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The uptake of bupivacaine in the liver and lung of the dog was studied 10,20,30 and 60 min after intramuscular injection of the drug. It was possible to quantify this uptake by combining measurements of concentrations and flows. The administration of bupivacaine (0.75 mg/kg b.w.) did not result in any significant circulatory changes. Arterial bupivacaine concentrations showed major variations, indicating interindividual differences in absorption rate. Lung uptake after 10 min was high in two dogs with initially high blood concentrations of bupivacaine, but low after 20 min or longer. The other dogs showed little or no uptake. Mean hepatic bupivacaine uptake was about 50% of the total dose during the first hour after injection, this indicates the central role of the liver in eliminating bupivacaine even during the initial period following administration. The hepatic extraction ratio showed interindividual variations, but the mean value of about 55% was constant throughout the observation period. This is in agreement with earlier findings indicating a first-order elimination of bupivacaine. | Bupivacaine |
Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine carcinoma that affects sun-damaged skin. Histologically, the tumor consists of round cells with fine chromatin positive for cytokeratin 20 in ~90% of cases. Rare cases of MCC can regress spontaneously and present as nodal metastasis. Nodal MCC of unknown primary can cause a potential pitfall as they can be misinterpreted as other neuroendocrine carcinomas such as small cell carcinoma. We report a case of nodal MCC with an atypical immunohistochemistry pattern presented as bilateral axillary lymphadenopathy in a 90-year-old man with a remote history of a skin lesion that healed spontaneously leaving a scar. | Keratin-20 |
Morphological changes of the uterus and alterations in its secretory activity under the influence of steroid hormones been well documented. The oestrous cycle is also associated with significant changes in plasma follicle-stimulating hormone (FSH), whose effects are mediated through its receptor (FSHR). Reports showed that in many mammals, FSHR was expressed in gonadal and extragonadal tissues including cervix, female reproductive tract, and pituitary gland. Follicle-stimulating hormone (FSH) signals through endothelial FSHR directly stimulate angiogenesis and involved in the timing of birth in human, and the presence of FSHR in the placenta is essential for normal pregnancy in mice. But little is known about FSHR expression in the yak uterus. The main objective of the present study was to determine the expression and localization of FSHR in the yak uterus during different phases of the oestrous cycle. Results showed that FSHR protein was localized in the surface and glandular epithelial cells, stroma cells, myometrial smooth muscle cells and blood vessel endothelial cells. The expression of FSHR protein peaked at oestrus, significantly decreased at dioestrus (p < 0.05) and increased again at proestrus. FSHR mRNA was highly expressed at both proestrus and oestrus, and decreased at metestrus with the lowest values at dioestrus (p < 0.05). In conclusion, FSHR expression in the yak uterus changed with the stage of the oestrous cycle suggesting that FSHR plays an essential role in regulating the endometrial and myometrial functions during the oestrus cycle in the yak. | Receptors, Gonadotropin |
Non-alcoholic fatty liver disease (NAFLD) and its progressive inflammatory form non-alcoholic steatohepatitis (NASH) are major health challenges due to a significant increase in their incidence and prevalence. While NAFLD is largely benign, the chronic liver inflammation in NASH patients may cause progression to liver cirrhosis and hepatocellular carcinoma. There is an urgent need for a better understanding of the factors, which drive the progression from NAFLD to NASH and how to use this information both to improve diagnostic and to develop new treatment strategies. Increasing evidence points to interferons (IFNs) as key players in NAFLD and particular in the progression to NASH. IFNs crucial role in disease development is supported by both genetic evidence and animal studies. In this review, we describe the involvement of both type I and type III IFNs in the development and progression of NAFLD and NASH. | Interferon Lambda |
Epigallocatechin gallate (EGCG), a major compound from green tea, reversibly inhibits beta-ketoacyl-[acyl carrier protein] reductase (FabG) from Escherichia coli. In this study, we found that EGCG exhibited an atypical time-dependent inhibition of FabG, which possibly resulted from the EGCG-induced aggregation of FabG. It was observed that FabG inactivation and aggregation occurred nearly simultaneously, with a lag time that decreased with increasing EGCG concentration. These results suggest that some chemical reactions, required for aggregation and inactivation, occurred during the lag time. Since EGC was detected by HPLC after the incubation of EGCG with FabG, EGCG probably covalently modified FabG. These further results showed that 1 tetramer of FabG must be modified by several, possibly 4, EGCG molecules before the formation of FabG aggregates. FabG aggregation was a first-order reaction independent of protein concentration. Due to an initial lag time, the first-order rate of aggregation gradually increased, reaching a maximal and constant value. The effect of increasing concentration of EGCG on the first-order rate constant for aggregation indicated that EGCG bound to FabG by affinity labeling. Based on the results, we propose a mechanism for the interaction of EGCG with FabG:EGCG first binds reversibly to each subunit of FabG, followed by covalent modification and then aggregation of the 4 EGCG-modified subunits. | Fatty Acid Synthase, Type II |
INTRODUCTION: Chlorhexidine is considered the most potent chemotherapeutic agent against Streptococcus mutans. However, its side effects due to prolonged use, indicates need for alternatives. The study intended to assess and compare antimicrobial efficacies of probiotic, xylitol and chlorhexidine mouth rinses in children and elderly. METHODS: The study was a Double blind Randomized Controlled Trial conducted among residential school children aged 5-12 years and elderly greater than 60 years residing in old age homes. (ClinicalTrials.gov ID: NCT04399161). 30 participants each among children and elderly were chosen based on eligibility criterion (high risk for caries). They were further randomly divided into 3 groups with 10 participants in each group. Participants were asked to rinse with 15 ml of freshly prepared mouth rinses once daily for 2 minutes for 14 days. Antimicrobial efficacy was determined by assessing change in Streptococcus mutans levels in dental plaque. RESULTS: Significant reduction in Streptococcus mutans counts were observed in both children and elderly (Chlorhexidine: mean difference = 3.11 log10CFU/g, p = 0.022, Xylitol: mean difference = 0.93 log10CFU/g, p = 0.046, Probiotic: mean difference = 1.91 log10CFU/g, p = 0.023 in children); (Chlorhexidine: mean difference = 2.23 log10CFU/g, p = 0.004, Xylitol: mean difference = 1.39 log10CFU/g, p = 0.009, Probiotic: mean difference = 1.61 log10CFU/g, p = 0.018 in elderly). Intergroup comparison showed no significant difference. CONCLUSIONS: Antimicrobial efficacy of xylitol and probiotic mouth rinses were comparable to that of chlorhexidine in both children and elderly. Probiotics could potentially be more efficacious than xylitol among children. | Xylitol |
