Non-structural protein 1 (NS1) variants from dengue virus clinical samples revealed mutations that influence NS1 production and secretion.
Dengue diagnosis primarily relies on NS1 ELISA and serological (IgG/IgM) tests. There are reports of low and variable sensitivity of the widely used NS1 ELISA tests. Poor sensitivity has been attributed to patient's infection status, prevalent serotypes, and the geographical origin of the samples. We investigated whether NS1 mutations directly have any impact on NS1 ELISA-based dengue virus (DENV) detection in clinical samples. Fifty-eight serum samples were collected from dengue-endemic area during 2015-2017 and tested with three commonly used NS1 ELISA kits. The samples were subjected to diagnostic RT-PCR and sequencing of structural gene(s). Sequencing of NS1 gene revealed amino acid changes which were transferred to respective wild type NS1 backbone to determine their effects on NS1 production and secretion in Huh-7, Vero, and A549 cells. Eighty-seven percent samples were virus RNA-positive but 65% of these were NS1 ELISA-positive. NS1-gene mutations like Val236➔Ala (DENV2) or Trp68➔stop codon in DENV3 were associated with decreased NS1 production and secretion. These mutations were originally identified in NS1 ELISA-negative clinical isolates. All DENV1 and > 80% DENV2 were NS1 ELISA-positive. The three NS1 ELISA could not detect recently circulating DENV3 single infections despite being RNA-positive. Among serotypes 1-3, wild-type NS1 production was highest for DENV1 and lowest for DENV3 in all cell lines tested. Mutations in circulating DENV directly correlated with NS1 production and secretion and, hence, ELISA-based NS1 detection. Further studies to define more NS1 mutations in clinical samples are needed to optimize ELISA kits for more sensitive dengue diagnosis.


6-[(2-Hy-droxy-5-methyl-anilino)methyl-idene]-4-nitro-cyclo-hexa-2,4-dien-1-one.
The title compound, C14H12N2O4, is nearly planar with a dihedral angle between the aromatic rings of 1.41 (8)°. The phenolic O atom is deprotonated and the N atom of the azomethine unit carries the proton, thereby forming an intra-molecular N-H⋯O hydrogen bond. In the crystal, the mol-ecules form inversion dimers via pairwise O-H⋯O hydrogen bonds.


Pre-cut papillotomy with a new papillotome.
A new papillotome has been developed, an isolated-tip needle-knife papillotome (Iso-Tome) that has a semi-oval-shaped tip of epoxide adhesive to prevent electric leakage from the tip of the incising needle. The coated tip aids in keeping the papillotome tightly in the orifice of the ampulla of Vater and is believed to prevent unintentional deep cuts or perforations. This study was done to evaluate the clinical usefulness of the new papillotome for pre-cut papillotomy. From June 2003 to November 2003, 115 patients underwent attempted ERCP. If biliary cannulation failed by the conventional method, pre-cut papillotomy was performed by using the Iso-Tome in the direction of the bile duct. After successful bile-duct cannulation, papillotomy was extended for therapeutic procedures, such as stone removal or stent insertion, in the majority of the cases. Post-ERCP complications were classified according to consensus guidelines. Pre-cut papillotomy with the Iso-Tome was done in 25 patients (21.7% of cases). Protective pancreatic stents were not used. Of these patients, 11 had common bile duct stones, 7 had pancreatitis, 5 had malignancies, one had sphincter of Oddi dysfunction, and one had bile-duct leak. After pre-cut papillotomy with the Iso-Tome, bile-duct cannulation was successfully achieved in 23 of 25 (92%) patients. Complications occurred in 7 of 25 patients (28%) and consisted of mild pancreatitis in 5 (20%), moderate bleeding in one (4%), and biliary pain in one (4%). All 7 patients with complications were managed medically, and there was no death. In this pilot study, the isolated-tip needle knife was found to be a clinically useful papillotome for pre-cut papillotomy. Further large comparative studies (with and without pancreatic protective stents) are needed to determine improved efficacy and safety compared with standard techniques.


Gene expression variance in hippocampal tissue of temporal lobe epilepsy patients corresponds to differential memory performance.
Temporal lobe epilepsy (TLE) is a severe brain disorder affecting particularly young adults. TLE is frequently associated with memory deterioration and neuronal damage of the hippocampal formation. It thereby reveals striking parallels to neurodegenerative disorders including Alzheimer's disease (AD). TLE patients differ with respect to their cognitive performance, but currently little is known about relevant molecular-genetic factors. Here, we correlated differential memory performance of pharmacoresistant TLE patients undergoing neurosurgery for seizure control with in-vitro findings of their hippocampal tissues. We analyzed mRNA transcripts and subsequently promoter variants specifically altered in brain tissue of individuals with 'very severe' memory impairment. TLE patients (n=79) were stratified according to preoperative memory impairment using an established four-tiered grading system ranging from 'average' to 'very severely'. Multimodal cluster analyses revealed molecules specifically associated with synaptic function and abundantly expressed in TLE patients with very impaired memory performance. In a subsequent promoter analysis, we found the single nucleotide polymorphism rs744373 C-allele to be associated with high mRNA levels of bridging integrator 1 (BIN1)/Amphiphysin 2, i.e. a major component of the endocytotic machinery and located in a crucial genetic AD risk locus. Using in vitro luciferase transfection assays, we found that BIN1 promoter activation is genotype dependent and strongly increased by reduced binding of the transcriptional repressor TGIF. Our data indicate that poor memory performance in patients with TLE strongly corresponds to distinctly altered neuronal transcript signatures, which - as demonstrated for BIN1 - can correlate with a particular allelic promoter variant. Our data suggest aberrant transcriptional signaling to significantly impact synaptic dynamics in TLE resulting in impaired memory performance and may serve as basis for future therapy development of this severe comorbidity.


Selective and organotypic culture of intrahepatic bile duct cells from adult pig liver.
Secondary culture of nontransformed bile duct epithelium has been difficult to achieve. STO feeder cell-dependent secondary cultures of adult pig bile duct cells were established from primary cultures of adult pig liver cells. Adult pig hepatocytes exhibited limited or no replication and were lost from the secondary culture at Passage 3 or 4. In contrast, adult pig bile duct cells replicated and were carried for 4-8 passages in secondary culture. A simple method to produce nearly pure pig intrahepatic bile duct cultures was first to freeze a relatively crude liver cell preparation. Upon subsequent thawing, all hepatocytes and most macrophages were lysed. Bile duct cells composed 95% of the surviving cells after the freeze/thaw, and they grew out rapidly. The bile duct cells grew on top of the STO feeder cells as closely knit epithelial, colonial outgrowths. Histocytochemical and biochemical analyses demonstrated high levels of gamma-glutamyltranspeptidase activity and low levels of P450 activity in the bile duct cultures. The bile duct cells spontaneously adopted a multicellular ductal morphology after 7-10 d in static culture which was similar to that found in in vivo pig liver. Transmission electron microscopic examination revealed complex junctions and desmosomes typical of epithelium, and lumenally projecting cilia typical of in vivo intrahepatic bile ductules. This simple method for the coculture of pig intrahepatic bile duct cells which adopt in vivo-like structure may facilitate biological studies of this important, but difficult to culture, cell type.


Grade-control outdoor turning flight of robo-pigeon with quantitative stimulus parameters.
The robo-pigeon using homing pigeons as a motion carrier has great potential in search and rescue operations due to its superior weight-bearing capacity and sustained flight capabilities. However, before deploying such robo-pigeons, it is necessary to establish a safe, stable, and long-term effective neuro-electrical stimulation interface and quantify the motion responses to various stimuli. In this study, we investigated the effects of stimulation variables such as stimulation frequency (SF), stimulation duration (SD), and inter-stimulus interval (ISI) on the turning flight control of robo-pigeons outdoors, and evaluated the efficiency and accuracy of turning flight behavior accordingly. The results showed that the turning angle can be significantly controlled by appropriately increasing SF and SD. Increasing ISI can significantly control the turning radius of robotic pigeons. The success rate of turning flight control decreases significantly when the stimulation parameters exceed SF > 100 Hz or SD > 5 s. Thus, the robo-pigeon's turning angle from 15 to 55° and turning radius from 25 to 135 m could be controlled in a graded manner by selecting varying stimulus variables. These findings can be used to optimize the stimulation strategy of robo-pigeons to achieve precise control of their turning flight behavior outdoors. The results also suggest that robo-pigeons have potential for use in search and rescue operations where precise control of flight behavior is required.


Vascular anastomoses in fused, dichorionic twin placentas resulting in twin transfusion syndrome.
We have provided pathologic documentation of vascular anastomoses across fused, dichorionic placentas. These placental anastomoses resulted in the twin transfusion syndrome.


Uranium removal from water using cellulose triacetate membranes added with activated carbon.
Ultrafiltration removal of uranium from water, with composite activated carbon cellulose triacetate membranes (AC-CTA), was investigated. The filtrate was provided by uraninite dissolution with pH=6-8. Removal efficiencies were calculated measuring solutions' radioactivities. Membranes were mainly characterized by microscopy analysis, revealing iron after permeation. Uranyl removal was 35±7%. Chemical speciation indicates the presence of (UO(2))(2)CO(3)(OH)(3)(-), UO(2)CO(3), UO(2)(CO(3))(2)(2-) and Fe(2)O(3)(s) as main compounds in the dissolution, suggesting co-adsorption of uranium and iron by the AC during filtration, as the leading rejection path.


Tailoring beta-cyclodextrin for DNA complexation and delivery by homogeneous functionalization at the secondary face.
An efficient general strategy for the incorporation of functional elements onto the secondary hydroxyl rim of beta-cyclodextrin has been developed and applied to the synthesis of a novel series of C7-symmetric homogeneous macromolecular polycations with improved DNA complexing and delivery properties.


