR) have great potential to improve outcome prediction and risk modeling. However, most clinical studies require careful study design, dedicated data collection efforts, and sophisticated modeling techniques before a hypothesis can be tested. We aim to bridge this gap, so that clinical domain users can perform first-hand prediction on existing repository data without complicated handling, and obtain insightful patterns of imbalanced targets for a formal study before it is conducted. We specifically target for interpretability for domain users where the model can be conveniently explained and applied in clinical practice. We propose an interpretable pattern model which is noise (missing) tolerant for practice data. To address the challenge of imbalanced targets of interest in clinical research, e.g., deaths less than a few percent, the geometric mean of sensitivity and specificity (G-mean) optimization criterion is employed, with which a simple but effective heuristic algorithm is developed. We compared pattern discovery to clinically interpretable methods on two retrospective clinical datasets. They contain 14.9% deaths in 1 year in the thoracic dataset and 9.1% deaths in the cardiac dataset, respectively. In spite of the imbalance challenge shown on other methods, pattern discovery consistently shows competitive cross-validated prediction performance. Compared to logistic regression, Naïve Bayes, and decision tree, pattern discovery achieves statistically significant (p-values < 0.01, Wilcoxon signed rank test) favorable averaged testing G-means and F1-scores (harmonic mean of precision and sensitivity). Without requiring sophisticated technical processing of data and tweaking, the prediction performance of pattern discovery is consistently comparable to the best achievable performance. Pattern discovery has demonstrated to be robust and valuable for target prediction on existing clinical data repositories with imbalance and noise. The prediction results and interpretable patterns can provide insights in an agile and inexpensive way for the potential formal studies.


Adlay hull extracts attenuate β-amyloid-induced neurotoxicity and oxidative stress in PC12 cells through antioxidative, anti-inflammatory, and antiapoptotic activities.
Alzheimer's disease (AD) is characterized by accumulation of β-amyloid (Aβ) in senile plaques, contributing to oxidative stress, mitochondrial diseases, and synaptic atrophy, consequently leading to the deterioration of brain function. Adlay (Coix lacryma-jobi L.) is an annual botanical. Here, a 95% ethanol extract of adlay hull (AHEE) was partitioned by ethyl acetate (AHEAE), n-butanol (AHBUE), and water (AHWE), and the effects of these extracts on lipopolysaccharide (LPS)-induced RAW264.7 cells and Aβ-induced PC12 cells, as experimental models of neurotoxicity, were evaluated. The expression of anti-inflammatory and antiapoptosis-related proteins was investigated and AHEE, AHEAE, and AHWE were found to exert anti-inflammatory effects. AHWE exhibited antiapoptotic effects and inhibited inducible nitric oxide synthase expression and nitric oxide production. We investigated the protective effects of AHWE against Aβ-induced neurotoxicity in dPC12 cells and explored the underlying mechanism. Pretreatment with AHWE significantly attenuated cell death and Aβ-mediated increase in B cell lymphoma (Bcl)-2/Bax ratio. AHWE significantly inhibited Aβ and enhanced protein kinase B (Akt) level in dPC12 cells, suggesting that its protective effect against Aβ-induced apoptosis in dPC12 cells was mediated through upregulation of the phosphoinositide 3-kinases (PI3K)/Akt signaling pathway. These extracts and its bioactive compound K36-21 may be potentially useful to treat neurodegenerative disorders.


Comparison between horse and rabbit antithymocyte globulin as first-line treatment for patients with severe aplastic anemia: a single-center retrospective study.
The best antithymocyte globulin preparation for first-line immune suppression in patients with severe aplastic anemia is still not clear. The aim of this study was to compare hematological response and overall survival in patients submitted to horse or rabbit antithymocyte globulin as first-line treatment for severe aplastic anemia. We retrospectively compared 71 consecutive patients with severe aplastic anemia, classified according to the antithymocyte globulin preparation. Analyses included variables related to patients and to immune suppression. Forty two patients (59.1%) received horse and 29 (40.9%) rabbit antithymocyte globulin. Response rates were higher at 6 months in patients submitted to horse in comparison to rabbit antithymocyte globulin (59.5% versus 34.5% respectively, p = 0.05). Median time to response was similar between the two groups (99 versus 88.5 days, respectively, for horse and rabbit antithymocyte globulin; p = 0.98). Overall survival at 2 years was significantly higher in patients submitted to horse in comparison to rabbit antithymocyte globulin (78.4% versus 55.4%, p = 0.03). Post-treatment response was strongly associated with survival at 2 years (97% in responders versus 41.2% in non-responders, p < 0.001). Use of rabbit antithymocyte globulin was an independent predictor of death (odds ratio 2.5; 95% confidence interval 1.03-6.04; p = 0.04). Rabbit antithymocyte globulin was associated with a significant and prolonged lymphopenia in comparison with horse antithymocyte globulin. Our data suggest the superiority of horse over rabbit antithymocyte globulin as first-line treatment for severe aplastic anemia, both regarding hematological response and survival.


Quantitative immunological studies of the albumins of several species of fire bellied toads, genus Bombina.
1. Rabbit antisera against purified serum albumin of Bombina bombina were used to study relationships between B. bombina, B. variegata, and B. orientalis. 2. Quantitative micro-complement fixation tests indicated the albumins of B. bombina from central Poland and Bulgaria were indistinguishable. The albumins from several populations of B. variegata differed very slightly from that of B. bombina. The albumin of B. orientalis was quite distinct from that of B. bombina. 3. Using albumin as a molecular clock, we estimated B. bombina and B. variegata diverged within the last million years, whereas the B. orientalis lineage diverged roughly 10-12 mil yr ago.


Balbc/3T3 cell transformation response to extracts of organic air samples as seen by their survival in aggregate form.
Extracts of organic matter from samples of airborne particulate matter have been shown to possess components capable of transforming mammalian cells. This study was done to determine if Balbc/3T3 cells exposed to extracts of air samples could, unlike their normal counterparts, in the absence of a surface for attachment, divide on agar to form aggregates, and if these cells would demonstrate a dose-response phenomenon. Untreated and solvent treated control cells failed to form large aggregates and showed a decline in viable cell number over a 6-day period. Cells treated with either cyclohexane or acetone extracts of airborne particulate matter showed a dose-response increase in cell number along with the formation of progressively larger aggregates, findings similar to those seen with the positive, benzo[a]pyrene (BaP), control. Furthermore, these findings are in direct agreement with those in the simultaneously performed standard cell transformation assay which required 21 days to perform. Results show that survival in aggregate form is a rapid in vitro test system capable of detecting potentially carcinogenic activity in complex environmental mixtures.