OBJECTIVE: To provide detailed demographic profiles of prescription drug utilization and expenditures in order to isolate the impact of demographic change from other factors that affect drug expenditure trends. DATA SOURCES/STUDY SETTING: Demographic information and drug utilization data were extracted for virtually the entire British Columbia (BC) population of 1996 and 2002. All residents had public medical and hospital insurance; however their drug coverage resembled the mix of private and public insurance in the United States. STUDY DESIGN: A series of research variables were constructed to illustrate profiles of drug expenditures and drug utilization across 96 age/sex strata. DATA COLLECTION/EXTRACTION METHODS: Drug use and expenditure information was extracted from the BC PharmaNet, a computer network connecting all pharmacies in the province. PRINCIPAL FINDINGS: Per capita drug expenditures increased at an average annual rate of 10.8 percent between 1996 and 2002. Population aging explained 1.0 points of this annual rate of expenditure growth; the balance was attributable to rising age/sex-specific drug expenditures. CONCLUSIONS: Relatively little of the observed increase in drug expenditures in BC could be attributed to demographic change. Most of the expenditure increase stemmed from the age/sex-specific quantity and type of drugs purchased. The sustainability of drug spending therefore depends not on outside forces but on decisions made by policy makers, prescribers, and patients. | Fees, Pharmaceutical |
The trans-cerebral v. have long been described, but there is little or no knowledge of their function and dysfunction. They are the site of fundamental interchange across the blood-brain barrier, a unique process within the organism. Two systems can be structurally distinguished: the venous system draining the white matter and the trans-cerebral anastomotic system. The former seems to be associated with the nutrition and drainage of the parenchyma, and is rendered visible at angiography by anatomic variations based on developmental venous anomalies. The anastomotic trans-cerebral ventriculo-cortical system seems concerned with the regulation of reabsorption of the cerebrospinal fluid. It is visualized only in exceptional situations where an increased flow (arteriovenous shunt) is combined with obstruction of the normal routes of venous drainage and collateral circulation. It usually functions in the ventriculo-cortical direction. No specific dysfunction of this system is currently recognized. | Cerebral Veins |
Acute brain insults elicit pronounced inflammation that amplifies brain damage in intracerebral hemorrhage (ICH). We profiled perihematomal tissue from patients with ICH, generating a molecular landscape of the injured brain, and identified formyl peptide receptor 1 (FPR1) as the most abundantly increased damage-associated molecular pattern (DAMP) receptor, predominantly expressed by microglia. Circulating mitochondrial N-formyl peptides, endogenous ligands of FPR1, were augmented and correlated with the magnitude of brain edema in patients with ICH. Interactions of formyl peptides with FPR1 activated microglia, boosted neutrophil recruitment, and aggravated neurological deficits in two mouse models of ICH. We created an FPR1 antagonist T-0080 that can penetrate the brain and bind both human and murine FPR1. T-0080 attenuated brain edema and improved neurological outcomes in ICH models. Thus, FPR1 orchestrates brain inflammation after ICH and could be targeted to improve clinical outcome in patients. | Receptors, Formyl Peptide |
The objective of this study was to evaluate the incidence of vancomycin resistant enterococci in sludge and sewage of urban and poultry-slaughterhouse wastewater treatment plants. A total of 17 vancomycin resistant enterococci (eight vanA -containing Enterococcus faecium and nine vanC1/vanC2 -containing Enterococcus gallinarum/casseliflavus) were found among 499 isolates of sewage and sludge samples of 14 urban and nine poultry-slaughterhouse wastewater treatment plants. These seventeen VRE isolates showed resistance to kanamycin (n = 8), tetracycline (n = 7), erythromycin (n = 7), ciprofloxacin (n = 7), ampicillin (n = 7), streptomycin (n = 6), and gentamicin (n = 2). The tetM gene, related with tetracycline resistance, was found in six of eight van A-containing isolates, in all seven vanC-1 isolates and in one of two vanC-2 isolates. The ermB gene in seven erythromycin-resistant isolates; and the aac6 '-aph2 '' gene in the two high-level-gentamicin-resistant isolates. Moreover, two vanA -containing E. faecium isolates harbored the hyl virulence gene, and three isolates the entA bacteriocin gene. The purK-1 allele was detected in our urban vanA -containing E. faecium isolate, and we found as well the purK-6 allele in one poultry-slaughterhouse vanA -containing E. faecium isolate. This study suggests that the wastewater treatment plants might be an important source of dissemination of antibiotic-resistant enterococci in Portugal. | Enterococcus |
A 57-year-old man, known with severe malnutrition, vitamin E deficiency and peripheral neuropathies, presented with vomiting and abdominal tenderness. There was a suspicion of ileus and small bowel obstruction. During the exploratory laparotomy a complete brown colored bowel without peristalsis was seen. | Avitaminosis |
Baculovirus has emerged as a novel vector for in vivo and in vitro gene delivery. In addition, the applications of baculovirus-mediated gene transfer have been explosively expanded to drug screening, eucaryotic gene display, cancer therapy and tissue engineering, etc. The capability of baculovirus viral envelope for protein/peptide display also renders itself a potential vaccine delivery platform. This paper reviews the history, factors influencing baculovirus-mediated gene delivery and emerging in vitro, in vivo and ex vivo applications. Efforts aimed at overcoming current existing bottlenecks and recent progresses in addressing the safety concerns are particularly emphasized. | Baculoviridae |