Incidence and risk factors for glaucoma development and progression after corneal transplantation.
To assess the cumulative incidence and risk factors for glaucoma development and progression within 1-2 years following corneal transplant surgery. Retrospective cohort study. Patients undergoing penetrating keratoplasty (PK), deep anterior lamellar keratoplasty (DALK), Descemet stripping endothelial keratoplasty (DSEK), Descemet membrane endothelial keratoplasty (DMEK), Boston keratoprosthesis type I (KPro) implantation, or endothelial keratoplasty (DSEK or DMEK) under previous PK (EK under previous PK) at one academic institution with at least 1 year of follow-up were included. Primary outcome measures were cumulative incidence of glaucoma development and progression after corneal transplant, in patients without and with preoperative glaucoma, respectively. Risk factors for glaucoma development and progression were also assessed. Four hundred and thirty-one eyes of 431 patients undergoing PK (113), DALK (17), DSEK (71), DMEK (168), KPro (35) and EK under previous PK (27) with a mean follow-up of 22.9 months were analyzed. The 1-year cumulative incidence for glaucoma development and progression was 28.0% and 17.8% in patients without and with preoperative glaucoma, respectively. In a Cox proportional hazards analysis, DSEK surgery, KPro implantation, average intraocular pressure (IOP) through follow-up and postoperative IOP spikes of ≥30 mmHg were each independently associated with glaucoma development or progression (p < 0.04 for all). A significant proportion of patients developed glaucoma or exhibited glaucoma progression within 1 year after corneal transplantation. Patient selection for DSEK may partly explain the higher risk for glaucoma in these patients. Postoperative IOP spikes should be minimized and may indicate the need for co-management with a glaucoma specialist.


Maize and oat antixenosis and antibiosis against Delphacodes kuscheli (Homoptera: Delphacidae), vector of "Mal de Rio Cuarto" of maize in Argentina.
"Mal de Rio Cuarto" (MRC) is the most important virus disease of maize, Zea mays L., in Argentina. Several maize lines show different levels of resistance to MRC in the field; however, no studies have been conducted to investigate resistance mechanisms against its insect vector, Delphacodes kuscheli Fennah (Homoptera: Delphacidae). Oat, Avena spp., is the main overwintering host of D. kuscheli and main source of populations that infest maize. Although oat varieties resistant to the greenbug, Schizaphis graminum (Rondani) (Homoptera: Aphididae) are commercially available, their effect on D. kuscheli is unknown. We conducted laboratory experiments to test for the presence of antixenosis and antibiosis resistance mechanisms on six maize lines with different levels of field resistance to MRC, and seven commercial oat cultivars that include two S. graminum-resistant varieties. We did not find antibiotic effects of maize lines on D. kuscheli longevity and survivorship patterns, but we obtained antixenotic effects from the LP2 line (field moderate) due to reduced settling preference and feeding. Oat 'Bonaerense Payé and 'Suregrain INTA' showed both antixenosis and antibiosis, with significantly less settling preference, oviposition in the no-choice test, and reduced total fecundity in comparison with the other varieties studied. The S. graminum-resistant 'Boyera F. A.' and 'Tambera F. A.' did not showed a consistent pattern of resistance versus D. kuscheli across all experiments. Our results indicate the presence of potential sources of insect resistance in the maize lines and oat cultivars tested that may be used in MRC integrated pest management programs.


A glance into the uterus during in vitro simulation of embryo transfer.
The currently low implantation rate after embryo transfer (ET) is partially attributed to technical aspects, such as catheter type, catheter load, placement of catheter tip and physician skills. Mock ET simulations were conducted with a transparent laboratory model of the uterine cavity. The catheter was loaded with alternating air and coloured liquid media. The transfer procedure was recorded by a digital video camcorder for later analysis. Different sequences of air and liquid volumes, as well as liquids of different viscosity were simulated. Injection of liquid with air into the uterus formed an air bubble which blocked the transport of the transferred liquid towards the fundus. The distribution of the transferred matter within the uterine cavity was determined by the composition of the liquid-air sequence and the viscosity ratio between the transferred liquid and the uterine fluid. It is suggested that the catheter load should contain minimal volumes of air in order to enhance the embryos' chances of reaching the site of implantation. The viscosity of the transferred liquid should be as close as possible to that of the uterine fluid in order to avoid transport of embryos towards the cervix.


The measurement of handedness.
A handedness scale consisting of 13 questionnaire items selected from those of D. Raczkowski, J. W. Kalat, and R. Nebes (1974, Neuropsychologia, 12, 43-47) was found to have high internal consistency for both males and females (coefficient alpha = .96 for both sexes), high test-retest reliability (r = .97 for males and .96 for females), and a correlation of .83 with a behavioral measure of handedness. Males exhibited more nonfamilial, but not familial, left-handedness than did females. Self-description as strongly right-handed or as strongly left-handed predicted questionnaire handedness categorization better than did hand used for writing.


Developmental changes in the translatable mRNA for beta subunit of S-100 protein in rat brain.
The presence of mRNA coding for beta subunit of S-100 protein was demonstrated in polyadenylated RNA from the rat brain in vitro translation in a reticulocyte lysate cell-free system. The products were identified with S-100 protein beta subunit using the immunoprecipitation of the reaction products with the specific antisera, comigration of the isolated, labelled peptide with the purified S-100 protein in SDS-polyacrylamide gel electrophoresis and fluorography and the same retention time of the labelled S-100 protein beta subunit with authentic S-100 beta subunit by high performance liquid chromatography. The size determination of mRNA for S-100 protein on sucrose density gradient centrifugation gave 6-8 S. The assay gave a linear response with increasing amounts of polyadenylated RNA, allowing quantitation of mRNA level for S-100 protein in polyadenylated RNA. During the prenatal period and 10 postnatal days, only minute amounts of mRNA for beta subunit of S-100 protein could be found, however a dramatic increase of mRNA for beta subunit of S-100 was observed within the period of 10 to about 30 days and the mRNA level maintained a plateau from 40 days to adult age. These date indicate that the development changes in the amount of S-100 protein in the rat brain found by other authors is strongly correlated with the changes in the level of its translatable mRNA.


Unilateral attention deficits and hemispheric asymmetries in the control of visual attention.
The present study sought to determine the roles of the two hemispheres in arousal and the selective components of attention. Ten patients with left and right parietal lesions and ten with left and right temporal lesions participated in the experiment. The hypothesis that posterior parietal lesions, whether left or right, cause two selective attentional deficits, namely, a reduced reactivity to stimuli in the visual field contralateral to the lesion, and a reduced reactivity to any stimulus which occupies a relative contralateral spatial position, was tested by asking the patient to tilt their head either to the left or to the right by 90 degrees and to respond to two stimuli displayed above and on either side of fixation mark. The arousal component of attention was studied by analysing the overall RT to visual stimuli independent of their spatial positions. The results showed that (1) patients with either left or right parietal damage are impaired in shifting attention from the ipsilateral to the contralateral visual field, and, within each visual field, in a direction contraversive to the lesion and (2) these two attentional deficits are more severe after right than after left parietal damage. Furthermore, the results show that the difficulty in maintaining a high level of alertness is a specific deficit of patients with right hemispheric lesion and not of patients with an extinction syndrome, insofar as there is no significant difference in overall RT between patients with parietal and temporal lesions.


MiR-139 protects against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced nerve injury through targeting c-Jun to inhibit NLRP3 inflammasome activation.
Cerebral ischemia/reperfusion (I/R) injury after ischemic stroke is usually accompanied with the activation of inflammasome which seriously impairs neurological function. MiR-139 has been reported to be associated with inflammatory regulation in multiple diseases. However, its effect and mechanism on inflammation regulation after cerebral I/R injury are still poorly understood. An in vitro model of cerebral I/R injury was constructed with oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. TargetScan bioinformatics analysis and dual luciferase reporter assay were utilized to confirm the targeted relationship between miR-139 and c-Jun. Cell pyroptosis was verified by flow cytometry and Caspase-1 Detection Kit. qRT-PCR assay was performed to detect the expression levels of miR-139, c-Jun, NLRP3 and ASC. Western blotting was applied to measure the protein levels of c-Jun and pyroptosis-related markers NLRP3, ASC, caspase-1, GSDMDNterm. The ELISA assay was applied to measure the release of IL-1β, IL-18 and LDH. MiR-139 was significantly downregulated whereas c-Jun was obviously upregulated after OGD/R treatment. TargetScan analysis predicted that c-Jun was a potential target of miR-139, which was verified by the dual-luciferase reporter assay. Also, overexpression of miR-139 repressed c-Jun expression. Furthermore, miR-139 inhibited OGD/R-induced cell pyroptosis and the upregulation of NLRP3, caspase-1, ASC, GSDMDNterm, and the release of IL-1β, IL-18 and LDH, while miR-139 inhibition exerted the opposite effects. However, overexpression of c-Jun aggravated OGD/R-induced nerve injury and partly abolished the neuroprotective effect of miR-139. Upregulation of miR-139 exerted neuroprotection against OGD/R-induced nerve injury by negatively regulating c-Jun/NLRP3 inflammasome signaling. This study offered insights for providing potential therapeutic targets for treating cerebral I/R injury.


Non-Newtonian effects of blood flow on hemodynamics in distal vascular graft anastomoses.
Non-Newtonian fluid flow in a stenosed coronary bypass is investigated numerically using the Carreau-Yasuda model for the shear thinning behavior of the blood. End-to-side coronary bypass anastomosis is considered in a simplified model geometry where the host coronary artery has a 75% severity stenosis. Different locations of the bypass graft to the stenosis and different flow rates in the graft and in the host artery are studied. Particular attention is given to the non-Newtonian effect of the blood on the primary and secondary flow patterns in the host coronary artery and the wall shear stress (WSS) distribution there. Interaction between the jet flow from the stenosed artery and the flow from the graft is simulated by solving the three-dimensional Navier-Stokes equation coupled with the non-Newtonian constitutive model. Results for the non-Newtonian flow, the Newtonian flow and the rescaled Newtonian flow are presented. Significant differences in axial velocity profiles, secondary flow streamlines and WSS between the non-Newtonian and Newtonian fluid flows are revealed. However, reasonable agreement between the non-Newtonian and the rescaled Newtonian flows is found. Results from this study support the view that the residual flow in a partially occluded coronary artery interacts with flow in the bypass graft and may have significant hemodynamic effects in the host vessel downstream of the graft. Non-Newtonian property of the blood alters the flow pattern and WSS distribution and is an important factor to be considered in simulating hemodynamic effects of blood flow in arterial bypass grafts.