The impact of learning abroad programs in developing countries: A scoping review.
An increasing number of higher education healthcare students from developed countries are undertaking short-term learning abroad programs in developing countries. However, sociocultural differences between the students and the communities could lead to unintended, possibly negative consequences for the community. The objective of this review was to explore what is known about the impact of learning abroad programs undertaken by healthcare students on the communities in the developing countries who host them. The six-step scoping review developed by Arksey and O'Malley (2005) provided a methodological framework for searching the literature and identifying records meeting the inclusion criteria. A comprehensive range of databases were used to facilitate the literature search (including CINHAHL, EBSCO, ERIC, Google Scholar, MEDLINE, PsycINFO, Scopus and Web of Science). A two-stage review process was undertaken. Stage 1 reviewed articles on learning abroad undertaken in developing countries by higher education healthcare students. Stage 2 identified articles that reported the impact on the host community. Articles meeting the stage 2 criteria were further assessed for methodological quality using the Critical Review Form for Qualitative Studies. The stage 2 review revealed less than one quarter of the included articles (n = 36) reported on the impact of the learning abroad program on the host community and across these eight articles, there was a significant diversity in the methodological rigour and outcomes presented. This review identified that most of the published research on learning abroad in developing countries focusses almost exclusively on the impact the programs have on the students, with a paucity of research considering how they impact host communities. Our findings suggest the need to further extend and strengthen the research on the host communities in order to understand the impact higher education healthcare students have on the international communities who host them.


Nature of subretinal fluid in patients undergoing vitrectomy for macular hole: a cytopathological and optical coherence tomography study.
Outer retinal defects (ORDs) may occur after surgical closure of full thickness macular holes (FTMH) and be associated with delayed visual recovery. This may be due to the nature of the subretinal fluid (SRF) cuff and/or the loss of retinal elements. Vitrectomy with internal limiting membrane (ILM) peel was performed for FTMH. After fluid-air exchange, SRF was either aspirated from the hole (group 1) or left in situ (group 2). The SRF specimens obtained were examined by light microscopy and correlated with optical coherence tomography (OCT). In group 1, cellular material was found in 6 out of 12 cases. Photoreceptors were seen in 3 and macrophages in 3 cases. Nine of 12 holes closed and ORDs were seen in 3 of these. In group 2, 7 out of 8 holes closed, with 4 having ORD. There was no difference in visual acuity (LogMAR) for closed holes at 3 months between groups 1 (0.61, range 0.3-1) and 2 (0.51, range 0.3-0.78) nor between patients with ORD (0.57, range 0.3-1.0) or without ORD (0.57, range 0.3-1.0). SRF from FTMH may contain macrophages and photoreceptors. Such photoreceptor loss may contribute to reduced retinal function. ORDs occur commonly in spite of fluid aspiration, but their presence is still compatible with good vision. Aspiration of SRF did not appear to confer added benefit in this series.


Regulation of MHC class II and CD86 expression by March-I in immunity and disease.
The expression of MHC-II and CD86 on the surface of antigen-presenting cells (APCs) must be tightly regulated to foster antigen-specific CD4 T-cell activation and to prevent autoimmunity. Surface expression of these proteins is regulated by their dynamic ubiquitination by the E3 ubiquitin ligase March-I. March-I promotes turnover of peptide-MHC-II complexes on resting APCs and termination of March-I expression promotes MHC-II and CD86 surface stability. In this review, we will highlight recent studies examining March-I function in both normal and pathological conditions.


Geometric morphometrics and paleoneurology: brain shape evolution in the genus Homo.
Paleoneurology concerns the study and analysis of fossil endocasts. Together with cranial capacity and discrete anatomical features, shape can be analysed to consider the spatial relationships between structures and to investigate the endocranial structural system. A sample of endocasts from fossil specimens of the genus Homo has been analysed using traditional metrics and 2D geometric morphometrics based on lateral projections of endocranial shape. The maximum and frontal widths show a size-related pattern of variation shared by all the taxa considered. Furthermore, as cranial capacity increases in the non-modern morphotypes there is a general endocranial vertical stretching (mainly centred at the anterior ascending circumvolution) with flattening and relative shortening of the parietal areas. This pattern could have involved some structural stress between brain development and vault bones at the parietal midsagittal profile in the heavy encephalised Neandertals. In contrast, modern humans show a species-specific neomorphic hypertrophy of the parietal volumes, leading to a dorsal growth and ventral flexion (convolution) and consequent globularity of the whole structure. Brain tensors such as the falx cerebri have been hypothesised to represent one of the main physical constraints on morphogenetic trajectories, with additional influences from cranial base structures. The neurofunctional inferences discussed here stress the role of the parietal areas in the visuo-spatial coordination and integration, which can be involved in higher cerebral functions and related to conceptual thinking.


The accuracy of ultrasonography in the preoperative diagnosis of cervical lymph node metastasis in patients with papillary thyroid carcinoma: A meta-analysis.
Ultrasonography has been proposed to enhance preoperative assessment of cervical lymph node status in patients with papillary thyroid carcinoma (PTC). Management is most controversial for patients with a clinically negative (cN0) neck. We aimed to evaluate the diagnostic properties of ultrasonography in the detection of cervical lymph node metastasis in patients with PTC. Studies evaluating the diagnostic accuracy of Ultrasonography in the diagnosis of cervical lymph node metastasis in patients with PTC were systematically searched for in the MEDLINE, EMBASE, Cancerlit and Cochrane Library and other database from January 1995 to November 2010. Two reviewers independently abstracted data including research design, sample size, imaging technique and technical characteristics, method of image interpretation. By patient-based and region- or node-based data analyses, we determined pooled sensitivities and specificities across studies, and constructed summary receiver operating characteristic curves, and area under summary receiver operating characteristic curves were calculated. The pooled patient-based sensitivity for ultrasonography was 0.72 (95% CI, 0.46-0.88), specificity was 0.98 (95% CI, 0.84-1.00), and the area under the curve (AUC) was 0.94 (95% CI, 0.92-0.0.96). The pooled region- or node-based sensitivity for ultrasonography was 0.63 (95% CI, 0.47-0.76), specificity was 0.93 (95% CI, 0.73-0.99), and the AUC was 0.81 (95% CI, 0.77-0.84). For lesion-based analysis, the subgroup of lateral compartment lymph node involvement was found to have the highest sensitivity (0.72, 95% CI 0.68-0.75) and specificity (0.97, 95% CI 0.93-0.99) among the studies (p<0.05). Study sensitivity was not correlated with the prevalence of cervical lymph node metastasis (patient-based: R(2)=0.0196, p=0.7915; region- or node-based: R(2)=0.3835, p=0.1381). We conclude that preoperative ultrasonography is a good technique for the preoperative lymph node staging of PTC and is helpful for detecting metastatic cervical lymph nodes at the lateral group. High-quality prospective studies regarding ultrasonography in the evaluation of cervical lymph node status in patients with PTC are still needed to be conducted.