CONTEXT: The number of patients with cancer is increasing. New therapeutic agents to overcome drug-resistant tumors are urgently needed. Cyrtosperma johnstonii N.E. Br. (Araceae) is used for treatment of cancer in Thai traditional medicine. This study aimed to evaluate antioxidant activity and cytotoxicity of C. johnstonii extracts on human cancer cells. MATERIALS AND METHODS: Dried powder of C. johnstonii rhizomes was extracted with several solvents. The 0.1 mg/ml extract solution was tested for antioxidant activity by 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and ferric reducing antioxidant power (FRAP) assays. Color formation from 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to determine cell viability. Standardization of the extract was performed by high-performance liquid chromatography (HPLC) with photodiode array detector at 254 and 360 nm. Cell cycle arrest was evaluated by flow cytometry after 5 min, 12 h and 24 h treated with 20 microg/ml of the acetone extract. RESULTS: The acetone extract exhibited the highest phenolic content and antioxidant activity (TEAC and EC values = 19.2 +/- 0.14 and 19.2 +/- 0.31 mM/mg, respectively). The IC(5)(0) values for leukemia ranged from 11 +/- 1 to 29 +/- 3 microg/ml and from 5 +/- 2 to 6 +/- 0 microg/ml for small cell lung carcinoma cells. Cell cycle arrest occurred at the G2/M phase followed by apoptosis. HPLC analysis revealed that rutin is the major constituents of the extract. DISCUSSION AND CONCLUSION: The acetone extract of C. johnstoni is a promising source of natural antioxidants and anticancer. The extract inhibits cancer cells effectively with less effect on normal cells. | Cyrtosperma |
Oxygen is considered as a limiting factor for nitrification in rice paddy soil. However, little is known about how the nitrifying microbial community responds to different oxygen concentrations at community and transcript level. In this study, soil and roots were harvested from 50-day-old rice microcosms and were incubated for up to 45 days under two oxygen concentrations: 2 % O(2) and 20 % O(2) (ambient air). Nitrification rates were measured from the accumulation of nitrite plus nitrate. The population dynamics of bacterial (AOB) and archaeal (AOA) ammonia oxidizers was determined from the abundance (using quantitative PCR (qPCR)) and composition (using terminal restriction fragment length polymorphism and cloning/sequencing) of their amoA genes, that of nitrite oxidizers (NOB) by quantifying the nxrA gene of Nitrobacter spp. and the 16S rRNA gene of Nitrospira spp. The activity of the nitrifiers was determined by quantifying the copy numbers of amoA and nxrA transcripts (using RT-qPCR). Different oxygen concentrations did not affect the community compositions of AOB, AOA, and NOB, which however were different between surface soil, bottom soil, and rice roots. However, nitrification rates were higher under ambient air than 2 % O(2), and abundance and transcript activities of AOB, but not of AOA, were also higher. Abundance and transcript copy numbers of Nitrobacter were also higher at ambient air. These results indicate that AOB and NOB, but not AOA, were sensitive to oxygen availability. | Nitrobacter |
We determined the blood groups ABO and Rh system in 8,728 patients in the Blood Transfusion Department of the Institute for Tumors and Allied Diseases in Zagreb. The patients were classified according to the localization of the tumor and the blood groups examined. The distribution of blood groups from our patients were compared with the distribution of blood groups in the controlled population. | Isoantigens |
OBJECTIVE: Anterior chest thrusts (with the subject sitting or standing and thrusts applied to the lower sternum) are recommended by the Australian Resuscitation Council as part of the sequence for clearing upper airway obstruction by a foreign body. Lateral chest thrusts (with the victim lying on their side) are no longer recommended due to a lack of evidence. We compared anterior, lateral chest and abdominal thrusts in the generation of airway pressures using a suitable animal model. METHODS: This was a repeated-measures, cross-over, clinical trial of eight anaesthetised, intubated, adult pigs. For each animal, ten trials of each technique were undertaken with the upper airway obstructed. A chest/abdominal pressure transducer, a pneumotachograph and an intra-oesophageal balloon catheter recorded chest/abdominal thrust, expiratory air flows, airway and intrapleural pressures, respectively. RESULTS: The mean (SD) thrust pressures generated for the anterior, lateral and abdominal techniques were 120.9 (11.0), 135.2 (20.0), and 142.4 (27.3)cmH(2)O, respectively (p<0.0001). The mean (SD) peak expiratory airway pressures were 6.5 (3.0), 18.0 (5.5) and 13.8 (6.7)cmH2O, respectively (p<0.0001). The mean (SD) peak expiratory intrapleural pressures were 5.4 (2.7), 13.5 (6.2) and 10.3 (8.5)cmH(2)O, respectively (p<0.0001). At autopsy, no rib, intra-abdominal or intra-thoracic injury was observed. CONCLUSION: Lateral chest and abdominal thrust techniques generated significantly greater airway and pleural pressures than the anterior thrust technique. We recommend further research to provide additional evidence that may inform management guidelines for clearing foreign body upper airway obstruction. | Heimlich Maneuver |
A protocol for the non-isotopic restriction mapping of cosmid DNA was developed. After digestion with lambda terminase and partial digestion with restriction enzymes, DNA fragments containing right or left cohesive cos termini were selectively captured by hybridization with biotinylated oligonucleotides, bound to magnetic beads coated with streptavidin and recovered by heating. Recovered DNA fragments containing cos ends were resolved by agarose gel electrophoresis, and fluorescence from the DNA fragments in the ethidium bromide-stained gel was detected with the fluorescent image analyzer, FMBIO. Restriction maps were directly determined from the ladder of the partial digestion products. Two micrograms of cosmid DNA for each partial digestion were sufficient for mapping the restriction enzyme sites. This procedure provides a prototype for other cos sequence-mediated or other specific sequence-mediated DNA isolation technologies and a convenient method for non-isotopic DNA analysis. The rapid physical analysis of cosmid DNA that we present here will contribute to large DNA structural analyses like the human genome project. | Restriction Mapping |
Nitric oxide and reactive oxygen species play a key role in the plant hypersensitive disease resistance response, and protein tyrosine nitration is emerging as an important mechanism of their co-operative interaction. Up to now, the proteins targeted by this post-translational modification in plants are still totally unknown. In this study, we analyzed for the first time proteins undergoing nitration during the hypersensitive response by analyzing via 1D- and 2D-western blot the protein extracts from Arabidopsis thaliana plants challenged with an avirulent bacterial pathogen (Pseudomonas syringae pv. Tomato). We show that the plant disease resistance response is correlated with a modulation of nitration of proteins involved in important cellular process, such as photosynthesis, glycolysis and nitrate assimilation. These findings shed new light on the signaling functions of nitric oxide and reactive oxygen species, paving the way on studies on the role of this post-translational modification in plants. | Nitrosation |