A multi-component cognitive behavioural intervention for the treatment of fear of falling after hip fracture (FIT-HIP): protocol of a randomised controlled trial.
Hip fracture is a common injury in the geriatric population. Despite surgical repair and subsequent rehabilitation programmes, functional recovery is often limited, particularly in individuals with multi-morbidity. This leads to high care dependency and subsequent use of healthcare services. Fear of falling has a negative influence on recovery after hip fracture, due to avoidance of activity and subsequent restriction in mobility. Although fear of falling is highly prevalent after hip fracture, no structured treatment programme is currently available. This trial will evaluate whether targeted treatment of fear of falling in geriatric rehabilitation after hip fracture using a multi-component cognitive behavioural intervention (FIT-HIP), is feasible and (cost) effective in reducing fear of falling and associated activity restriction and thereby improves physical functioning. This multicentre cluster randomised controlled trial will be conducted among older patients with hip fracture and fear of falling who are admitted to a multidisciplinary inpatient geriatric rehabilitation programme in eleven post-acute geriatric rehabilitation units. Fifteen participants will be recruited from each site. Recruitment sites will be allocated by computer randomisation to either the control group, receiving usual care, or to the intervention group receiving the FIT-HIP intervention in addition to usual care. The FIT-HIP intervention is conducted by physiotherapists and will be embedded in usual care. It consists of various elements of cognitive behavioural therapy, including guided exposure to feared activities (that are avoided by the participants). Participants and outcome assessors are blinded to group allocation. Follow-up measurements will be performed at 3 and 6 months after discharge from geriatric rehabilitation. (Cost)-effectiveness and feasibility of the intervention will be evaluated. Primary outcome measures are fear of falling and mobility. Targeted treatment of fear of falling may improve recovery and physical and social functioning after hip fracture, thereby offering benefits for patients and reducing healthcare costs. Results of this study will provide insight into whether fear of falling is modifiable in the (geriatric) rehabilitation after hip fracture and whether the intervention is feasible. Netherlands Trial Register: NTR 5695 .


Cholesterol absorption and synthesis during pravastatin, gemfibrozil and their combination.
The study evaluates cholesterol metabolism off and on treatment with pravastatin (P), gemfibrozil (G) and their combination (PG) in 38 middle-age hyperlipidemic primary care patients with serum cholesterol > 6 mmol/l and serum triglycerides < 4 mmol/l after a low-fat low-cholesterol diet. The subjects were randomized to P (40 mg/g), G (1200 mg/day), PG (40 + 1200 mg/day) or placebo for 12 weeks. We analyzed serum lipids, apolipoproteins A-I, B and E, serum cholesterol precursors (markers of cholesterol synthesis), serum plant sterols and cholestanol (markers of cholesterol absorption) and cholesterol metabolism by the sterol balance technique and cholesterol absorption efficiency. P alone or in combination with G lowered apoprotein E concentration, and serum cholesterol levels by inhibiting cholesterol synthesis measured by the precursor/cholesterol proportions with inconsistent change in fecal output of cholesterol. G alone decreased bile acid synthesis and increased biliary cholesterol secretion which were associated with reduced cholesterol absorption efficiency and the serum plant sterol and cholestanol proportions, and increased synthesis of cholesterol as measured both by the sterol balance technique and the precursor sterol proportions. A combination of PG also lowered LDL cholesterol similarly but triglyceride-rich lipoproteins significantly more than P alone, and otherwise inhibited the changes caused by G in cholesterol metabolism except that the precursor sterol proportions still indicated reduced cholesterol synthesis. Overall, the changes of the cholesterol precursor proportions were negatively related to that of cholesterol absorption efficiency and positively to that of cholesterol synthesis. The respective plant sterol and cholestanol values correlated oppositely to cholesterol absorption efficiency and synthesis. Serum precursor sterols reflected changes in cholesterol synthesis more sensitively than the sterol balance technique, even though only the latter method can quantitate cholesterol synthesis.


The effect of betaine for mouse sperm cryopreservation.
Sperm cryopreservation is an effective method of preserving male fertility in humans, as well as domestic and experimental animals. However, various factors such as ice crystal formation, osmotic stress, and oxidative stress, negatively influence the motility and viability of post-thawed spermatozoa. Betaine, which works as an osmoprotectant is known to work as a nontoxic cryoprotectant. However, the protective effects during mouse sperm cryopreservation are still unclear. Thus, the purpose of this study was to investigate whether betaine has protective effects during the process of mouse sperm cryopreservation. In this study, betaine was found to be effective in maintaining sperm motility during the freezing procedure and 1% (85.4 mM) betaine was identified as the optimal concentration to be added to cryopreservation solutions. It was also found that betaine improves the integrity of the plasma membranes of sperm tails, suggesting that betaine has a positive effect on sperm motility.


Review and improvement of conventional models for reservoir sediment trapping efficiency.
Sediment accumulation has been the most important factor influencing the comprehensive benefit of reservoirs. A quantitative investigation of the sediment trapping efficiencies of reservoirs is a key to understanding the impact of sedimentation on reservoirs. Generally, the simplest method to assess sediment accumulation ratio is adopting sediment concentration curve with trap efficiency (TE) of the reservoir. Many empirical and semi-empirical models have been proposed to determine this term related to the average annual inflow, features and characteristics of the reservoir watershed area. In this article four different empirical models decided by capacity to inflow ratio (C/I), capacity to watershed ratio (C/W) were used. These different models were summarized and utilized to determine TE of large reservoirs on the Upper Yangtze River for recent decades. Based on these conventional models, an improved model to estimate sediment trapping efficiency is proposed, and experimental data from other 18 reservoirs come from different basins were used to validate the model. The results indicate that the sediment trapping efficiencies that were estimated by the four empirical model were similar to the measured efficiencies for reservoirs on the Upper Yangtze River. Among the the Brune and Siyam empirical models were the most reliable and can be applied to estimate sediment trapping efficiency for reservoirs on the Upper Yangtze River. The improved model takes the capacity/annual inflow ratio and capacity/watershed area ratio into account comprehensively, the effect of particle size and settling velocity of the sediment are also considered, it is more applicable and accuracy to predict large reservoir sediment trapping efficiency. The results of this study provide a valuable reference for predicting large reservoir sedimentation and sediment regulation.


Meta-analysis of the association between cognitive abilities and everyday functioning in bipolar disorder.
Neurocognitive deficits are common in bipolar disorder and contribute to functional disability. However, the degree to which general and specific cognitive deficits affect everyday functioning in bipolar disorder is unknown. The goal of this meta-analysis was to examine the magnitude of the effect of specific neurocognitive abilities on everyday functioning in bipolar disorder. We conducted a comprehensive meta-analysis of studies that reported associations between performance on objective neuropsychological tasks and everyday functioning among individuals with bipolar disorder. From an initial pool of 486 papers, 22 studies met inclusion criteria, comprising a total of 1344 participants. Correlation coefficients were calculated for 11 cognitive domains and four measurement modalities for functioning. We also examined effect moderators, such as sample age, clinical state, and study design. The mean Pearson correlation between neurocognitive ability and functioning was 0.27, and was significant for all cognitive domains and varied little by cognitive domain. Correlations varied by methods of everyday functioning assessment, being lower for clinician and self-report than performance-based tasks and real-world milestones such as employment. None of the moderator analyses were significant. Overall, the strength of association between cognitive ability and everyday functioning in bipolar disorder is strikingly similar to that seen in schizophrenia, with little evidence for differences across cognitive domains. The strength of association differed to a greater extent according to functional measurement approach.


Difference Fourier analysis of "surface features" of bacteriorhodopsin using glucose-embedded and frozen-hydrated purple membrane.
A difference Fourier map of the projected structure of bacteriorhodopsin has been synthesized from electron diffraction amplitudes collected from membranes prepared in the glucose-embedded state and the frozen-hydrated state. Phases of a recently published data set for glucose-embedded specimens were used for the difference Fourier map. Moderate resolution (9 A) and high resolution (4.25 A) maps both indicate that glucose is exchangeable for water in the region of the map corresponding to the lipid regions. We interpret this as indicating that there is a small surface depression in this region of the structure. The depth of this feature is estimated to be 1/6 the thickness of the protein region in the membrane. The data obtained in this study rules out the existence of an aqueous transmembrane channel, the dimensions of which are large enough to allow free exchange of glucose for water. Several new features are also observed in the protein region of the membrane. These features are probably due to segments of the polypeptide at the aqueous interface that are well ordered in frozen-hydrated specimens but not in glucose-embedded specimens. Candidate structures for the origin of these features are extensions of the helices, or linker regions connecting the helices.


Dry-weight reduction improves intradialytic hypertension only in patients with high predialytic blood pressure.
The aim of this study was to investigate whether additional volume reduction by ultrafiltration can improve blood pressure in patients with intradialytic hypertension (IDH) defined as at least 10 mmHg systolic blood pressure (SBP) rise during hemodialysis. This prospective, open-label, single-center study included 11 IDH patients with normal predialytic blood pressure (BP) (group A), 11 IDH patients with high predialytic BP (group B), and 18 patients without IDH as control. Serum angiotensin-II, aldosterone (ALD), angiotensin-converting enzyme, endothelin-1, nitric oxide, and asymmetric dimethylarginine were measured before and after the treatments. Basic angiotensin-converting enzyme, ALD, endothelin-1, and asymmetric dimethylarginine serum levels were significantly increased in group B compared with control (P < 0.05). On comparing the results from the first and 13th dialysis sessions in group A, the dry weight was reduced by - 0.15 ± 0.16 kg after 12 sessions and the predialytic SBP increased by 3.18 ± 6.25 mmHg before and by 7.37 ± 14.90 mmHg at 4 h during the 13th session. In group B, the dry weight was reduced by 0.67 ± 0.53 kg (P = 0.006 vs. group A) at the 13th session and they had - 12.09 ± 16.20 mmHg less SBP before (P = 0.009 vs. group A) and - 11.82 ± 14.66 mmHg at 4 h of the 13th session. The decrease in dry weight was associated with significantly higher decreases in angiotensin-II and ALD serum levels in group B compared with group A. Reducing fluid overload in IDH patients with high predialytic BP can effectively improve their BP, but had no effect on BP in normal predialytic BP IDH cases.


A method for the gross and microscopic investigation of vascular reperfusion in ischemic myocardium.
Fluorescein-isothiocyanate dextran (FITC-dextran; MW approximately 70,000) was used in isolated rat hearts to compare normal vascular perfusion of ventricular myocardium with the pattern and extent of reperfusion following 60 minutes of global ischemia. Its gross distribution in frozen transverse sections through the ventricles was similar to that of sodium fluorescein. However, unlike 0.1% sodium fluorescein, 6.7% FITC-dextran has a viscosity similar to that of blood, and its much higher molecular weight prevents its diffusion beyond the ischemically injured vessels. Furthermore, staining by the alcoholic periodic acid-Schiff technique enabled tracer distribution to be confirmed microscopically and distinguished competent from incompetent vessels in paraffin embedded material.