Antigenic characterization of the live attenuated Japanese encephalitis vaccine virus SA14-14-2: a comparison with isolates of the virus covering a wide geographic area.
In China, a live attenuated Japanese encephalitis (JE) vaccine, based on strain SA14-14-2, has been derived from the wild-type strain SA14 as an alternative to the current inactivated vaccines such as Nakayama-NIH and P-3. SA14-14-2 has been characterized using monoclonal antibodies derived in mice, using HAI and neutralization tests, and compared with other Chinese live vaccine clones and 14 wild-type strains of JE virus. Wild-type strain SA14 was found to be a poor immunogen and antigenically distant from all other viruses examined. The vaccine derivatives SA14-5-3 was more immunogenic than its wild-type parent, while SA14-14-2 (derived from SA14-5-3) was more immunogenic than SA14-5-3 and elicited a cross neutralizing antibody response. Our studies indicated that JE virus strain Nakayama elicited as good a neutralizing antibody response in hyperimmunized mice as the SA14-14-2 vaccine clones grown in either primary hamster kidney (PHK) or primary dog kidney (PDK) cells. A single dose of live SA14-14-2 (PHK) also elicited a good antibody response. Antigenic variation between wild-type and vaccine clones of JE virus were detected but were not considered significant in terms of controlling JE virus infections by vaccination.


Obstruction of the swing phase during gait: phase-dependent bilateral leg muscle coordination.
We have investigated bilateral leg muscle activation following an obstruction of the forward swinging leg during gait. When the holding impulse was released at the beginning of the swing phase, weak gastrocnemius (GM) and biceps femoris (BF) responses appeared in the contralateral, standing leg. When the holding impulse was released at the end of the swing phase, strong tibialis anterior (TA) and rectus femoris (RF) responses appeared in the swinging leg, and GM and BF responses in the standing leg. In the latter condition the TA response was followed by a premature impact associated with a GM activation. The latency between onset of impulse and appearance of the responses was 65-70 ms in both legs. While in the first condition the duration of GM and BF response corresponded to the duration of the impulse, it was independent for the duration of GM and BF response in the latter. It is concluded that different strategies for compensation are at work. In the first condition, body stability is maintained during the obstruction by the standing leg. In the second condition, body support is provided by a premature touchdown of the swinging leg. It is suggested that the appropriate pattern is, in part, released by a spinal generator.


Brachytherapy evolution as seen today.
While brachytherapy is the oldest form of radiation therapy, it is also a very exciting field from both physics and clinical perspectives. From the physics standpoint, brachytherapy dosimetry is largely being governed by the inverse-square law, leading to an unparalleled dose deposition kernel (dose emitted by a seed or single dwell position), even compared to proton or heavy-ion beamlets. There is slightly more dose beyond the central deposition point, but comparatively very little prior to it, that is, little or no entrance dose! It is easy to sum multiple dwell positions that cover a tumor, and the intensity can be modulated quite effectively using dwell times. From a clinical perspective, what sets brachytherapy apart from other intraoperative modalities (e.g., laser, radiofrequency, cryogenic) is our ability to precisely calculate the energy deposited across the relevant patient geometry, anticipate the effect from known dose-outcome relationships, and deliver that energy with exquisite control and selectively to the target volume while sparing organs at risks. This targeting ability has improved substantially over the last two decades. It is built upon key foundational elements, many of which stem from the research and development within our medical physics community. This article provides an overview of these elements that combine to make brachytherapy a successful and developing radiotherapy modality.


Systemic arterial compliance is decreased in newly-diagnosed patients with coronary heart disease: implications for prediction of risk.
Proximal aortic compliance has been shown to be lower in coronary heart disease (CHD) patients compared with healthy matched controls. Assessment of proximal systemic compliance can be performed non-invasively and, therefore, the measurement of proximal compliance may be useful as a risk marker of the likelihood of significant coronary disease. Systemic arterial compliance (SAC) and regional aortic stiffness (beta-index of the transverse arch) were measured non-invasively in a group of 20 newly-diagnosed CHD subjects and compared with an otherwise matched control group. These measurements were used to obtain an estimate of the predictive power of mechanical indices in CHD. Significant differences between subjects and controls were found in both SAC and regional aortic stiffness in the absence of differences in blood pressure. Use of loge(SAC) resulted in correct identification of 60% of the cases and 85% of controls. Use of both mechanical indices improved discrimination to 100% for cases, and 87% for controls. Equal likelihood points (case/control), derived from the estimated group distributions, corresponded to loge(SAC) = -1.30 and loge (beta-index) = -2.25. Arbitrarily requiring a 20:1 odds ratio of lack of disease required loge(SAC) > -1.40 and loge (beta-index) < 2.25. For the same odds ratio of presence of disease, loge(SAC) < -2.70 and loge (beta-index) > 3.50 were required. Non-invasive assessment of aortic elastic properties is not a definitive diagnostic test for CHD. Our results demonstrate the potential for repeatable, non-invasive methods of assessment of arterial mechanical properties to provide useful additional information for the overall assessment of an individual's cardiovascular risk. Our results also provide a basis for selecting arbitrary break points by which to group subjects in prospective studies.


Easy parameter identifiability analysis with COPASI.
Differential equation systems modeling biochemical reaction networks can only give quantitative predictions, when they are in accordance with experimental data. However, even if a model can well recapitulate given data, it is often the case that some of its kinetic parameters can be arbitrarily chosen without significantly affecting the simulation results. This indicates a lack of appropriate data to determine those parameters. In this case, the parameter is called to be practically non-identifiable. Well-identified parameters are paramount for reliable quantitative predictions and, therefore, identifiability analysis is an important topic in modeling of biochemical reaction networks. Here, we describe a hidden feature of the free modeling software COPASI, which can be exploited to easily and quickly conduct a parameter identifiability analysis of differential equation systems by calculating likelihood profiles. The proposed combination of an established method for parameter identifiability analysis with the user-friendly features of COPASI offers an easy and rapid access to parameter identifiability analysis even for non-experts. COPASI is freely available for academic use at http://www.copasi.org.