Globoid cell leukodystrophy (Krabbe disease) in man is a rare genetic disorder caused by deficiency of galactosylceramidase activity. Clinical and pathological manifestations are almost exclusively confined to the nervous system, particularly to the white matter and the peripheral nerve. The disease also occurs in four other mammalian species: dog, cat, sheep and mouse. Except for the feline disease, for which enzymatic information is lacking, these animal models are genetically equivalent to the human disease. The clinical and pathological features are fundamentally similar in all species, as might be expected from the same underlying genetic defect. Nevertheless, significant species differences are observed in the clinical course, severity of pathological alterations, and analytical biochemistry. These genetically authentic" animal models provide an invaluable tool for studies of the rare human genetic disorder. Results of studies already done and the future potentials are discussed." | Leukodystrophy, Globoid Cell |
The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum ('mutatome') in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia. | Core Binding Factors |
The cobalt(II), nickel(II) and copper(II) complexes of N1-isonicotinoyl-3-methyl-4-(p-hydroxybenzilidene)-2-pyrazolin+ ++-5-one (IMHBP) with different counter anions have been prepared and characterized. An octahedral geometry has been assigned to the cobalt(II) and nickel(II) complexes and a square-planar structure to the copper(II) complexes. IMHBP acts as a neutral bidentate ligand in all these complexes by coordinating through the oxygen atoms of the amide group and carbonyl at position-5. The other coordination sites are satisfied by anions alone or anions and water molecules. The ligand and the complexes were screened for their possible antitumour activity. The copper(II) complexes are appreciably active in reducing mice tumours. | Isonicotinic Acids |
Immunobiological significance of Forssman (F) glycoprotein expressed on rat tumor cells derived from transfection of a fibroblast line with whole DNA (WY-3); EcoRI-C fragment, 0-16.5 map units (CY-1); and Accl-H fragment, 0-4.7 map units (HY-1) of adenovirus 12 was investigated. Culturing of F-positive WY-3 and CY-1 cells, but not F-negative HY-1 cells, with monoclonal rat F-antibody resulted in the blocking of their cell-cell adhesion and attachment to plastic surface and inhibition of their growth. Immunization of WY-3 or CY-1 tumor-bearing F344 rats with sheep red blood cells or purified F-antigen in adjuvants brought regression of the tumor in 13 of 19 rats. No such antitumor effect was observed in F-negative HY-1 tumor-bearing rats upon immunization with the F-antigens. Results of this study indicated that the membrane glycoprotein with F-epitope may play a role in lodgement of the tumor cells in vitro and serve as an in vivo target of specific immune effectors. | Forssman Antigen |
To provide insight in the molecular basis for intestinal host-microbe interactions, we determined the genome-wide transcriptional response of human intestinal epithelial cells following exposure to cells of Bifidobacterium breve. To select an appropriate test system reflecting inflammatory conditions, the responsiveness to TNF-alpha was compared in T84, Caco-2 and HT-29 cells. The highest TNF-alpha response was observed in HT-29 cells and this cell line was selected for exposure to the B. breve strains M-16V, NR246 and UCC2003. After one hour of bacterial pre-incubation followed by two hours of additional TNF-alpha stimulation, B. breve M-16V (86%), but to a much lesser extent strains NR246 (50%) or UCC2003 (32%), showed a strain-specific reduction of the HT-29 transcriptional response to the inflammatory treatment. The most important functional groups of genes that were transcriptionally suppressed by the presence of B. breve M-16V, were found to be involved in immune regulation and apoptotic processes. About 54% of the TNF-alpha induced genes were solely suppressed by the presence of B. breve M-16V. These included apoptosis-related cysteine protease caspase 7 (CASP7), interferon regulatory factor 3 (IRF3), amyloid beta (A4) precursor proteinbinding family A member 1 (APBA1), NADPH oxidase (NOX5), and leukemia inhibitory factor receptor (LIFR). The extracellular IL-8 concentration was determined by an immunological assay but did not change significantly, indicating that B. breve M-16V only partially modulates the TNF-alpha pathway. In conclusion, this study shows that B. breve strains modulate gene expression in HT-29 cells under inflammatory conditions in a strain-specific way. | HT29 Cells |
In this paper, two ferrocenyl-triphenyltin complexes were synthesized and characterized. Complex 2 is constructed as new multifunctional therapeutic platform for lysosome-targeted imaging and displayed much higher cytotoxicity than its analogue 1 by the introduction of a methyl group instead of a hydrogen atom in acylhydrazone. The cyclic voltammograms and reaction with GSH (glutathione) further confirmed that complex 1 has a reversible redox peak and can react with GSH, which indicate that complex 1 might lose its anticancer effect by undergoing reaction with GSH once it enters the cancer cell. Complex 2 could effectively catalyze the oxidation of NADH (the reduced form of nicotinamide adenine dinucleotide) to NAD(+) and induce the production of reactive oxygen species (ROS), lead to caspase-dependent apoptosis through damaged mitochondria, simultaneously, accounting for the mitochondrial vacuolization and karyorrhexis. The caspase-3 activation and cytoplasmic vacuolation karyorrhexis induced by complex 2 revealed that the A549 cell lines might undergo cell death primarily mediated by apoptosis and oncosis; however, 1 cannot reproduce this effect. Taken together, these results indicated that complex 2 has more potential for evolution as a new bioimaging and anticancer agent. | Organometallic Compounds |
Minamata disease is a relatively new disease entity secondary to an environmental pollution, methyl mercury poisoning. The pathogenesis and pathology are described. The disease is a preventable one and precautionary steps through more stringent environmental policies are currently under way. | Mercury Poisoning |
Bufalin possesses a strong anti-cancer effect, but the cardiac toxicity targeting the Na(+), K(+)-ATPase limits its application. Here, two bufalin derivatives, bufadienolactam (1) and secobufalinamide (2), were synthesised by treating bufalin with ammonium acetate in dimethylformamide solution. Their structures were elucidated by extensive spectroscopic methods. The structure of compound 2 was further confirmed by single-crystal X-ray diffraction analysis. Compounds 1 and 2 expressed strong inhibitory activities against androgen-dependent prostate cancer cells (IC(5)(0) values about 10 muM), but only weak inhibition on Na(+), K(+)-ATPase (Ki about 70 muM), indicating that they might be potential anti-prostate cancer agents without severe cardiac toxicity. | Bufanolides |
Pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) is the first line of defense in plant disease resistance. However, the molecular mechanisms of plant PTI vary across species, making it challenging to identify a core set of trait-associated genes. This study aimed to investigate key factors that influence PTI and identify the core molecular network in Sorghum bicolor, a C4 plant. We performed comprehensive weighted gene co-expression network analysis and temporal expression analysis of large-scale transcriptome data from various sorghum cultivars under different PAMP treatments. Our results revealed that the type of PAMP had a stronger influence on the PTI network than did the sorghum cultivar. Following PAMP treatment, 30 genes with stable downregulated expression and 158 genes with stable upregulated expression were identified, including genes encoding potential pattern recognition receptors whose expression was upregulated within 1 h of treatment. PAMP treatment altered the expression of resistance-related, signaling, salt-sensitive, heavy metal-related, and transporter genes. These findings provide novel insights into the core genes involved in plant PTI and are expected to facilitate the identification and application of resistance genes in plant breeding studies. | Innate Immunity Recognition |