A modified hip screw incorporating injected cement for the fixation of osteoporotic trochanteric fractures.
To evaluate a modified sliding hip screw for the fixation of trochanteric fractures that provides increased fixation strength in osteoporotic bones and allows for the safe intraoperative application of bone cement. Biomechanical cadaver study. Unstable trochanteric fractures were simulated by osteotomy in nine pairs of cadaveric femurs and stabilized by a standard sliding hip screw randomly assigned to the left or right femur. The contralateral femur was stabilized with a newly designed hip screw, which was augmented with low-viscosity bone cement. Femoral bone mineral density was measured by dual x-ray absorptiometry and quantitative computed tomography. Fixation stability of the hip was assessed after dynamic loading by displacement measurement of the femoral head in a simulated one-leg stance configuration. Modification of the hip screw together with cement augmentation significantly (p < 0.05) increased the initial stability of the fracture fixation technique. The total displacement of the femoral head was reduced by 39 percent on average using cement augmentation in the modified screw compared with the standard sliding hip screw. The largest improvement in initial fixation stability was found for the most osteoporotic bones. This modified hip screw augmented with bone cement can significantly enhance the initial fixation stability of trochanteric fractures in osteoporotic femurs.


The novel allele HLA-B*35:564, identified by next-generation sequencing in a Chinese individual.
The novel HLA-B*35:564 allele differs from the HLA-B*35:01:01:01 allele by one nucleotide in exon 3 at position 490.


External validation of the Endometriosis Fertility Index in a French population.
To show an external validation of the Endometriosis Fertility Index (EFI) and to observe cumulated pregnancy rates after infertility management combining surgery and assisted reproductive technologies (ART). Observational study from January 2004 to December 2012. Tertiary-care university hospital and ART center. Four hundred twelve infertile and endometriotic patients after laparoscopic surgery. Surgical diagnosis and treatment followed by spontaneous fertility or ART management. Spontaneous pregnancy rates and cumulative (spontaneous and ART) pregnancy rates according to the EFI. A significant relationship between EFI and spontaneous pregnancy rates was observed at 12 months (P=.001). The least function score and complete removal of endometriotic lesions and pelvic adhesions were significantly associated with spontaneous pregnancy (P=.006). Cumulative pregnancy rate at 18 months was 78.8%. ART benefits for pregnancy rates were higher for patients with poor EFI. External validation of the EFI in a French population was demonstrated. Combining surgery for endometriosis and ART led to a 78.8% pregnancy rate at 18 months after surgery.


Serotonergic Regulation of Corticoamygdalar Neurons in the Mouse Prelimbic Cortex.
Neuromodulatory transmitters, such as serotonin (5-HT), selectively regulate the excitability of subpopulations of cortical projection neurons to gate cortical output to specific target regions. For instance, in the mouse prelimbic cortex, 5-HT selectively excites commissurally projecting (COM) intratelencephalic neurons via activation of 5-HT2A (2A) receptors, while simultaneously inhibiting, via 5-HT1A (1A) receptors, corticofugally projecting pyramidal neurons targeting the pons. Here we characterize the physiology, morphology, and serotonergic regulation of corticoamygdalar (CAm) projection neurons in the mouse prelimbic cortex. Layer 5 CAm neurons shared a number of physiological and morphological characteristics with COM neurons, including higher input resistances, smaller HCN-channel mediated responses, and sparser dendritic arbors than corticopontine neurons. Across cortical lamina, CAm neurons also resembled COM neurons in their serotonergic modulation; focally applied 5-HT (100 μM; 1 s) generated 2A-receptor-mediated excitation, or 1A- and 2A-dependent biphasic responses, in ipsilaterally and contralaterally projecting CAm neurons. Serotonergic excitation depended on extrinsic excitatory drive, as 5-HT failed to depolarize CAm neurons from rest, but could enhance the number of action potentials generated by simulated barrages of synaptic input. Finally, using dual tracer injections, we identified double-labeled CAm/COM neurons that displayed primarily excitatory or biphasic responses to 5-HT. Overall, our findings reveal that prelimbic CAm neurons in layer 5 overlap, at least partially, with COM neurons, and that neurons projecting to either, or both targets, exhibit 2A-dependent serotonergic excitation. These results suggest that 5-HT, acting at 2A receptors, may promote cortical output to the amygdala.


Prevalence of rheumatic diseases in Raramuri people in Chihuahua, Mexico: a community-based study.
This study aimed to determine the prevalence of musculoskeletal (MSK) pain and rheumatic diseases in the Raramuri population (also known as Tarahumaras) who are an indigenous group in the northern state of Chihuahua in Mexico. We used the Community-Oriented Program for Control of Rheumatic Diseases (COPCORD) methodology. An analytical cross-sectional study was conducted including indigenous Raramuri aged ≥18 years from communities settled in Chihuahua City. Subjects with positive MSK pain were evaluated by primary care physicians and rheumatologists. Demographic and occupational factors such as gender and job type associated with rheumatic disease were investigated. A total of 380 indigenous Raramuri (mean age 33.6 ± 13.1 years; 37.9 % male) were interviewed. Seventy-six individuals (20 %) reported MSK pain in the last 7 days. Pain intensity was reported as "severe" and "the most severe" in 30 % of the cases. Fifty-six individuals (14.7 %) reported pain in the past and 86 (22.6 %) had either past or current pain. The prevalence of rheumatic diseases was 10.5 %. Diagnosed diseases were osteoarthritis (6.6 %), low back pain (1.6 %), spondyloarthritis (0.8 %), rheumatoid arthritis (0.5 %), non-specific arthritis (0.5 %), rheumatic regional pain syndromes (0.3 %), and fibromyalgia (0.3 %). Rheumatic disease was associated with the following variables: age (odds ratio (OR) 1.04, 95 % confidence interval (CI) 1.02-1.08; p = 0.006), family history of rheumatic symptoms (OR 6.9; 95 % CI 2.6-18.7; p < 0.001), and Health Assessment Questionnaire-Disability Index (OR 28.9; 95 % CI 2.8-289.7; p < 0.001). A high prevalence of non-traumatic MSK pain suggests the need for a rheumatic disease prevention program in the Raramuri people in Chihuahua, Mexico.


Restricted access supramolecular solvent based magnetic solvent bar liquid-phase microextraction for determination of non-steroidal anti-inflammatory drugs in human serum coupled with high performance liquid chromatography-tandem mass spectrometry.
A hexafluroisopropanol (HFIP)-alkanol supramolecular solvent (SUPRAS) based magnetic solvent bar (MSB) liquid-phase microextraction (LPME) method was proposed for extraction of non-steroidal anti-inflammatory drugs (NSAIDs, including ketoprofen, naproxen, indomethacin and diclofenac) in human serum. The restricted access HFIP-alkanol SUPRAS was prepared by injecting a mixture of HFIP and alkanol into water. A stainless-steel needle was inserted into a piece of hollow fiber to prepare a magnetic bar. Then the magnetic bar was dipped in SUPRAS to impregnate the wall pores of the hollow fiber, followed by placing it into the serum sample for extraction. Only 4 μL of SUPRAS was consumed per bar. The MSB not only functioned for stirring, but also played the role of extraction and magnetic separation. Under the optimal extraction conditions (seven MSBs, extraction time 33 min and stirring rate 730 rpm), which was obtained by one variable-at-a-time and response surface methodology, the novel MSB-LPME was coupled with high performance liquid chromatography-tandem mass spectrometry to determine NSAIDs in human serum. The method showed a good linear relationship (correlation coefficients ≥ 0.9939). Method limits of detection and method limits of quantitation were in the range of 0.25-0.95 μg L-1 and 0.83-3.16 μg L-1, respectively. The recoveries for the spiked human serum samples ranged from 86.8% to 125.1% with intra- and inter-day relative standard deviations less than 9.2% and 18.1%, respectively. Moreover, the method did not require a protein precipitation step, and matrix effects of 72.8%-117.7% showed little interference with mass spectrometry detection, which was due to the double cleanup provided by the restricted access property of SUPRAS and the filtration capacity of hollow fiber. The HFIP-alkanol SUPRAS-based MSB-LPME method proved to be simple, highly efficient and environment-friendly for the pretreatment of serum/plasma.


Inhaled deep eutectic solvent based-nanoemulsion of pirfenidone in idiopathic pulmonary fibrosis.
Pirfenidone (PRF), the first FDA-approved drug to treat idiopathic pulmonary fibrosis (IPF) and formulated as an oral dosage form, has many side effects. To enhance the therapeutic effect, we discovered a high-load nanoemulsion using a novel deep eutectic solvent (DES) and developed an inhalation drug with improved bioavailability. The DES of PRF and N-acetylcysteine were discovered, and their physicochemical properties were evaluated in this study. The mechanism of DES formation was confirmed by FT-IR and 1H NMR and suggested to involve hydrogen bonding. The DES nanoemulsion in which the nano-sized droplets were dispersed is optimized by mixing the DES and distilled water in a ratio. The in vivo pharmacokinetic study showed that the pulmonary route of administration is superior to that of the oral route, and the DES nanoemulsion is superior to that of the PRF solution in achieving better bioavailability and lung distribution. The therapeutic effect of PRF for IPF could be confirmed through in vivo pharmacodynamics studies, including lung function assessment, enzyme-linked immunosorbent assay, histology, and micro-computed tomography using the bleomycin-induced IPF rat model. In addition, the pulmonary route administration of PRF is advantageous in reducing the toxicity risk.


Gender differences in epigastric hernia repair: a propensity score matching analysis of 15,925 patients from the Herniamed registry.
In recent surgical literature, gender-specific differences in the outcome of hernia surgery has been analyzed. We already know that female patients are at higher risk to develop chronic postoperative pain after inguinal, incisional, and umbilical hernia surgery. In this study, we evaluated the impact of gender on the outcome after epigastric hernia surgery. A covariable-adjusted matched-paired analysis with data derived from the Herniamed registry was performed. In total of 15,925 patients with 1-year follow-up data were included in the study. Propensity score matching was performed for the 7786 female (48.9%) and 8139 male (51.1%) patients, creating 6350 pairs (81.6%). Matched-paired analysis revealed a significant disadvantage for female patients for pain on exertion (12.1% vs. 7.6%; p < 0.001) compared to male patients. The same effect was demonstrated for pain at rest (6.2% in female patients vs. 4.1% in male patients; p < 0.001) and pain requiring treatment (4.6% in female patients vs. 3.1% in male patients; p < 0.001). All other outcome parameters showed no significant differences between female and male patients. Female patients are at a higher risk for chronic pain after elective epigastric hernia repairs compared to the male patient population. These results complete findings of previous studies showing the same effect in inguinal, umbilical, and incisional hernia repair.