Consumption and drinking frequency of alcoholic beverage among women in Ghana: a cross-sectional study.
The consumption and drinking frequency of alcoholic beverage are identified with various individual factors. The aim of this study was to identify background characteristics of women associated with the consumption and drinking frequency of alcoholic beverage. Data was extracted from the 2008 Ghana Demographic and Health Survey. The data consisted of women's (aged 15-49 years) background characteristics and their reported history of consumption and drinking frequency of alcoholic beverage. A weighted sample size of 4916 women was used in the present study. Binary logistic regression and multinomial logistic regression were applied to examine the independent association between the covariates and the consumption and drinking frequency of alcoholic beverage respectively. Out of the 4916 women that were included in the study, 17.5% consumed alcoholic beverage in the past week. Factors that were found to be associated with women who consumed alcoholic beverage in a binary logistic regression model were age (15-19 years up to 45-49 years), region (Central, Greater Accra, Volta, Ashanti, Northern, Upper East, and Upper West), ethnicity (Ga or Dangme, Mole-Dagbani, Grussi, Gruma or Mande), wealth quintile (middle), and employment status [past 12 months] (those employed). In the multinomial logistic regression model, drinking frequency of alcoholic beverage was associated with women in the Central (none), Greater Accra Region (none and 4 or more times), Eastern (none and 2-3 times), Brong Ahafo (none), Upper East (none), those who attained primary education (4 or more times), Ga/Dangme ethnic group (none), those of middle wealth quintile (none), and those employed (4 or more times). In the country, about 2 in 10 women consume alcoholic beverage and the drinking frequency of alcoholic beverage varied among women in the country. Hence, the maintenance of moderate alcoholic beverage consumption among women, where applicable, should be encouraged.


Corrigendum: Inhibition of TGF-β/Smad3 Signaling Disrupts Cardiomyocyte Cell Cycle Progression and Epithelial-Mesenchymal Transition-Like Response During Ventricle Regeneration.
[This corrects the article DOI: 10.3389/fcell.2021.632372.].


Gender Differences in the Associations Between Health Literacy and Medication Adherence in Hypertension: A Population-Based Survey in Heris County, Iran.
We examined the gender-based associations of health literacy (HL) with self-reported medication adherence (MEDA) among patients with primary hypertension (pHTN). The subjects were recruited from the general population through all health centers of the Heris county, east Azarbaijan. They were to be adults (30+ years age), with pHTN of any stage, of any gender, and without comorbid illness. All underwent detailed face-to-face interview. We used valid questionnaires for HL and MEDA. Hierarchical regression was done to establish the association between MEDA, socio-demographic variables, and nine HL domains by gender. Other statistical procedures were also done. A total of 300 (48.6% males, mean age: 56.7±9.3) subjects participated; 43.0% were uneducated, 73.0% had moderate socioeconomic status, 68.0% had poor HL, and 7.0% maintained high adherence. Men were better in reading skills (p=0.002), and accessing (p=0.01) and using (p=0.02) health information, but women were better in health knowledge (p=0.004). The average regression estimate (±standard deviation) between HL and MEDA was 0.37±0.09, lower among men (0.361±0.11) than women (0.396±0.08), p=0.003. Upon hierarchical regression, the association between HL and MEDA was significant for communication and decision-making skills alone among both men (34.5%) and women (40.6%), individually. HL had substantial association with MEDA among those with HTN, for both men and women, particularly the communication and decision-making. With considerations on gender differences, this association should be confirmed through interventional studies to help make HL a formal mitigating strategy for MEDA and other public health goals.


Urinary and Fecal Continence in Adolescent and Adult Patients With Cloacal Exstrophy.
To evaluate the prevalence of urinary (UI) and fecal incontinence (FI) and the incontinence-related quality of life (QoL) in adolescent and adult patients with cloacal exstrophy (CE) in Germany. CE-patients of a tertiary care center and the German support group for anorectal malformations (SoMA e.V.) were included (October 2015 until September 2020). Data were assessed using a composed questionnaire consisting of 18 self-generated questions and two validated German questionnaires (King's health questionnaire, Questionnaire on Quality of Life in Fecal Incontinence (FLQAI)). Out of 23 included patients, 19 had continent and 3 incontinent urinary diversions (UD), 1 was unspecified; 2/23 were on dialysis. 73.7% (14/19) had undergone bladder augmentation, 4/19 had a pouch, 1/19 a neobladder. 94.7% (18/19) had a continent cutaneous channel and performed intermittent self-catheterization. UI was common (71.4%, 15/21). Neither the UD nor the involuntary loss of urine itself had a significant impact on QoL. Comparing the King's health questionnaire results, UI-related QoL of CE-patients was significantly lower than in a published reference group. 78.3% (18/23) had a bowel stoma. 34.8% (8/23) reported involuntary stool-soiling. Neither the way of bowel-emptying nor involuntary stool-soiling itself showed significant influence on FI-related QoL in the FLQAI. FLQAI items showed significant differences only for one of two published reference groups. Long-term incontinence rates in adolescent and adult CE-patients are high. Incontinence-related QoL was reduced compared to published reference groups but was minimally influenced by incontinence itself, the type of UD or the way of bowel-emptying, respectively.


Human macrophages stimulate expression of inflammatory mediators in adipocytes; effects of second-generation antipsychotics and glucocorticoids on cellular cross-talk.
Adipose tissue inflammation and distorted macrophage-adipocyte communication are positively associated with metabolic disturbances. Some pharmacological agents, such as second-generation antipsychotics (SGAs) and synthetic glucocorticoid (GC) dexamethasone, tend to induce adverse metabolic side effects and the underlying mechanisms are not fully understood. Our work aimed to study whether SGAs and dexamethasone affect macrophage phenotype and macrophage-adipocyte communication on gene expression level. We selected the model involving THP-1-derived macrophages, polarized into M0, M1, and M2 phenotypes, and primary human mature subcutaneous adipocytes. Abdominal subcutaneous adipose tissue needle biopsies were obtained from 6 healthy subjects (4F/2M; age: 22-64 yr; BMI: 21.7-27.6 kg/m2) followed by isolation of mature adipocytes. THP-1-human monocytic cell line was used for the study. THP-1 monocytes were differentiated and polarized into M0 (naïve), M1 (classically activated), and M2 (alternatively activated) macrophages. During and after polarization the macrophages were treated for 24 h without (control) or with therapeutic and supra-therapeutic concentrations of olanzapine (0.2 µM and 2.0 µM), aripiprazole (1.0 µM and 10 µM) and its active metabolite dehydroaripiprazole (0.4 µM and 4.0 µM). Isolated mature human adipocytes were co-incubated with THP-1-derived polarized macrophages pre-treated with SGAs after their polarization. Adipocytes and macrophages were collected before and after co-culture for mRNA expression analysis of genes involved in inflammation. Co-incubation of mature human adipocytes with human macrophages, regardless of polarization, resulted in a marked induction of pro-inflammatory cytokines in adipocytes, including IL1B, IL6, TNFA, and IL10. Remarkably, it did not affect the expression of adipokines and genes involved in the regulation of energy, lipid, and glucose metabolism in adipocytes. Dexamethasone markedly reduced gene expression of pro-inflammatory cytokines in macrophages and prevented macrophage-induced inflammatory response in adipocytes. In contrast, SGAs did not affect macrophage-adipocyte communication and had a minute anti-inflammatory effect in macrophages at supra-therapeutic concentrations. Interestingly, the adipocytes co-incubated with M1 macrophages pre-treated with dexamethasone and SGAs particularly the supra-therapeutic concentration of olanzapine, reduced expression of LPL, LIPE, AKT1, and SLC2A4, suggesting that the expression of metabolic genes in adipocytes was dependent on the presence of pro-inflammatory M1 macrophages. Together, these data suggest that macrophages induce expression of pro-inflammatory genes in human subcutaneous adipocytes without affecting the expression of adipokines or genes involved in energy regulation. Furthermore, our findings demonstrated that SGAs and dexamethasone had a mild effect on macrophage-adipocyte communication in M1 macrophage phenotype.