Chemical graph generators are software packages to generate computer representations of chemical structures adhering to certain boundary conditions. Their development is a research topic of cheminformatics. Chemical graph generators are used in areas such as virtual library generation in drug design, in molecular design with specified properties, called inverse QSAR/QSPR, as well as in organic synthesis design, retrosynthesis or in systems for computer-assisted structure elucidation (CASE). CASE systems again have regained interest for the structure elucidation of unknowns in computational metabolomics, a current area of computational biology. | Cheminformatics |
In Europe, it is estimated that more than 50% of total food waste - of which most is avoidable - is generated at household level. Little attention has been paid to the impact on food waste generation of consuming food products that differ in their method of food preservation. This exploratory study surveyed product-specific possible impacts of different methods of food preservation on food waste generation in Dutch households. To this end, a food waste index was calculated to enable relative comparisons of the amounts of food waste from the same type of foods with different preservation methods on an annual basis. The results show that, for the majority of frozen food equivalents, smaller amounts were wasted compared to their fresh or ambient equivalents. The waste index (WI) proposed in the current paper confirms the hypothesis that it may be possible to reduce the amount of food waste at household level by encouraging Dutch consumers to use (certain) foods more frequently in a frozen form (instead of fresh or ambient). However, before this approach can be scaled to population level, a more detailed understanding of the underlying behavioural causes with regard to food provisioning and handling and possible interactions is required. | Frozen Foods |
Five ambulatory children with various types of chronic arthritis developed renal papillary necrosis (RPN), as documented by intravenous pyelography. Each child was being treated with nonsteroidal anti-inflammatory drugs (NSAIDs) at the time of diagnosis of RPN and had had episodes of gross or microscopic hematuria for several months prior to diagnosis. In each child hematuria was associated with more than one NSAID, and three of the five children also had ingested acetaminophen intermittently. Glomerular function has remained normal and hypertension has not developed, but management of these children has necessitated reduction or elimination of NSAIDs. As evidenced by these five cases, microscopic or gross hematuria in a child with chronic arthritis treated with anti-inflammatory drugs should raise the possibility of RPN. | Kidney Papillary Necrosis |
Food insecurity, the state of being without reliable access to a sufficient quantity of safe, nutritious food, is a persistent problem in rural Ethiopia. However, little qualitative research has explored how food insecurity affects children over time, from their point of view. What are the effects of economic 'shocks' such as illness, death, loss of livestock, drought and inflation on availability of food, and children's well-being? To what extent do social protection schemes (in this case, the Productive Safety Net Programme) mitigate the long-term effects of food insecurity for children? The paper uses a life-course approach, drawing on analysis of four rounds of qualitative longitudinal research conducted in 2007, 2008, 2011 and 2014, with eight case study children, as part of Young Lives, an ongoing cohort study. Children's descriptions of the importance of food and a varied diet (dietary diversity) in everyday life were expressed in a range of qualitative methods, including interviews, group discussions and creative methods. The paper suggests that while the overall picture of food security in Ethiopia has improved in the past decade, for the poorest rural families, food insecurity remains a major factor influencing decisions about a range of matters - children's time allocation, whether to continue in school, whether to migrate for work, and whether they marry. The paper argues that experiences of food insecurity need to be understood holistically, in relation to other aspects of children's lives, at differing stages of the life-course during childhood. The paper concludes that nutritional support beyond early childhood needs to be a focus of policy and programming. | Food Assistance |
The joint commission is arguably the most powerful accrediting agency in health care today. Mahrenholz reviews the historical relationship of this organization with nursing and looks (longingly) at the future." | Joint Commission on Accreditation of Healthcare Organizations |
An adequate general drought tolerance and the ability to acclimate to changing hydraulic conditions are important features for long-lived woody plants. In this study, we compared hydraulic safety (water potential at 50% loss of conductivity, Psi(50)), hydraulic efficiency (specific conductivity, k(s)), xylem anatomy (mean tracheid diameter, d(mean), mean hydraulic diameter, d(h), conduit wall thickness, t, conduit wall reinforcement, (t/b)(h)(2)) and stomatal conductance, g(s), of forest plants as well as irrigated and drought-treated garden plants of Ligustrum vulgare L. and Viburnum lantana L. Forest plants of L. vulgare and V. lantana were significantly less resistant to drought-induced cavitation (Psi(50) at -2.82 +/- 0.13 MPa and -2.79 +/- 0.17 MPa) than drought-treated garden plants (- 4.58 +/- 0.26 MPa and -3.57 +/- 0.15 MPa). When previously irrigated garden plants were subjected to drought, a significant decrease in d(mean) and d(h) and an increase in t and (t/b)(h)(2) were observed in L. vulgare. In contrast, in V. lantana conduit diameters increased significantly but no change in t and (t/b)(h)(2) was found. Stomatal closure occurred at similar water potentials (Psi(sc)) in forest plants and drought-treated garden plants, leading to higher safety margins (Psi(sc) - Psi(50)) of the latter (L. vulgare 1.63 MPa and V. lantana 0.43 MPa). These plants also showed higher g(s) at moderate Psi, more abrupt stomatal closure and lower cuticular conductivity. Data indicate that the development of drought-tolerant xylem as well as stomatal regulation play an important role in drought acclimation, whereby structural and physiological responses to drought are species-specific and depend on the plant's hydraulic strategy. | Viburnum |