Murine models of psoriasis and its applications in drug development.
Psoriasis is an autoimmune skin disease which characteristic of a well-demarcated, erythematous, raised lesion with silvery-white dry scale. Although the mechanism of psoriasis has not been fully understood so far, much progress has been made in understanding many of its complex potential mechanism, particularly the crucial role of the IL-23/Th17 axis. There are a large number of psoriasis models that reflect the complexity of the psoriasis mechanisms. In this review, we summarize various psoriasis mouse models, detail the features and molecular mechanisms of these mouse models, and discuss their strengths and limitations for psoriasis research. The development of mouse models of psoriasis provide an important basis for studying psoriasis pathogenesis and antipsoriatic drugs development. Therefore, the application of various psoriasis mouse models in antipsoriatic drug development are also discussed.


Improved purification procedure for the extracellular D-glucosyltransferase from Streptococcus mutans 6715.
The exocellular D-glucosyltransferase from Streptococcus mutans 6715 has been highly purified with minimal loss of enzymic activity. The organisms were cultured in trypticase soy-broth that had been treated with invertase and filtered through an ultrafilter fitted with a membrane having a cut-off molecular weight at 10,000. To the growth medium was added Tween 80, which prevented the enzyme from aggregating. The final step in the purification employed insoluble, streptococcal dextran as an affinity support. Two D-glucosyltransferase activities were detected, viz., one that did not adsorb to the insoluble dextran and one that did. The enzymic fraction that had adsorbed to the insoluble dextran in the affinity column was strongly inhibited by added insoluble dextran.


Construction of a cDNA clone for a nuclear-coded subunit of cytochrome c oxidase from rat liver.
A cDNA library for 6S-9S poly(A)-containing RNA from rat liver was constructed in E. coli. Initial screening of the clones was carried out using single stranded 32P-labeled cDNA prepared against poly(A)-containing RNA isolated from immunoadsorbed polyribosomes enriched for the nuclear-coded subunit messenger RNAs of cytochrome c oxidase. One of the clones, pCO89, was found to hybridize with the messenger RNA for subunit VIC. The DNA sequence of the insert in pCO89 was carried out and it has got extensive homology with the C-terminal 33 amino acids of subunit VIC from beef heart cytochrome c oxidase. In addition, the insert contained 146 bp, corresponding to a portion of the 3'-non-coding region. Northern blot analysis of rat liver RNA with the nick-translated insert of pCO89 revealed that the messenger RNA for subunit VI would contain around 510 bases.


The correlation between headache and refractive errors.
To compare the prevalence of refractive errors in patients with headache and a control population. Three hundred ten patients with headache and 843 controls were retrospectively evaluated. Complete ophthalmologic examination was performed in the headache group. Autorefraction was performed in all participants (with cycloplegia under 10 years of age). Myopia was defined as the spherical equivalent refraction of at least -0.50 D, hyperopia as the spherical equivalent refraction of at least +2.0 D, and astigmatism as the cylinder of at least 1.0 D. Main outcome measures were refractive error, anisometropia, and previous miscorrection of refractive error. Chi-square and Student's t-tests were used for statistical analysis. Total prevalence of refractive errors was higher in the headache group (p = 0.002). The rate of astigmatism was higher in the headache group (p < 0.0001), while that of myopia and hyperopia were similar in both groups (p = 0.74, p = 0.79, respectively). The rates of compound and mixed astigmatism were higher in the headache group (p = 0.026, p < 0.001, respectively). The rates of anisometropia and previous miscorrection of refractive error were higher in the headache group (p < 0.0001 for both). Children with headache have a statistically significant increased risk of total refractive errors (OR = 1.57, 95% CI: 1.18-2.07), anisometropia (OR = 9.59, 95% CI: 5.72-16.1), and miscorrection of refractive error (OR = 9.57, 95% CI: 5.43-16.9). Compound and mixed types of astigmatism, anisometropia, and miscorrection of refractive error were found more often in patients with headache than in control subjects.


Molecular and functional characterization of the murine glucocerebrosidase gene.
A genomic clone of glucocerebrosidase (D-glucosyl-N-acyl-sphingosine glucohydrolase; E.C. 188.8.131.52) purified from a genomic library derived from a Balb/c mouse was analyzed by restriction mapping and nucleotide sequencing of its promoter and protein coding regions. Promoter activity was functionally assessed by ligation of a 2 kb glucocerebrosidase fragment to the protein coding segment of a bacterial neomycin resistance gene. Smaller segments of the 5' flanking sequence were then analyzed for their ability to initiate transcription of the chloramphenicol acetyltransferase reporter gene. A 319 bp Eco RI-Bgl II fragment (containing 259 bp upstream of the cDNA 5' limit) ligated to the chloramphenicol acetyltransferase open reading frame produced considerable activity.


Eating behaviors, dietary patterns and weight status in emerging adulthood and longitudinal associations with eating behaviors in early childhood.
Eating behaviors may contribute to differences in body weight and diet over time. Our study aims to examine how eating behaviors of young adults relate to their current weight status and dietary patterns and to explore longitudinal associations with eating behaviors in early childhood. Study participants are young adults (n = 698) taking part in the Quebec Longitudinal Study of Child Development. At age 22, eating behaviors were assessed using the Adult Eating Behavior Questionnaire. Dietary patterns were derived from information collected by food frequency questions. Weight status was based on self-reported data. Information on eating behaviors in childhood had been collected when participants were 2.5 to 6 years old. Pearson's correlations were used to determine associations between adult eating behaviors and body mass index. Simple and multivariate linear regression analyses were used to examine associations between eating behaviors and dietary patterns at age 22, and longitudinal associations with behaviors in early childhood. Ordinal logistic regression analyses were used to assess associations between overeating and fussy eating in childhood and weight status at age 22. Body mass index was positively correlated with Emotional overeating, Enjoyment of food, and Food responsiveness and negatively correlated with Satiety responsiveness, Emotional undereating, Slowness in eating and Hunger. A Healthy dietary pattern was positively associated with both Enjoyment of food and Hunger, and negatively associated with Food fussiness. Inversely, a Beverage-rich dietary pattern was negatively associated with Enjoyment of food and positively associated with Food fussiness. A Protein-rich pattern was positively associated with Enjoyment of food, while a High energy density pattern was positively associated with Food fussiness. Young adults with higher scores for fussy eating in early childhood were more likely to manifest Food fussiness and Emotional undereating, and less likely to adopt a Healthy dietary pattern. Young adults with higher scores for overeating in early childhood were less likely to show traits such as Slowness in eating and more likely to be overweight. Our findings suggest that eating behaviors in childhood have long-term influence on diet and weight status, thereby reinforcing the importance of early interventions that promote healthy eating.


Effects of naloxone and its quaternary analogue on fluid consumption in water-deprived rats.
The effects of subcutaneous administration of naloxone and its quaternary analogue on the consumption of water, saline and saccharin solution were investigated in the water-deprived rat. Quaternary naloxone (0.01-10 mg . kg-1), effective in blocking peripheral opiate receptors, had no effect on fluid intake. In contrast, naloxone (0.01-10 mg . kg-1), produced dose-dependent attenuation of intake for each of the three fluids, indicating a central location of the relevant opiate receptors. Access to saline induced additional drinking, compared with water intake, due to an extension of the initial avid consumption which follows the period of water-deprivation. This enhancement of drinking was blocked by naloxone, but not by its quaternary analogue. Interactions between naloxone and taste factors in drinking may, therefore, depend on blockade of central opiate receptors.


Rapid and simple diagnosis of Chlamydophila pneumoniae pneumonia by an immunochromatographic test for detection of immunoglobulin M antibodies.
To evaluate a newly developed immunochromatographic test (the MySet test) for the detection of Chlamydophila pneumoniae-specific immunoglobulin M antibodies, the results obtained by the MySet test were compared with those obtained by two serological tests. The sensitivity and specificity of the MySet test were 100% and 92.9%, respectively. The MySet test is rapid and simple to use and is thought to be a useful tool for the selection of appropriate antibiotic therapy.


Deletion mutation analysis on C-terminal domain of plant vacuolar H(+)-pyrophosphatase.
Vacuolar H(+)-translocating inorganic pyrophosphatase (V-PPase; EC 188.8.131.52) is a homodimeric proton-translocase; it contains a single type of polypeptide of approximately 81kDa. A line of evidence demonstrated that the carboxyl terminus of V-PPase is relatively conserved in various plant V-PPases and presumably locates in the vicinity of the catalytic site. In this study, we attempt to identify the roles of the C-terminus of V-PPase by generating a series of C-terminal deletion mutants over-expressed in Saccharomyces cerevisiae, and determining their enzymatic and proton translocating reactions. Our results showed that the deletion mutation at last 5 amino acids in the C-terminus (DeltaC5) induced a dramatic decline in enzymatic activity, proton translocation, and coupling efficiency of V-PPase; but the mutant lacking last 10 amino acids (DeltaC10) retained about 60-70% of the enzymatic activity of wild-type. Truncation of the C-terminus by more than 10 amino acids completely abolished the enzymatic activity and proton translocation of V-PPase. Furthermore, the DeltaC10 mutant displayed a shift in T(1/2) (pretreatment temperature at which half enzymatic activity is observed) but not the optimal pH for PP(i) hydrolytic activity. The deletion of the C-terminus substantially modified apparent K(+) binding constant, but exert no significant changes in the Na(+)-, F(-)-, and Ca(2+)-inhibition of the enzymatic activity of V-PPase. Taken together, we speculate that the C-terminus of V-PPase may play a crucial role in sustaining enzymatic activity and is likely involved in the K(+)-regulation of the enzyme in an indirect manner.


Delivery of oncolytic adenovirus into the nucleus of tumorigenic cells by tumor microparticles for virotherapy.
Oncolytic viruses have been utilized for the treatment of various cancers. However, delivery of the viral particles to tumor cells remains a major challenge. Microparticles (MP) are vesicle forms of plasma membrane fragments of 0.1-1 μm in size that are shed by cells. We have previously shown the delivery of chemotherapeutic drugs using tumor cell-derived MPs (T-MP). Here we report that T-MPs can be utilized as a unique carrier system to deliver oncolytic adenoviruses to human tumors, leading to highly efficient cytolysis of tumor cells needed for in vivo treatment efficacy. This T-MP-mediated oncolytic virotherapy approach holds multiple advantages, including: 1) delivery of oncolytic adenovirus by T-MPs is able to avoid the antiviral effect of host antibodies; 2) delivery of oncolytic adenovirus by T-MPs is not limited by virus-specific receptor that mediates the entry of virus into tumor cells; 3) T-MPs are apt at delivering oncolytic adenoviruses to the nucleus of tumor cells as well as to stem-like tumor-repopulating cells for the desired purpose of killing them. These findings highlight a novel oncolytic adenovirus delivery system with highly promising clinical applications.