The 'dark side' of knowledge brokering.
Deploying knowledge brokers to bridge the 'gap' between researchers and practitioners continues to be seen as an unquestionable enabler of evidence-based practice and is often endorsed uncritically. We explore the 'dark side' of knowledge brokering, reflecting on its inherent challenges which we categorize as: (1) tensions between different aspects of brokering; (2) tensions between different types and sources of knowledge; and (3) tensions resulting from the 'in-between' position of brokers. As a result of these tensions, individual brokers may struggle to maintain their fragile and ambiguous intermediary position, and some of the knowledge may be lost in the 'in-between world', whereby research evidence is transferred to research users without being mobilized in their day-to-day practice. To be effective, brokering requires an amalgamation of several types of knowledge and a multidimensional skill set that needs to be sustained over time. If we want to maximize the impact of research on policy and practice, we should move from deploying individual 'brokers' to embracing the collective process of 'brokering' supported at the organizational and policy levels.


Surgical Site Infection After Arthroplasty: Comparative Effectiveness of Prophylactic Antibiotics: Do Surgical Care Improvement Project Guidelines Need to Be Updated?
Prophylactic antibiotics decrease surgical site infection (SSI) rates, and their timing, choice, and discontinuation are measured and reported as part of the Surgical Care Improvement Project (SCIP). The aim of this study was to assess the comparative effectiveness of the SCIP-approved antibiotics for SSI prevention. This retrospective cohort study utilized national Veterans Affairs (VA) data on patients undergoing elective hip or knee arthroplasty from 2005 to 2009. Data on prophylactic antibiotics were merged with VA Surgical Quality Improvement Program data to identify patient and procedure-related risk factors for SSI. Patients were stratified by documented penicillin allergy. Chi-square and Wilcoxon rank-sum tests were used to compare SSI rates among patients receiving SCIP-approved prophylactic antibiotics. A total of 18,830 elective primary arthroplasties (12,823 knee and 6007 hip) were included. Most patients received prophylactic cefazolin as the sole agent (81.9%), followed by vancomycin as the sole agent (8.0%), vancomycin plus cefazolin (5.6%), and clindamycin (4.5%). Documented penicillin allergy accounted for 54.1% of cases involving vancomycin administration compared with 94.6% of cases involving clindamycin. The overall thirty-day SSI rate was 1.4%, and the unadjusted rate was 2.3% with vancomycin only, 1.5% with vancomycin plus cefazolin, 1.3% with cefazolin only, and 1.1% with clindamycin. Unadjusted analysis of penicillin-allergic patients revealed an SSI rate of 2.0% with vancomycin only compared with 1.0% with clindamycin (p = 0.18). For patients without penicillin allergy, the SSI rate was 2.6% with vancomycin only compared with 1.6% with vancomycin plus cefazolin (p = 0.17) and 1.3% with cefazolin only (p < 0.01). Current SCIP guidelines address antibiotic timing but not antibiotic dosage. (The generally accepted recommendation for vancomycin is 15 mg/kg.) Although vancomycin is a narrower-spectrum antibiotic than either cefazolin or clindamycin, our finding of higher SSI rates following prophylaxis with vancomycin only may suggest a failure to use an appropriate dosage rather than an inequality of antibiotic effectiveness. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Induction of clastogenesis and gene mutations by carbamazepine (at its therapeutically effective serum levels) in mammalian cells and the dependence on human CYP2B6 enzyme activity.
Carbamazepine (CBZ, an antiepileptic) is metabolized by multiple CYP enzymes to its epoxide and hydroxides; however, whether it is genotoxic remains unclear. In this study, molecular docking (CBZ to CYPs) and cytogenotoxic toxicity assays were employed to investigate the activation of CBZ for mutagenic effects, in various mammalian cell models. Docking results indicated that CBZ was valid as a substrate of human CYP2B6 and 2E1, while not for CYP1A1, 1A2, 1B1 or 3A4. In the Chinese hamster (V79) cell line and its derivatives genetically engineered for the expression of human CYP1A1, 1A2, 1B1, 2E1 or 3A4 CBZ (2.5 ~ 40 μM) did not induce micronucleus, while in human CYP2B6-expressing cells CBZ significantly induced micronucleus formation. In a human hepatoma C3A cell line, which endogenously expressed CYP2B6 twofold higher than in HepG2 cells, CBZ induced micronucleus potently, which was blocked by 1-aminobenzotriazole (inhibitor of CYPs) and ticlopidine (specific CYP2B6 inhibitor). In HepG2 cells CBZ did not induce micronucleus; however, pretreatment of the cells with CICTO (CYP2B6 inducer) led to micronucleus formation by CBZ, while rifampicin (CYP3A4 inducer) or PCB126 (CYP1A inducer) did not change the negative results. Immunofluorescent assay showed that CBZ selectively induced centromere-free micronucleus. Moreover, CBZ induced double-strand DNA breaks (γ-H2AX elevation, by Western blot) and PIG-A gene mutations (by flowcytometry) in C3A (threshold being 5 μM, lower than its therapeutic serum concentrations, 17 ~ 51 μM), with no effects in HepG2 cells. Clearly, CBZ may induce clastogenesis and gene mutations at its therapeutic concentrations, human CYP2B6 being a major activating enzyme.


[Paradoxical reactions and responses during antibiotic treatment for Mycobacterium ulcerans infection (Buruli ulcer). Four cases from French Guiana].
In recent years, first-line therapy for Mycobacterium ulcerans infection in French Guiana has consisted of antibiotics active against this organism. Two regimens are used comprising rifampicin associated with clarithromycin or amikacin. We describe four patients presenting apparent worsening of their lesions during treatment: ulceration of a nodular lesion in a 32-year-old woman and worsening of an ulcerated lesion in three patients aged 16, 27 and 79 years. In these 4 patients, we concluded that the symptoms were caused by a paradoxical response or a reaction, a phenomenon already described in tuberculosis and leprosy. Such worsening is transient and must not be misinterpreted as failure to respond to treatment. The most plausible pathophysiological hypothesis involves the re-emergence of potentially necrotizing cellular immunity secondary to the loss of mycolactone, a necrotizing and immunosuppressive toxin produced by M. ulcerans, resulting from the action of the antibiotics.