Ductal carcinoma in situ (DCIS) of the breast is a non-invasive tumour that has the potential to progress to invasive ductal carcinoma (IDC). Thus, it represents a treatment dilemma: alone it does not present a risk to life, however, left untreated it may progress to a life-threatening condition. Current clinico-pathological features cannot accurately predict which patients with DCIS have invasive potential, and therefore clinicians are unable to quantify the risk of progression for an individual patient. This leads to many women being over-treated, while others may not receive sufficient treatment to prevent invasive recurrence. A better understanding of the molecular features of DCIS, both tumour-intrinsic and the microenvironment, could offer the ability to better predict which women need aggressive treatment, and which can avoid therapies carrying significant side-effects and such as radiotherapy. In this review, we summarise the current knowledge of DCIS, and consider future research directions. | Breast Carcinoma In Situ |
Statistics such as the mean difference (MD), standardized mean difference (SMD), relative risk (RR), odds ratio (OR), hazard ratio (HR), and others are meant to be examined along with their 95% confidence intervals (CIs), and their significance can be understood by viewing these CIs as compatibility intervals. The 95% CIs around the MD and SMD are easily understood because they are expressed along a linear scale. The 95% CIs around the RR, OR, and HR are harder to understand because they are expressed along an exponential scale; however, when the numbers are log-transformed, they are linearized, and understanding becomes easy. Another approach to understanding the CIs around the RR, OR, or HR is to examine the reciprocal of the lower limit of the CI; however, because the reciprocal also lies along an exponential scale, this method is inferior to the log-transformation method. These approaches may seem daunting, but the difficulty is an illusion because log transformation or reciprocal transformation takes only a few seconds when a statistical calculator is opened. All terms and concepts are explained with extreme simplification and with the help of examples. | Probability |
Protein A chromatography has been a popular method for purification of therapeutic monoclonal antibodies (mAb). Protein A chromatographic media using alkali-resistant rProtein A ligands from site-directed coupling method have been pursued for both high dynamic capacities and excellent stabilities. However, the mechanism of rProtein A leaking under cleaning-in-place (CIP) conditions is not very clear and difficulties have been commonly encountered when improving the media's chromatographic performance. We investigated the chromatographic performance of site-directed coupled rProtein A chromatographic media during CIP procedure. Trace amount of ligands leaked during the chromatographic media's incubation in 0.5â¯M NaOH was detected, explaining for the decline of chromatographic media's CIP performance. Decrease of rProtein A's concentration in 0.5â¯M NaOH was consistent with chromatographic media's binding capacity. A novel rProtein A chromatographic media were prepared by site-directed coupling a newly-constructed alkali-resistant rProtein A to highly cross-linked agarose-based matrix. The media had a dynamic binding capacity of 63.2â¯mg hIgG/mL higher than 48.1â¯mg hIgG/mL of the commercial one, and the CIP performance was improved greatly with the remained dynamic binding capacity increased from 86% to 95% of the initial value after 40 CIP cycles. | Immunoglobulin G |
The aim of this study was to determine the biological effects of dietary supplementation with 0.05% and 0.1% cinnamon essential oil extracted from Cinnamomum cassia on silver catfish (Rhamdia quelen). The final body weight, weight gain, and specific growth rate were significantly higher in fish supplemented with 0.05% cinnamon essential oil than in the control(untreated) group. Muscle reactive oxygen species and lipid peroxidation levels were significantly lower in fish supplemented with 0.05% cinnamon essential oil but higher at the 0.1% concentration. Muscle antioxidant capacity against peroxyl radicals (ACAP) and superoxide dismutase activity were significantly higher in fish supplemented with 0.05% cinnamon essential oil, while ACAP levels were lower in fish supplemented with 0.1%. The total saturated fatty acid content was significantly higher in the muscle of supplemented fish than in controls, while the total monounsaturated fatty acid content was significantly higher only in fish fed 0.1% cinnamon essential oil. Finally, the total content of polyunsaturated fatty acids was significantly lower in fish fed 0.1% essential oil. Thus, data demonstrated that 0.05% C. cassia essential oil improves fish health by improving performance and muscle oxidant/antioxidant status. Higher doses of cinnamon essential oil produced oxidative stress in muscle, suggesting toxicity at the 0.1% level. Although this cinnamon essential oil diet exerted positive health effects, this diet impaired the muscle fatty acid profile, suggesting adverse impacts on human health. | Cinnamomum |
High rates of mortality and morbidity stemming from cardiovascular diseases unveil extreme limitations in current therapies despite enormous advances in medical and pharmaceutical sciences. Following myocardial infarction (MI), parts of myocardium undergo irreversible remodeling and is substituted by a scar tissue which eventually leads to heart failure (HF). To address this issue, cardiac patches have been utilized to initiate myocardial regeneration. In this study, a porous cardiac patch is fabricated using a mixture of decellularized myocardium extracellular matrix (ECM) and chitosan (CS). Results of rheological measurements, SEM, biodegradation test, and MTT assay showed that the scaffold composed of 3.5% (w/w) CS and 0.5% ECM has the best potential in providing cardiac progenitor cells (CPCs) with a suitable microenvironmental condition for both attachment and growth. This study demonstrates that the fabricated scaffold is capable of transmitting both mechanical and chemical cues that is native to myocardial tissue and supports efficient growth of the CPCs. | Myoblasts, Cardiac |
Increasing crop production is necessary to feed the world's expanding population, and crop breeders often utilize genetic variations to improve crop yield and quality. However, the narrow diversity of the wheat D genome seriously restricts its selective breeding. A practical solution is to exploit the genomic variations of Aegilops tauschii via introgression. Here, we established a rapid introgression platform for transferring the overall genetic variations of A. tauschii to elite wheats, thereby enriching the wheat germplasm pool. To accelerate the process, we assembled four new reference genomes, resequenced 278 accessions of A. tauschii and constructed the variation landscape of this wheat progenitor species. Genome comparisons highlighted diverse functional genes or novel haplotypes with potential applications in wheat improvement. We constructed the core germplasm of A. tauschii, including 85 accessions covering more than 99% of the species' overall genetic variations. This was crossed with elite wheat cultivars to generate an A. tauschii-wheat synthetic octoploid wheat (A-WSOW) pool. Laboratory and field analysis with two examples of the introgression lines confirmed its great potential for wheat breeding. Our high-quality reference genomes, genomic variation landscape of A. tauschii and the A-WSOW pool provide valuable resources to facilitate gene discovery and breeding in wheat. | Genetic Introgression |