Natural occurrence ofAlternaria mycotoxins in the grain and chaff of cereals.
Samples of wheat and rye heads with evident black discoloration were collected in 1986 and 1987. Four fungal genera colonized such heads:Alternaria, Cladosporium, Drechslera, andEpicoccum. In chaff of wheat (19%) and rye (10%) samples alternariol was present in amounts up to 1.8mg/kg, and alternariol methyl ether up to 0.51 mg/kg. In 1 out of 21 wheat samples alternariol was also present in kernels (0.59mg/kg).


Relative Tranquility in Ostomy Patients' Social Life: A Qualitative Content Analysis.
Ostomy significantly alters one's elimination pattern and can affect the individual in physiological, psychosocial and spiritual aspects. Over time, the ostomy patient's experience changes and they develop coping strategies to handle the new reality. The aims of this study sought Iranian ostomy patients' main problem, how they deal and the outcome of their efforts to manage that problem in their daily lives. A qualitative content analysis was conducted involving twenty-seven ostomy patients that were chosen by purposeful sampling and referred to the Iranian Ostomy Association from October 2015 to June 2016. The mean age of the participants was 55 years, 15 were males, the major cause of ostomy was colorectal cancer and the colostomy was the most common type of ostomy, and nineteen of them between one and twenty years lived with an ostomy. Most of them were married, had bachelor degree and received adjuvant therapy, and few were employed. Guarantee indecisive to maintain a stable life with an ostomy and the possibility of ostomy disclosure unpredictability show relative tranquility in patients' social life. Because of the ostomy nature, there is not the possibility of full control over life with an ostomy and this issue is causing concerns in their family and social life.


A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration.
Treprostinil is available in three different formulations and four different routes of administration: Remodulin® (treprostinil sodium, intravenous and subcutaneous administration), Tyvaso® (treprostinil sodium, inhaled administration), and Orenitram® (treprostinil diolamine, oral administration) for the treatment of pulmonary arterial hypertension (PAH). Pharmacokinetic studies have been performed in healthy volunteers and patients with PAH. The intent of this review is to outline pharmacokinetic considerations of the three treprostinil formulations and provide clinicians with a resource that may support clinical decisions in treating patients with PAH.


Extreme Selection Unifies Evolutionary Game Dynamics in Finite and Infinite Populations.
We show that when selection is extreme-the fittest strategy always reproduces or is imitated-the unequivalence between the possible evolutionary game scenarios in finite and infinite populations resolves, in the sense that the three generic outcomes-dominance, coexistence, and mutual exclusion-emerge in well-mixed populations of any size. We consider the simplest setting of a 2-player-2-strategy symmetric game and the two most common microscopic definitions of strategy spreading-the frequency-dependent Moran process and the imitation process by pairwise comparison-both in the case allowing any intensity of selection. We show that of the seven different invasion and fixation scenarios that are generically possible in finite populations-fixation being more or less likely to occur and rapid compared to the neutral game-the three that are possible in large populations are the same three that occur for sufficiently strong selection: (1) invasion and fast fixation of one strategy; (2) mutual invasion and slow fixation of one strategy; (3) no invasion and no fixation. Moreover (and interestingly), in the limit of extreme selection 2 becomes mutual invasion and no fixation, a case not possible for finite intensity of selection that better corresponds to the deterministic case of coexistence. In the extreme selection limit, we also derive the large population deterministic limit of the two considered stochastic processes.


Characterization of a clinically used charcoal suspension for in vivo EPR oximetry.
Electron paramagnetic resonance (EPR) oximetry using particulate materials allows repeatable measurements of oxygen in tissues. However, the materials identified so far are not medical devices, thus precluding their immediate use in clinical studies. The aim of this study was to assess the magnetic properties of Carbo-Rep®, a charcoal suspension used as a liquid marker for preoperative tumor localization. Calibration curves (EPR linewidth as a function of pO2) were built using 9-GHz EPR spectrometry. The feasibility of performing oxygen measurements was examined in vivo by using a low-frequency (1 GHz) EPR spectrometer and by inducing ischemia in the gastrocnemius muscle of mice or by submitting rats bearing tumors to different oxygen-breathing challenges. Paramagnetic centers presenting a high oxygen sensitivity were identified in Carbo-Rep®. At 1 GHz, the EPR linewidth varied from 98 to 426 µT in L-band in nitrogen and air, respectively. The sensor allowed repeated measurements of oxygen over 6 months in muscles of mice. Subtle variations of tumor oxygenation were monitored in rats when switching gas breathing from air to carbogen. The magnetic properties of Carbo-Rep® are promising for its future use as oxygen sensor in clinical EPR oximetry.


A computational screen for type I polyketide synthases in metagenomics shotgun data.
Polyketides are a diverse group of biotechnologically important secondary metabolites that are produced by multi domain enzymes called polyketide synthases (PKS). We have estimated frequencies of type I PKS (PKS I) - a PKS subgroup - in natural environments by using Hidden-Markov-Models of eight domains to screen predicted proteins from six metagenomic shotgun data sets. As the complex PKS I have similarities to other multi-domain enzymes (like those for the fatty acid biosynthesis) we increased the reliability and resolution of the dataset by maximum-likelihood trees. The combined information of these trees was then used to discriminate true PKS I domains from evolutionary related but functionally different ones. We were able to identify numerous novel PKS I proteins, the highest density of which was found in Minnesota farm soil with 136 proteins out of 183,536 predicted genes. We also applied the protocol to UniRef database to improve the annotation of proteins with so far unknown function and identified some new instances of horizontal gene transfer. The screening approach proved powerful in identifying PKS I sequences in large sequence data sets and is applicable to many other protein families.


How does magnetic resonance imaging influence staging according to AJCC staging system for nasopharyngeal carcinoma compared with computed tomography?
To analyze the degree and pattern of influence of magnetic resonance imaging (MRI) on staging according to the 6th edition of the American Joint Committee on Cancer staging system compared with computed tomography (CT). The MRI and CT scans and medical records of 420 consecutive patients with newly diagnosed nasopharyngeal carcinoma (NPC) were analyzed retrospectively. The tumors of all patients were staged according to the 6th edition of the American Joint Committee on Cancer staging system. A significant difference (p <0.05) was found between CT and MRI in demonstrating involvement in the oropharynx (CT, 25.0% vs. MRI, 14.5%), prevertebral muscle (CT, 18.4% vs. MRI, 36.0%), parapharyngeal space (CT, 82.6% vs. MRI, 68.8%), skull base (CT, 31.0% vs. MRI, 52.6%), sphenoid sinus (CT, 13.6% vs. MRI, 16.7%), ethmoid sinus (CT, 7.1% vs. MRI, 3.3%), intracranial area (CT, 4.8% vs. MRI, 16.0%), and retropharyngeal lymph nodes (CT, 52.1% vs. MRI, 69.0%). The incidence of cervical lymph node metastasis and lymph node metastasis at each level was similar according to CT and MRI. MRI resulted in changes in 49.8% of T stage cases, 10.7% of N stage cases, and 38.6% of clinical stage cases. MRI demonstrated early primary tumor involvement more precisely and deep primary tumor infiltration more easily. The use of MRI caused dramatic changes in the results of the T stage and clinical staging and should be preferred to CT in staging NPC. Patients would benefit from changes in treatment strategies resulting from the use of MRI.


Lupus anticoagulant and HELLP syndrome complicated by placental abruption, hepatic, dermal and adrenal infarction.
Pregnancy complicated by the HELLP syndrome and antiphospholipid antibodies has not previously been documented. The patient suffered a significant placental abruption, hepatic, adrenal and cutaneous infarctions, and ongoing adrenal insufficiency. Attention is drawn to the serious clinical potential of this association.


Characterization of spontaneously-developed non-alcoholic fatty liver disease in aged rhesus monkeys.
Non-alcoholic fatty liver disease (NAFLD) is a global epidemic afflicting 20-30% in the general population. The animal model of NAFLD available at the present are less clinically relevant. In this study. We aimed to establish a NAFLD model of rhesus monkeys and develop an ultrasonographic steatosis score (USS) system to grade hepatic steatosis in this model. We performed hepatic ultrasonography and blood biochemical tests on 86 rhesus monkeys with and without metabolic syndrome (MetS), among which 45 animals were further assessed by histopathological analysis. The liver histological features of rhesus monkeys NAFLD were resemble to those of NAFLD patients. There was a close correlation between the histological steatosis grade and the USS (Spearman's coefficient, 0.705, p < 0.001). The USS sensitivity was 87.5% and the specificity was 94.6% when the cut-off was USS2. In addition, the prevalence of MetS was significantly higher in the USS2-3 group. Multiple risk factors of cardiometabolic disease, including obesity, insulin resistance and dyslipidemia were significantly correlated with the USS. NAFLD was developed spontaneously among aging in rhesus monkeys (with increased prevalence in the MetS monkeys), which provided an ideal model for NAFLD. The newly developed USS system can be used to evaluate fatty liver in the rhesus monkey. The model as well as the noninvasive assessment methodology will provide a powerful tool for mechanistic studies and preclinical test of novel therapies for NAFLD.


The role of sex, gender, and education on depressive symptoms among young adults in the United States.
Men are less likely to experience depression and both women and men who self-assess as high in traits associated with masculinity are less likely to experience depression. Recent theoretical developments stress that the context of gender construction varies by other aspects of social status such as education. Data come from the National Longitudinal Study of Adolescent Health Wave III, romantic relationship sub-sample, a nationally representative sample of middle and high school students in the U.S. in 1997. Wave III data were collected in 2001-2002 when they are ages 18-26. A subsample of individuals who were or currently are in a romantic relationship (N=4302) were administered the Bem Sex Role Inventory (BSRI). We find that femininity, not masculinity, results in less depressive symptoms among women regardless of education. Femininity is associated with less depressive symptoms among college educated men, but masculinity is associated with less depressive symptoms among non-college educated men. Sex differences in the association between gender traits and depression symptoms are smaller among those who have attended college. Results stress the importance of context for understanding the relationship between sex, gender, and depression. Individuals benefit more from both masculinity and femininity with increased education. Conversely, those with less education may be penalized for sex-gender incongruent traits in terms of mental health. These analyses are cross-sectional, making causal inference impossible. This sample is limited to young adults who were or had been in a romantic relationship at the time of the survey.