Mitochondrial myopathy.
Six clinically affected and 18 asymptomatic members of a six-generation family were investigated clinically, by estimation of serum CK levels, and in some cases by quantitative electromyographic techniques and muscle biopsy. It was concluded that the myopathy was probably inherited as an autosomal dominant trait with variable expression and incomplete penetrance although the possibility of mitochondrial inheritance could not be excluded in view of the almost exclusive transmission through the female line. Eight members of the family with myopathy also had diabetes mellitus, and 2 of these also had cerebellar ataxia. It is suggested that the myopathy, the cerebellar disorder and the diabetes may all be manifestations of the same underlying metabolic defect.


Advantages of endoscopic submucosal dissection with needle-knife over endoscopic mucosal resection for small rectal carcinoid tumors: a retrospective study.
Endoscopic submucosal dissection (ESD) is a new, widely accepted method for the treatment of early gastric cancer and was developed to increase the en bloc resection rate. This study aimed to evaluate the efficacy and safety of ESD compared with conventional endoscopic mucosal resection (EMR) for small rectal carcinoid tumors. A retrospective study was carried out that included 43 patients with small rectal carcinoid tumors (< 10 mm). The cohort comprised two groups: Group A (N = 23) underwent conventional EMR from January 2004 to August 2005, while group B (N = 20) underwent ESD with needle-knife from September 2005 to December 2006. The rate of curative en bloc resection, the procedure time, and the incidence of complications were evaluated. The en bloc resection rate and the rate of completeness of resection of group B were higher than those of group A (100 vs. 87%, 100 vs. 52.5%, respectively). The average operation time required for resection was significantly longer in group B (28.4 ± 17.2 min) compared with group A (12.3 ± 15.4 min) (p < 0.05). None of the patients had immediate or delayed bleeding during the procedure. Perforation occurred in one case of group B and the patient recovered after several days of conservative treatment. Three patients had local recurrence after EMR, while no patient experienced recurrence after ESD. ESD, compared with conventional EMR, increased en bloc and histologically complete resection rates and may reduce local recurrence rate for small rectal carcinoid tumors. Increased operation time and complication risks with ESD remain problematic. Further technique and investigation are required to confirm the safety and to assess the long-term prognosis of ESD.


Animal models of maple syrup urine disease.
Maple syrup urine disease (MSUD) is an inherited aminoacidopathy resulting from dysfunction of the branched-chain keto acid dehydrogenase (BCKDH) complex. This disease is currently treated primarily by dietary restriction of branched-chain amino acids (BCAAs). However, dietary compliance is often challenging. Conversely, liver transplantation significantly improves outcomes, but donor organs are scarce and there are high costs and potential risks associated with this invasive procedure. Therefore, improved treatment options for MSUD are needed. Development of novel treatments could be facilitated by animal models that accurately mimic the human disease. Animal models provide a useful system in which to explore disease mechanisms and new preclinical therapies. Here we review MSUD and currently available animal models and their corresponding relevance to the human disorder. Using animal models to gain a more complete understanding of the pathophysiology behind the human disease may lead to new or improved therapies to treat or potentially cure the disorder.


Models and molecular mechanisms for trade-offs in the context of metabolism.
Accumulating evidence for trade-offs involving metabolic traits has demonstrated their importance in the evolution of organisms. Metabolic models with different levels of complexity have already been considered when investigating mechanisms that explain various metabolic trade-offs. Here we provide a systematic review of modelling approaches that have been used to study and explain trade-offs between: (i) the kinetic properties of individual enzymes, (ii) rates of metabolic reactions, (iii) the rate and yield of metabolic pathways and networks, (iv) different metabolic objectives in single organisms and in metabolic communities, and (v) metabolic concentrations. In providing insights into the mechanisms underlying these five types of metabolic trade-offs obtained from constraint-based metabolic modelling, we emphasize the relationship of metabolic trade-offs to the classical black box Y-model that provides a conceptual explanation for resource acquisition-allocation trade-offs. In addition, we identify several pressing concerns and offer a perspective for future research in the identification and manipulation of metabolic trade-offs by relying on the toolbox provided by constraint-based metabolic modelling for single organisms and microbial communities.


Tissue Expander Complications Do Not Preclude a Second Successful Implant-Based Breast Reconstruction.
Implant-based breast reconstruction is the most common method of breast reconstruction in the United States, but the outcomes of subsequent implant-based reconstruction after a tissue expander complication are rarely studied. The purpose of this study was to determine the long-term incidence of implant loss in patents with a previous tissue expander complication. This is a retrospective review of the long-term outcomes of all patients with tissue expander complications at a large academic medical center from 2003 to 2013. Patients with subsequent tissue expander or implant complications were compared to those with no further complications to assess risk factors for additional complications or reconstructive failure. One hundred sixty-two women were included in this study. The mean follow-up period was 8.3 ± 3.1 years. Forty-eight women (30 percent) went on to undergo a second tissue expander or implant placement. They did not differ from women who went on to autologous reconstruction or no further reconstruction. Of these, 34 women (71 percent) had no further complications and 38 women (79 percent) had a successful implant-based reconstruction at final follow-up. There were no patient or surgical factors significantly associated with a second complication or implant loss. Following tissue expander complications, it is reasonable to offer women a second attempt at tissue expansion and implant placement. This study demonstrates that long-term success rates are high, and there are no definitive patient or surgical factors that preclude a second attempt at implant-based breast reconstruction. Risk, III.


Self-reported handwashing and surface disinfection behaviors by U.S. adults with disabilities to prevent COVID-19, Spring 2020.
Handwashing and surface cleaning and disinfection are two hygiene behaviors promoted to prevent the spread of COVID-19. Persons with disabilities may be at increased risk for severe COVID-19 illness due to underlying medical conditions that have been associated with COVID-19. This study aims to describe self-reported hygiene behaviors among U.S. adults with disabilities to prevent transmission of COVID-19. Data were obtained from the March 2020 Porter Novelli ConsumerStyles survey. This study includes 6463 U.S. adults (≥18 years) who participated in the survey (58.2% response rate). Participants were asked about frequent handwashing and surface disinfection. Participants were also asked six questions to assess disability status and disability type. Prevalence estimates with 95% confidence intervals were calculated; chi-square tests were conducted. A total of 1295 (20.3%) of survey participants reported at least one disability and their hygiene-related behavior. Overall, 91.3% of respondents with disabilities reported frequent handwashing; only 72% reported frequent surface disinfection. Those with hearing, vision, cognition, mobility, self-care, and independent living disabilities (range: 77.9%-90.6%) were significantly less likely than those without any disability (94.0%) to report frequent handwashing. People with vision (62.2%) and independent living (66.8%) disabilities were less likely to report frequent surface disinfection than those without any disability (74.6%). Practices such as handwashing and disinfecting surfaces are effective for reducing and preventing the spread of COVID-19. Promotion of hygiene-related practices among people with disabilities is essential. Tailored communications and implementation of evidence-based strategies are needed to address hygiene-related behaviors among the subgroups of people with disabilities most affected.