SIGNIFICANCE: Sessile plants respond to oxidative stress caused by internal and external stimuli by producing diverse forms of enzymatic and nonenzymatic antioxidant molecules. Peroxiredoxins (Prxs) in plants, including the Prx1, Prx5, Prx6, and PrxQ isoforms, constitute a family of antioxidant enzymes and play important functions in cells. Each Prx localizes to a specific subcellular compartment and has a distinct function in the control of plant growth, development, cellular metabolism, and various aspects of defense signaling. Recent Advances: Prx1, a typical Prx in plant chloroplasts, has redox-dependent multiple functions. It acts as a hydrogen peroxide (H(2)O(2))-catalyzing peroxidase, a molecular chaperone, and a biological circadian marker. Prx1 undergoes a functional switching from a peroxidase to a molecular chaperone in response to oxidative stress, concomitant with the structural changes from a low-molecular-weight species to high-molecular-weight complexes mediated by the post-translational modification of its active site Cys residues. The redox status of the protein oscillates diurnally between hyperoxidation and reduction, showing a circadian rhythmic output. These dynamic structural and functional transformations mediate the effect of plant Prx1 on protecting plants from a myriad of harsh environmental stresses. CRITICAL ISSUES: The multifunctional diversity of plant Prxs and their roles in cellular defense signaling depends on their specific interaction partners, which remain largely unidentified. Therefore, the identification of Prx-interacting proteins is necessary to clarify their physiological significance. FUTURE DIRECTIONS: Since the functional specificity of the four plant Prx isoforms remains unclear, future studies should focus on investigating the physiological importance of each Prx isotype. Antioxid. Redox Signal. 28, 625-639. | Peroxiredoxins |
The Netrin-1/DCC guidance cue pathway plays a critical role in guiding growing axons toward the prefrontal cortex during adolescence and in the maturational organization and adult plasticity of prefrontal cortex connectivity. In this review, we put forward the idea that alterations in prefrontal cortex architecture and function, which are intrinsically linked to the development of major depressive disorder, originate in part from the dysregulation of the Netrin-1/DCC pathway by a mechanism that involves microRNA-218. We discuss evidence derived from mouse models of stress and from human postmortem brain and genome-wide association studies indicating an association between the Netrin-1/DCC pathway and major depressive disorder. We propose a potential role of circulating microRNA-218 as a biomarker of stress vulnerability and major depressive disorder. | DCC Receptor |
BACKGROUND: Antibiotic-resistant Streptococcus pneumoniae strains may cause infections that fail to respond to antimicrobial therapy. Results reported from hospitalized patients with invasive, bacteremic infections may not be the same as those observed in a primary care setting where young children receive care for noninvasive infections. Young children experience the highest burden of pneumococcal disease. The aim of this study was to determine the antibiotic susceptibility of S. pneumoniae strains isolated from children in a primary care setting in the post-13-valent pneumococcal conjugate vaccine (PCV13) era. METHODS: This was a prospective collection of 1201 isolates of S. pneumoniae from 2006 through 2016 in a primary care setting. Antibiotic susceptibility testing to 16 different antibiotics of 10 classes was performed. Participants were children aged 6-36 months. Nasopharyngeal swabs were obtained from patients during acute otitis media (AOM) visits and routine healthy visits. Middle ear fluid was obtained by tympanocentesis. RESULTS: After introduction of PCV13, antibiotic susceptibility of pneumococci, especially to penicillin, initially improved largely due to disappearance of serotype 19A, included in PCV13. However, beginning in 2013, antibiotic susceptibility among pneumococcal strains began decreasing due to new serotypes not included in PCV13. In addition to reduced susceptibility to penicillin, the most recent isolates show reduced susceptibility to third-generation cephalosporins, fluoroquinolones, and carbapenems, antibiotics commonly used to treat life-threatening, invasive pneumococcal diseases. CONCLUSIONS: In recent years, pneumococcal nasopharyngeal and AOM isolates from children exhibit reduced susceptibility to penicillin, third-generation cephalosporin, fluoroquinolone, and carbapenem antibiotics. The new strains have a different profile of resistance compared to the pre-PCV13 era. | Pneumococcal Infections |
Excessive microglial cell activation is related to the progression of chronic neuro-inflammatory disorders. Heme oxygenase-1 (HO-1) expression mediated by the NFE2-related factor (Nrf-2) pathway is a key regulator of neuro-inflammation. Nardostachys chinensis is used as an anti-malarial, anti-nociceptive, and neurotrophic treatment in traditional Asian medicines. In the present study, we examined the effects of an ethyl acetate extract of N. chinensis (EN) on the anti-neuro-inflammatory effects mediated by HO-1 up-regulation in Salmonella lipopolysaccharide (LPS)- or Staphylococcus aureus lipoteichoic acid (LTA)-stimulated BV2 microglial cells. Our results indicated that EN suppressed pro-inflammatory cytokine production and induced HO-1 transcription and translation through Nrf-2/antioxidant response element (ARE) signaling. EN markedly inhibited LPS- and LTA-induced activation of nuclear factor-kappa B (NF-kappaB) as well as phosphorylation of mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT). Furthermore, EN protected hippocampal HT22 cells from indirect neuronal toxicity mediated by LPS- and LTA-treated microglial cells. These results suggested that EN impairs LPS- and LTA-induced neuro-inflammatory responses in microglial cells and confers protection against indirect neuronal damage to HT22 cells. In conclusion, our findings indicate that EN could be used as a natural anti-neuro-inflammatory and neuroprotective agent. | Nardostachys |