Toxicity of aflatoxin B1 to Helicoverpa zea and bioactivation by cytochrome P450 monooxygenases.
Infestation of corn (Zea mays) by corn earworm (Helicoverpa zea) predisposes the plant to infection by Aspergillus fungi and concomitant contamination with the carcinogenic mycotoxin aflatoxin B1 (AFB1). Although effects of ingesting AFB1 are well documented in livestock and humans, the effects on insects that naturally encounter this mycotoxin are not as well defined. Toxicity of AFB1 to different stages of H. zea (first, third, and fifth instars) was evaluated with artificial diets containing varying concentrations. Although not acutely toxic at low concentrations (1-20 ng/g), AFB1 had significant chronic effects, including protracted development, increased mortality, decreased pupation rate, and reduced pupal weight. Sensitivity varied with developmental stage; whereas intermediate concentrations (200 ng/g) caused complete mortality in first instars, this same concentration had no detectable adverse effects on larvae encountering AFB1 in fifth instar. Fifth instars consuming AFB1 at higher concentrations (1 microg/g), however, displayed morphological deformities at pupation. That cytochrome P450 monooxygenases (P450s) are involved in the bioactivation of aflatoxin in this species is evidenced by the effects of piperonyl butoxide (PBO), a known P450 inhibitor, on toxicity; whereas no fourth instars pupated in the presence of 1 mug/g AFB1 in the diet, the presence of 0.1% PBO increased the pupation rate to 71.7%. Pupation rates of both fourth and fifth instars on diets containing 1 mug/g AFB1 also increased significantly in the presence of PBO. Effects of phenobarbital, a P450 inducer, on AFB1 toxicity were less dramatic than those of PBO. Collectively, these findings indicate that, as in many other vertebrates and invertebrates, toxicity of AFB1 to H. zea results from P450-mediated metabolic bioactivation.


Preliminary characterization and grouping of Candida species by numerical analysis of protein profiles obtained by polyacrylamide gel electrophoresis.
Whole-cell proteins from isolates of five Candida species (Candida albicans, Candida krusei, Candida parapsilosis, Candida tropicalis and Candida guilliermondii) were separated by SDS-PAGE and the profiles obtained were converted into a binary data matrix that produced a cophenetic correlation phenogram. The analysis of the phenogram allowed detection of the cophenetic correlation levels existing among these species.


Do pre-adenotonsillectomy echocardiographic findings change postoperatively in children with severe adenotonsillar hypertrophy.
Hypertrophy of adenotonsillar tissue is one of the most common problems in childhood age and causes upper airway obstruction and even obstructive sleep apnea symptoms in severe forms. The aim of this study is to evaluate the changes of pre-adentonsillectomy echocardiographic findings after operation. From August 2007 to November 2008, 55 children with adenotonsillar hypertrophy and obstructive-sleep symptoms (aged 3-11 years old of which 35 were males and 20 females) were randomly selected. Preoperatively echocardiography was performed for all patients by the pediatric cardiologist. In control group 55 children who referred to otolaryngology clinic because of non adenotonsillar related disease evaluated. One month and six months after operation, patients with positive findings were followed up and again echocardiography was performed separately. No complaints of apnea were reported. Tonsillar grades of all cases were type III or IV. The preoperative mean pulmonary arterial pressure levels of the 4 (7.3%) children were higher than normal range (25 mm Hg) and it decreased significantly after operation (P < 0.000) (Preoperative MPAP = 32 ± 3 mm Hg, and six months postoperative follow up, MPAP = 11 ± 5 mm Hg). All the patients' parents complained about severe open mouth snoring, agitated sleep and hyperpnoea of their children. The preoperative tricuspid regurgitation pressure level of 7 children was higher than normal range and it decreased significantly after operation (P < 0.000 preoperative TR = 34 ± 8 mm Hg postoperative TR = 19 ± 6 mm Hg). AC/ET in these seven patients were lower than 0.4. In control group echocardiography findings are normal. Severe chronic hypertrophic adenotonsillar tissue caused higher tricuspid regurgitation pressure and mean pulmonary arterial pressure.


Signal-averaged electrocardiography and ventricular tachycardia as predictors of mortality after acute myocardial infarction in elderly patients.
Signal-averaged electrocardiography and 24-hour ambulatory electrocardiographic monitoring were performed in 121 elderly patients > 6 months after acute myocardial infarction. All patients had asymptomatic complex ventricular arrhythmias and a left ventricular ejection fraction > or = 40%. Rates of sudden, cardiac, and total death were compared between groups with and without nonsustained ventricular tachycardia and between normal and abnormal signal-averaged electrocardiographic studies. The prevalence of an abnormal signal-averaged electrocardiographic study was 36%. Thirty-seven percent of the patients had nonsustained ventricular tachycardia, and the remaining patients had complex ventricular arrhythmias other than ventricular tachycardia. There were 27 sudden and 48 total cardiac deaths, and 66 deaths from all causes during a mean follow-up period of 30 months. Kaplan-Meier survival analysis showed a lower rate of sudden and cardiac death in the group without nonsustained ventricular tachycardia. Although there was a trend toward a lower rate of sudden death in patients with a normal signal-averaged electrocardiogram, there was no statistical difference in the rates of sudden, total cardiac, or total death between patients with normal or abnormal studies. The negative predictive value of having neither an abnormal signal-averaged electrocardiogram nor nonsustained ventricular tachycardia was 94% for sudden death. In elderly patients with complex ventricular arrhythmias and ejection fraction > or = 40% at least 6 months after an acute myocardial infarction, presence of nonsustained ventricular tachycardia predicted a higher rate of sudden and cardiac death. Signal-averaged electrocardiography alone was not predictive.


GABAergic fibers from substantia nigra pars reticulata modulate escape behavior induced by midbrain central gray stimulation.
Electrical stimulation of microinjection of GABA antagonists into the dorsal periaqueductal gray (DPAG) produces escape behavior. In order to determine whether the nigrocollicular gabaergic fibers exert some control over this behavior, rats bearing kainic acid lesion of the substantia nigra pars reticulata were submitted to microinjections of bicuculline or electrical stimulation of the DPAG at the escape threshold. Rats thus treated exhibited a significant decrease in the escape threshold while bicuculline increased the expression of flight behavior. These results suggest an inhibitory control of gabaergic fibers from the substantia nigra pars reticulata on aversive behavior induced by DPAG stimulation.


Opposite regulation of metabotropic glutamate receptor 3 and metabotropic glutamate receptor 5 by inflammatory stimuli in cultured microglia and astrocytes.
Metabotropic glutamate receptors (mGluRs) were previously shown to modulate several essential functions in glial cells, including cell proliferation, glutamate uptake, neurotrophic support, and inflammatory responses. As these receptors are regularly proposed as promising targets for the treatment of a wide range of neurological disorders, we herein examined the reciprocal modulation of glial mGluRs by inflammation. Such regulation of mGluRs was also studied in cultures from an experimental model of amyotrophic lateral sclerosis (ALS). Indeed, ALS is characterized by increased neuroinflammation, and glial cell cultures derived from the animal model (rat expressing hSOD1(G93A)) show enhanced glial reactivity. Within 72 h, the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) induced an increase in mGluR3 and a decrease in mGluR5 gene expression. A similar regulation of these receptors was observed in microglia 48 h after an initial 4-h exposure to lipopolysaccharide. In hSOD1(G93A)-derived glial cultures, the gene up-regulation of mGluR3 (but not the gene down-regulation of mGluR5) was found to be enhanced in both astrocytes and microglia. Together, these results indicate that an inflammatory environment triggers an opposite regulation in the gene expression of the two predominant mGluR subtypes found in glial cells, and that these regulations were particularly robust in hSOD1(G93A) glial cultures. As neuroinflammation commonly occurs in several nervous diseases, its influence on mGluR expression should be taken into account when considering these receptors as future drug targets.


Sphingosine 1-phosphate pathway is dysregulated in adenomyosis.
Is sphingosine 1-phosphate (S1P) pathway involved in the process of fibrosis in adenomyosis? RNA was extracted from paraffin-embedded slices collected from the ectopic endometrium of patients with nodular adenomyosis (n = 27) and eutopic endometrium of healthy controls women (n = 29). Expression of genes involved in the metabolism and signalling of S1P, and actin-alpha-2 smooth muscle, encoded by ACTA2 gene, a gene involved in fibrogenesis, was evaluated by real-time polymerase chain reaction analysis. In adenomyotic samples, the expression of sphingosine kinase 1 (SPHK1), the enzyme responsible for the synthesis of S1P, and of S1P phosphatase 2 (SGPP2), the enzyme responsible for the conversion of S1P back to sphingosine, was lower (P = 0.0006; P = 0.0015), whereas that of calcium and integrin-binding protein 1, responsible for membrane translocation of SPHK1, was higher (P = 0.0001) compared with healthy controls. In S1P signalling, a higher expression of S1P receptor S1P3 (P = 0.001), and a lower expression of S1P2 (P = 0.0019) mRNA levels, were found compared with healthy endometrium. In adenomyotic nodules, a higher expression of ACTA2 mRNA levels were observed (P = 0.0001), which correlated with S1P3 levels (P = 0.0138). Present data show a profound dysregulation of the S1P signalling axis in adenomyosis. This study also highlights that the bioactive sphingolipid might be involved in the fibrotic tract of the disease, correlated with the expression of ACTA2, suggesting its role as novel potential biomarker of adenomyosis.


Denaturation of a membrane transport protein by urea: the erythrocyte anion exchanger.
Chloride equilibrium exchange was measured in the presence of intracellular and extracellular urea, several different alkylureas and thiourea. Urea half-inhibited Cl exchange at about 2.5 M, but the other, less polar analogs had significantly higher potencies; e.g., butylurea half-inhibited at about 60 mM. Onset and reversal of inhibition occurred within less than 2 sec. The inhibition exhibited no obvious sigmoidal dependence on urea concentration, and at low concentrations dimethylurea was a noncompetitive inhibitor of Cl exchange. However, at higher concentrations the Dixon plots were curved upward and a Hill analysis of the dimethylurea data yielded a Hill coefficient of at least 1.5. When present on only one side of the membrane, the slowly penetrating thiourea inhibited Cl exchange with a higher potency from the outside of the cell. Cl/Br exchange was inhibited less under conditions of self-inhibition of anion exchange than in the absence of self-inhibition. These data indicate that the ureas inactivate the anion transporter by a reversible denaturation process, and that the function of the anion transport mechanism may be more sensitive to small perturbations of protein structure than are spectroscopically derived structural parameters.