Functional and compositional characteristics of nitrifiers reveal the failure of achieving mainstream nitritation under limited oxygen or ammonia conditions.
For understanding the potential of achieving nitritation under different oxygen and ammonia levels, two activated sludge reactors with high (RH) and low (RL) dissolved oxygen (DO) were parallelly operated. During over two months continuous operation, rare nitrite accumulation was observed in both reactors. K-strategists Nitrosomonas oligotropha and r-strategists Nitrosomonas europaea were enriched in the RH and RL, respectively, yet their response to DO variations was almost identical. Although K-strategists Nitrospira defluvii dominated both reactors, species cultured with low-DO exhibited higher oxygen affinity. Instead of DO, ammonia and nitrite availability should be the key factor for the selective enrichment of these nitrifiers. Taken together, the limiting ammonia for ammonia oxidizing bacteria and the better oxygen-uptake capacity of nitrite oxidizing bacteria wasrespectively responsible for the failure of nitrite accumulation in the RH and RL. This study supported that high DO coupled with excess ammonia would favor the achievement of mainstream nitritation.


Ultrastructure of marginal zone during prenatal development of human spinal cord.
Electron microscopic studies were conducted in the marginal zone (lamina I) in human fetuses ranging from 8-25 weeks of gestational age. At 8 weeks the neurons have indented nuclei and sparse organelles in the cytoplasm. The neuropil shows contacts between the axons and dendritic profiles. Some of them are well defined synapses with post synaptic thickening and agranular spherical vesicles in the presynaptic terminal. At 18 weeks compactly packed organelles with long cisternae of rough endoplasmic reticulum could be visualized in the neuronal cytoplasm. At 25 weeks the neurons have heterochromatin patches in the nuclei. Axosomatic, dendrodendritic, axoaxonic, symmetrical, asymmetrical and multisynaptic contacts with agranular and dense core vesicles are seen at different sequential age periods.


Phenotypic variability in patients with unique double homozygous mutations causing variant ataxia telangiectasia.
Ataxia-Telangiectasia (A-T) is a neurodegenerative disease caused by bi-allelic mutations in the Ataxia-Telangiectasia-Mutated (ATM) gene. Complete lack of ATM activity leads to severe A-T and mutations allowing for residual activity cause a milder phenotype, termed variant A-T. There are only sparse data on the variability in phenotypes of variant A-T patients carrying the same mutations. A retrospective study of 15 patients with variant A-T, all double homozygous for the same mutations was conducted. The age of first symptom ranged from 4-180 months, including: truncal ataxia at <18 months of age in 9 patients, ataxia and instability only during fever in one patient, dystonia in one patient and malignancy in 4 patients. Global developmental delay and occulo-motor apraxia were recorded in 4/14 patients. Variant A-T patients with the same mutations in ATM, have variable phenotypes. Environmental, epigenetic, and post translational factors are likely to play a role in creation of the phenotype in variant A-T patients.


Unifying concepts in mechanism of amblyopia.
Most of the evidence of formation of amblyopia is derived traditionally from electrophysiological studies. Recently, there have been many discoveries from genetics, histopathology, biochemistry, immunology and interventional studies. On the basis of evidence gathered in the last five years, the various types of amblyopia (strabismic and non-strabismic amblyopia) can be seen not only as disturbance of the development of the visual system at different points but as basically different pathologic processes. It is postulated here that strabismic amblyopia is initiated as a maladaptive differentiation in the ocular dominance columns, whereas the non-strabismic amblyopia may be initiated from the ganglion cell population of the amblyopic eye. The total clinical picture is confusing because of secondary changes in other parts of the central nervous system. The manifested features can be due to a slower, more enduring type of change (pooling, loss and re-wiring of the neurones) as well as a more transient, adaptive type of response (such as suppression of diplopia). Neurotransmitter replacement has a potential therapeutic application.


Implanted subcutaneous versus intraperitoneal bioscaffold seeded with hepatocyte-like cells: functional evaluation.
The X-linked bleeding disorder, hemophilia A, is caused by defective production of factor VIII (FVIII). Hemophilic patients require regular FVIII infusions. Recombinant factor replacement poses the safest line of therapy. However, its main drawbacks are high expenses and the higher liability for formation of inhibitors. Recent studies confirmed the ability of bone marrow-derived stem cells to secrete FVIII. This study aims to generate bioscaffold from decellularized liver and subsequently seed it with trans-differentiated human stem cells into hepatic-like cells. This scaffold can then be implanted intraperitoneally or subcutaneously to provide FVIII. After generation of the bioscaffold, seeding of discoid scaffolds with trans-differentiated human hepatocyte-like cells was performed. Then, the generated organoid was implanted into peritoneal cavity or subcutaneous tissue of experimental rats. Serum human FVIII was significantly increased in rats subjected to subcutaneous implantation compared intraperitoneal implantation. Immunostaining for detecting Cytokeratin 19 and human anti-globulin confirmed the presence of mature human hepatocytes that were significantly increased in subcutaneous implanted scaffold compared to the intraperitoneal one. Implantation of decellularized bioscaffold seeded with trans-differentiated stem cells in rats was successful to establish production of FVIII. Subcutaneous implantation showed higher FVIII levels than intraperitoneal implantation.


When to initiate ACEI/ARB therapy in patients with type 1 and 2 diabetes.
Angiotensin converting enzyme inhibitors (ACEI) and angiotensin 2 receptor blockers (ARB) have become a mainstay of adjunctive therapy for the prevention and amelioration of diabetic nephropathy. Although ACEI were shown over 20 years ago to slow the rate of loss of renal function in diabetic subjects with decreased renal function, the question of how early in the course of diabetes to introduce them remains unresolved. Recent studies suggest that very early initiation of ACEI/ARB therapy may not have demonstrable beneficial effects even over a period of years.


[Detection of lymph node involvement and surgical treatment of pulmonary neoplastic processes. Current state of diagnostic and therapeutic procedures].
An analysis is made of different publications associated with the surgical staging and treatment of primary and metastasic pulmonary neoplastic processes. A suitable treatment program is essential to determine lymph node involvement in patients with bronchogenic carcinoma. The indication and sequence of the procedure to use (CT-PET, transbronchial puncture, videomediastinoscopic ultrasound guided transbronchial needle aspiration) is evaluated in accordance to the sensitivity, specificity and positive and negative predictive value of the different methods. Another interesting challenge is to define the criteria for indicating a sublobar resection in certain tumours and patients. Different factors, age, lung function, tumour location and type of sublobar resection, are analysed. Levels of evidence and recommendations of the procedure are also considered. Surgical resection is an accepted therapeutic option in the treatment of colorectal cancer lung metastases. Its indication is based on acceptable survival rates and knowledge of the impact of various factors (interval free of disease, number of metastases, presence of liver metastasis, presence of lymph node involvement, or increased pre-operative levels of carcinoembryonic antigen), is analysed in detail.