Immobilizing magnesium ions on 3D printed porous tantalum scaffolds with polydopamine for improved vascularization and osteogenesis.
Large bone defects remain a worldwide healthy problem needing to be solved. 3D printed tantalum (Ta) scaffolds have enormous potential to repair bone defects and have applied in clinic in recent years. Although the porous structure of 3D printed Ta scaffolds could allow bone ingrowth, the surface property that reactive with surrounding tissue is still unfavorable and thus the early osteointegration is impeded. Magnesium (Mg), a necessary element during bone development, has been reported with effectively osteogenesis and angiogenesis capacity. Hence, in this study, three concentrations of Mg were doped on the surface of 3D printed tantalum scaffolds utilizing the surface adhesion ability of polydopamine (Ta-PDA-Mg) to improve its surface bioactivity. The physiochemical property of resultant Ta-PDA-Mg scaffold was characterized and their osteogenic and angiogenic effects were tested through a serial of experiments both in vitro and in vivo. Results show that Ta-PDA-Mg2 possessed the highest ion release, and all scaffolds showed excellent biocompatibility. The adhesion, angiogenesis and osteogenesis were all improved in Mg doping groups in vitro, while the Ta-PDA-Mg2 exhibited the best performances. Then the in vivo performance was examined through rat femur condyles bone defect model. Results demonstrate that the Ta-PDA-Mg2 significantly enhanced the vascularized bone formation and the osteointegration, which was further confirmed through pull out test. Therefore, Mg doped 3D printed Ta scaffold could improve surface bioactivity and lead to better osteogenesis and angiogenesis, which may provide novel strategy to develop bioactive customized implants in orthopedic applications.


Synthesis and dipeptidyl peptidase inhibition of N-(4-substituted-2,4-diaminobutanoyl)piperidines.
In this paper, we report the synthesis of diastereomerically pure N-(4-substituted-2,4-diaminobutanoyl)piperidines. These compounds were prepared to investigate the influence of the 4-substitution on the dipeptidyl peptidase II (DPP II) activity and selectivity of the parent N-(2,4-diaminobutanoyl)piperidine. The (4S)-methyl compound showed subnanomolar inhibition, comparable with the parent compound. The (4R)-methyl group or bigger substituents decreased the activity.


Multifractal analysis of ventricular fibrillation and ventricular tachycardia.
A study of ventricular fibrillation and ventricular tachycardia was undertaken using multifractal analysis. By applying the method of direct determination of the f(alpha) singularity spectrum, the value of the area of the VF and VT singularity spectrum was calculated. The comparison between the results showed that the value of the area of the VF singularity spectrum tended to be larger than that of the value of the area of the VT singularity spectrum. This makes the multifractal singularity spectrum a powerful criterion for discriminating between VF and VT.


Heterologous pericardium for the closure of pericardial defects.
Patches of glutaraldehyde-preserved porcine pericardium were transplanted orthotopically into 20 dogs to see if they might make a satisfactory pericardial substitute. Two dogs had mediastinal infections and were excluded from this study. All animals were reoperated on at regular intervals between 15 and 300 days. In 15 dogs there were no adhesions between the porcine pericardium and the host's epicardium. Histological study showed healing between both pericardiums and no degenerative changes in transplanted pericardium. Glutaraldehyde porcine pericardium has been utilized in 8 patients to close the pericardial cavity. There have been no problems related to the pericardial grafts after a maximum follow-up of 9 months.


Lysine tRNAs from cytoplasm, chloroplasts and mitochondria of the lupin seedling cotyledons.
1. The lupin cotyledons contain two cytoplasm-specific lysine tRNAs, one chloroplast-specific, one mitochondria-specific species, and three species common to all the cell compartments investigated; the lysine tRNAs were separated by reversed-phase chromatography (RPC-5). 2. The two cytoplasmic lysine tRNAs are predominant in the tRNALys isolated from the whole tissue. Their level and relative ratios change during germination (Augustyniak & Pawełkiewicz, 1978, Phytochemistry, 17, 15-18). 3. The organellar tRNA constitutes about 20% of the total tRNA in the cotyledons of 7-day-old lupin seedlings.


Parallel synthesis of terminal alkynes using a ROMPgel-supported ethyl 1-diazo-2-oxopropylphosphonate.
ROMPgel-supported ethyl 1-diazo-2-oxopropylphosphonate has been prepared, and the supported reagent has been effectively employed in the conversion of a variety of aldehydes into terminal alkynes under mild reaction conditions. The influence of cross-link structure, comonomers, and polymer structure on reaction efficiency has been examined. [structure: see text]


Past, present, and future of chemically induced hepatocarcinogenesis rodent models: Perspectives concerning classic and new cancer hallmarks.
Hepatocellular carcinoma (HCC), the main primary liver cancer, accounts for 5 % of all incident cases and 8.4 % of all cancer-related deaths worldwide. HCC displays a spectrum of environmental risk factors (viral chronic infections, aflatoxin exposure, alcoholic- and nonalcoholic fatty liver diseases) that result in molecular complexity and heterogeneity, contributing to a rising epidemiological burden, poor prognosis, and non-satisfactory treatment options. The emergence of HCC (i.e., hepatocarcinogenesis) is a multistep and complex process that addresses many (epi)genetic alterations and phenotypic traits, the so-called cancer hallmarks. "Polymorphic microbiomes", "epigenetic reprogramming", "senescent cells" and "unlocking phenotypic plasticity" are trending hallmarks/enabling features in cancer biology. As the main molecular drivers of HCC are still undruggable, chemically induced in vivo models of hepatocarcinogenesis are useful tools in preclinical research. Thus, this narrative review aimed at recapitulating the basic features of chemically induced rodent models of hepatocarcinogenesis, eliciting their permanent translational value regarding the "classic" and the "new" cancer hallmarks/enabling features. We gathered state-of-art preclinical evidence on non-cirrhotic, inflammation-, alcoholic liver disease- and nonalcoholic fatty liver-associated HCC models, demonstrating that these bioassays indeed express the recently added hallmarks, as well as reflect the interplay between classical and new cancer traits. Our review demonstrated that these protocols remain valuable for translational preclinical application, as they recapitulate trending features of cancer science. Further "omics-based" approaches are warranted while multimodel investigations are encouraged in order to avoid "model-biased" responses.


Individual variation in first-pass metabolism.
Individual variation in pharmacokinetics has long been recognised. This variability is extremely pronounced in drugs that undergo extensive first-pass metabolism. Drug concentrations obtained from individuals given the same dose could range several-fold, even in young healthy volunteers. In addition to the liver, which is the major organ for drug and xenobiotic metabolism, the gut and the lung can contribute significantly to variability in first-pass metabolism. Unfortunately, the contributions of the latter 2 organs are difficult to quantify because conventional in vivo methods for quantifying first-pass metabolism are not sufficiently specific. Drugs that are mainly eliminated by phase II metabolism (e.g. estrogens and progestogens, morphine, etc.) undergo significant first-pass gut metabolism. This is because the gut is rich in conjugating enzymes. The role of the lung in first-pass metabolism is not clear, although it is quite avid in binding basic drugs such as lidocaine (lignocaine), propranolol, etc. Factors such as age, gender, disease states, enzyme induction and inhibition, genetic polymorphism and food effects have been implicated in causing variability in pharmacokinetics of drugs that undergo extensive first-pass metabolism. Of various factors considered, age and gender make the least evident contributions, whereas genetic polymorphism, enzymatic changes due to induction or inhibition, and the effects of food are major contributors to the variability in first-pass metabolism. These factors can easily cause several-fold variations. Polymorphic disposition of imipramine and propafenone, an increase in verapamil first-pass metabolism by rifampicin (rifampin), and the effects of food on propranolol, metoprolol and propafenone, are typical examples. Unfortunately, the contributions of these factors towards variability are unpredictable and tend to be drug-dependent. A change in steady-state clearance of a drug can sometimes be exacerbated when first-pass metabolism and systemic clearance of a drug are simultaneously altered. Therefore, an understanding of the source of variability is the key to the optimisation of therapy.


[Patient selection for the implantation of a left atrial appendage occluder in primary and secondary prevention of cardioembolic stroke in atrial fibrillation].
The implantation of a left atrial appendage (LAA) occluder has evolved into an established non-pharmacological alternative to oral anticoagulation (OAC) in the prevention of cardioembolic stroke in patients with atrial fibrillation. While 2 randomized trials investigated the LAA occluder as an alternative treatment in patients who can also undergo OAC, current guidelines recommend the LAA occluder rather as a second line therapy if permanent OAC is not possible due to contraindications. This is in line with current practice where an LAA occluder is usually only implanted if OAC is contraindicated or stopped due to bleeding. The LAA occluder seems most promising for patients with a high risk for both, stroke without OAC and severe bleeding with OAC. After patient informed consent, the LAA occluder may also represent an option for patients who are unwilling to undergo OAC. Since a large proportion of patients do not receive OAC despite an indication (because of contraindications or mere fear of bleeding) and since the majority of patients have to stop OAC during the course of 2 years, mostly due to bleeding, the LAA occluder may play an important role in the long-term prophylaxis of cardioembolic stroke due to atrial fibrillation.


Are There Differences in Treatment and Survival Between Poor, Older Black and White Women with Breast Cancer?
To explore differences in treatment and survival outcome between poor, older black and white women with breast cancer. Retrospective cohort study. Public safety net hospital. Women aged 65 and older diagnosed with breast cancer from 1999 to 2008 (n = 1,000). Breast cancer treatments that black and white women sought were compared using the Pearson chi-square test. All-cause mortality of black and white women was compared using hazard ratios derived from a multivariate Cox proportional hazards model. There was no significant difference between older black and white women in surgical treatment, radiation therapy, chemotherapy, or hormone therapy over the study period. Race was not a significant predictor of survival in the Cox proportional hazards model that controlled for stage of cancer, age at diagnosis, dual-eligibility status, comorbid conditions, body mass index, smoking history, mammogram screening, and treatment for breast cancer. Race did not appear to affect treatment or mortality in a cohort of older women with low socioeconomic status. This may be associated with similar healthcare delivery and equivalent access to health care for the older black and white women in this study.


[Release of the carpal tunnel by endoscopy].
Review of the results of 67 endoscopic carpal tunnel releases and description of the surgical technique. Between 1994 and 96, 67 endoscopic carpal tunnel release have been performed on 49 patients with a mean age of 58 years. Our mean follow-up is 13 months. 31 patients (65%) reported an excellent result, 14 patients (28.5%) reported an improvement of their symptoms and 3 patients (6.5%) no improvement at all. The mean time for return to work was 4.5 weeks and 40% return after 3 weeks. Endoscopic carpal tunnel release is effective in relieving symptoms and is associated with an early return to work and minimal palmar pain. The endoscopic release has advantages over open release but this technique has her own complications.