The nitric oxide system in insects.
It is well established that nitric oxide (NO) acts as a signalling molecule in the nervous system of both mammals and insects. In contrast to classical transmitters, the membrane-permeant NO can act on neighbouring targets limited by half-life and diffusion barriers. This type of diffuse signalling seems to be evolutionarily highly conserved and recent findings concerning the characterization and function of the NO system in insects are summarized in this review. Firstly, the properties and the localization of the NO forming enzyme, the NO synthase (NOS), are described. In the nervous system the brain contains by far the highest NOS activity. As an evolutionary peculiarity, a blood-feeding bug exhibits high NOS activity in the salivary glands. Secondly, the soluble guanylate cyclase (sGC), a major target of NO action, and cGMP-regulated enzymes like cGMP-dependent protein kinase and cyclic nucleotide gated channels are described. Anatomical organization of the NO/cGMP system in insects reveals evidence for a cellular separation of the release site and target site of NO, although in the antennal lobes of the locust an exception from this rule exists. Thirdly, the implication of the NO system in neuronal function in insects is described. In the honeybee, the NO/cGMP system in the antennal lobes is implicated in the processing of adaptive mechanisms during chemosensory processing, and recent findings support a specific role of the NO system in memory formation. Discussion of the results in insects with regard to properties and functions of the vertebrate NO system is attempted.


Mutagenic activity of amino acid pyrolyzates in Salmonella typhimurium TA 98.
Pyrolyzates of 25 amino acids and 5 indole derivatives were tested for mutagenicity in the histidine-requiring mutant Salmonella typhimurium TA 98. Significant mutagenic activity was detected with pyrolyzates of most of the amino acids. These pyrolyzates required a liver microsomal fraction, as representative of mammalian metabolism, to be detected as mutagens. Among the pyrolyzates tested, the highest mutagenic activity was observed with that of L-tryptophan. As little as 10 microgram of the pyrolyzate of L-tryptophan had detectable mutagenic activity toward TA 98. The optimal pyrolysis temperatures for the formation of mutagenic products were shown to be 500 degrees C for L-tryptophan and 600 degrees C for the other amino acids. The results from pyrolyses of some indole derivatives suggest that an amino group at the alpha-position to the carboxyl group of L-tryptophan plays an important role in the formation of mutagens.


Antitumor activity of the progesterone antagonists ZK 98.299 and RU 38.486 in the hormone-dependent MXT mammary tumor model of the mouse and the DMBA- and the MNU-induced mammary tumor models of the rat.
The antitumor activities of the antiprogesterones ZK 98.299 and RU 38.486 (RU 486) were tested in the hormone-dependent MXT(+) mammary tumor model of the mouse and the DMBA- and MNU-induced mammary tumor models of the rat. In the MXT(+)-tumor model, treatment with the two antiprogesterones (1-10 mg/kg daily) starting on day 1 after tumor implantation led to an almost complete inhibition of tumor growth identical to that accomplished with tamoxifen. Treatment of established MXT(+) tumors with ZK 98.299 (1, 10 and 50 mg/mg) resulted in a strong, dose-dependent inhibition of tumor growth. At the 10 and 50 mg doses, the effect of ZK 98.299 was superior to that of tamoxifen (4 mg/kg) and equal to that of ovariectomy and of RU 486, whereas megestrol acetate and medroxyprogesterone acetate had no significant effect. In contrast to the massive induction of cell degeneration and cytolysis in the MXT mammary tumors resulting from ovariectomy, the treatment with the two progesterone antagonists seems rather to trigger differentiation of the mitotically active polygonal tumor cells towards glandular structures and acini with secretory activity as well as towards the development of spindle-shaped necrobiotic cell populations. The weights of the ovaries were increased after therapy with ZK 98.299 and RU 486. Due to this inhibition of the negative feedback and an 'unopposed estrogen effect', uterine weight was also significantly increased. In the DMBA-induced mammary carcinoma, ZK 98.299 (10 mg/kg) caused strong tumor-inhibiting activity almost comparable to that of ovariectomy. The inhibition was very uniform and in this regard superior to RU 486. The MNU-induced mammary carcinoma of the rat was significantly inhibited by ZK 98.299, whereas RU 486 showed only a weak effect. In the light of these results antiprogesterones can be considered to be a very promising new class of mammary tumor inhibitors.


ATP-binding cassette G1 membrane transporter-mediated cholesterol efflux capacity influences coronary atherosclerosis and cardiovascular risk in Rheumatoid Arthritis.
Cholesterol efflux capacity (CEC) measures the ability of high-density lipoprotein (HDL) to remove cholesterol from macrophages and reduce the lipid content of atherosclerotic plaques. CEC inversely associated with cardiovascular risk beyond HDL-cholesterol levels. CEC through the ATP-binding-cassette G1 (ABCG1) membrane transporter is impaired in rheumatoid arthritis (RA). We evaluated associations of ABCG1-CEC with coronary atherosclerosis, plaque progression and cardiovascular risk in RA. Coronary atherosclerosis (noncalcified, partially, fully-calcified, low-attenuation plaque) was assessed with computed tomography angiography in 140 patients and reevaluated in 99 after 6.9 ± 0.3 years. Cardiovascular events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization and hospitalized heart failure were recorded. ABCG1-CEC was measured in Chinese hamster ovary cells as percentage of effluxed over total intracellular cholesterol. ABCG1-CEC inversely associated with extensive atherosclerosis (≥5 plaques) (adjusted odds ratio 0.50 [95% CI 0.28-0.88]), numbers of partially-calcified (rate ratio [RR] 0.71 [0.53-0.94]) and low-attenuation plaques (RR 0.63 [0.43-0.91] per standard deviation increment). Higher ABCG1-CEC predicted fewer new partially-calcified plaques in patients with lower baseline and time-averaged CRP and fewer new noncalcified and calcified plaques in those receiving higher mean prednisone dose. ABCG1-CEC inversely associated with events in patients with but not without noncalcified plaques, with <median but not higher CRP and in prednisone users but not nonusers (p-for-interaction = 0.021, 0.033 and 0.008 respectively). ABCG1-CEC inversely associated with plaque burden and vulnerability, and plaque progression conditionally on cumulative inflammation and corticosteroid dose. ABCG1-CEC inversely associated with events specifically in patients with noncalcified plaques, lower inflammation and in prednisone users.