Intravenous anaesthetics such as ketamine, propofol, and thiamylal are widely used, although the direct effects of these anaesthetics on the renal blood flow (RBF) have not been well elucidated. In this study, we examined the effects of bolus and continuous administrations of ketamine, propofol, and thiamylal on cortical RBF and the effects of noradrenaline (NA) on RBF under continuous administration of these anaesthetics. We used laser Doppler flowmetry to measure the effects of bolus injection and continuous infusion of ketamine, propofol, and thiamylal on cortical RBF in male Wistar rats. We also examined the effects of the anaesthetics on mean arterial blood pressure (MAP) and heart rate (HR). Bolus injections of ketamine, propofol, or thiamylal (1-8 mg/kg each, n = 10) at clinically relevant concentrations did not affect MAP, HR, or RBF. Continuous administration of ketamine, propofol, or thiamylal (1-8 mg/kg/h each, n = 10) did not affect MAP, HR or RBF. Exogenous NA (2 microg/kg) caused an increase in MAP and a decrease in RBF and HR. In experiments with continuous infusions of propofol or thiamylal (1-8 mg/kg/h each, n = 10), similar results were observed without infusion of any anaesthetics. However, bolus injection of NA did not result in a decrease in RBF during continuous ketamine infusion (98.8 +/- 6.7% of control, n = 6, p < 0.05), while ketamine did not affect the NA-induced increase in MAP. In conclusion, bolus and continuous administrations of ketamine, propofol, and thiamylal did not affect the RBF. From our present findings, ketamine would be useful for maintaining the RBF. | Thiamylal |
Sebastian Ocklenburg and colleagues have written an important and exciting summary of where laterality research might go. Perhaps reiterating some of their points, it seems important to understand the nuances of laterality. Laterality research can fall into the trap of dichotomania" - where all laterality is seen in terms of left versus right. However, important insights can also be gained by examining the strength of laterality as well as the cooperation and competition between the hemispheres. Care also needs to be taken when examining individual differences between left- and right-handers. Studies, which may suffer from type 1 errors, often stigmatise left-handers with a host of negative traits. Pre-registration and the reporting of effect size may eliminate this bias." | Individuality |
Cleveland Health Quality Choice (CHQC) is an ongoing collaborative partnership between business, hospitals, and physicians designed to assess the performance of health care institutions in the greater Cleveland metropolitan area. CHQC coordinates the collection of data for analysis of intensive care unit outcomes; general medical, surgical and obstetric outcomes; and patient satisfaction. CHQC has documented improved outcomes in all measured spheres over a 4-year period. Its success can be attributed to a leadership strategy focused on providing rigorously tested analytic tools and a shared vision regarding the value of outcome information in assessing institutional performance. CHQC can serve as a model for communities interested in creating joint programs between purchasers and providers of health care to measure health outcomes. | Health Care Coalitions |
Our understanding of the functions of vitellogenin (Vtg) in reproduction has undergone an evolutionary transformation over the past decade. Primarily, Vtg was regarded as a female-specific reproductive protein, which is cleaved into yolk proteins including phosvitin (Pv) and lipovitellin (Lv), stored in eggs, providing the nutrients for early embryos. Recently, Vtg has been shown to be an immunocomponent factor capable of protecting the host against the attack by microbes including bacteria and viruses. Moreover, Pv and Lv that both are proteolytically cleaved products of maternal Vtg, as well as Pv-derived small peptides, all display an antibacterial role in developing embryos. In addition, both Vtg and yolk protein Pv possess antioxidant activity capable of protecting cells from damage by free radicals. Collectively, these data indicate that Vtg, in addition to being involved in yolk protein formation, also plays non-nutritional roles via functioning as immune-relevant molecules and antioxidant reagents. | Phosvitin |
During the past few years significant progress has been made in our understanding of the structure and function of the proteins involved in eukaryotic DNA replication. Data from several laboratories suggest that, in contrast to prokaryotic DNA replication, two distinct DNA polymerases are required for eukaryotic DNA replication, i.e. DNA polymerase delta for the synthesis of the leading strand and DNA polymerase alpha for the lagging strand. Several accessory proteins analogous to prokaryotic replication factors have been identified and some of these are specific for pol delta whereas others affect both DNA replicases. The replicases and their accessory proteins appear to be highly conserved in eukaryotes, as homologous proteins have been found in species ranging from humans to yeast. | DNA-Directed DNA Polymerase |
Apoptosis is characterized by cell shrinkage, nuclear condensation and internucleosomal DNA cleavage. Besides the central role of caspases and other proteases, cell death triggers DNA degradation so that DNases have an active role in apoptotic cell death. The best-characterized apoptotic DNase is CAD, a neutral Mg-dependent endonuclease. Its activity is regulated by its inhibitor, ICAD, which is cleaved by caspases. Other neutral DNases have been shown to cleave nuclear DNA in apoptotic conditions: endonuclease G, GADD. In cells, the cytosolic pH is maintained to 7.2, mostly due to the activity of the Na(+)/H(+) exchanger. In many apoptotic conditions, a decrease of the intracellular pH has been shown. This decrease may activate different acid DNases, mostly when pH decreases below 6.5. Three acidic DNases II are so far known: DNase II alpha, DNase II beta and L-DNase II, a DNase II, derived from the serpin LEI (Leukocyte Elastase Inhibitor). Their activation during cell death is discussed in this review. | Endonucleases |
One potential unknown impurity was detected during the analysis of stability batches of brimonidine tartrate (BMT) in the level ranging from 0.03 % to 0.06 % by high-performance liquid chromatography (HPLC). Based on the liquid chromatography-mass spectrophotometry (LC-MS) analysis, the unknown impurity structure was presumed as 3,6,11,13,16-pentaazatetracyclo [8.6.0.0(2),(7).0(1)(2),(1)(6)] hexadeca-1,3,5,7,9,12-hexaene. The proposed structure was elucidated, after its isolation using preparative liquid chromatography from the impurity enriched reaction crude sample, using analytical applications such as 1D NMR ((1)H, (13)C and DEPT-135), 2D NMR (HMBC and COSY), high-resolution mass spectrometry (HRMS) and infrared spectroscopy (IR). The unknown impurity was prepared from brimonidine by following Ullman coupling reaction in the presence of CuBr(2) in gram scale with optimum purity to use further in analytical developments. The identification, structural elucidation and synthesis of unknown degradation impurity such as BMT-cyclized impurity, and HPLC method validation were reported for the first time in this paper. | Brimonidine Tartrate |
alpha-Difluoromethylornithine, an inhibitor of polyamine biosynthesis, affected the pathogenicity of Trichomonas vaginalis in two model systems. Firstly, it blocked the cytotoxic effect of the parasite towards mammalian cells in culture: at a concentration of 1 mM it prevented the death of mouse myeloma cells in mixed culture with trichomonads. Secondly, when administered orally to mice (multiple doses of 750 mg/kg body wt), the drug delayed the development of subcutaneous abscesses due to T. vaginalis infection. The same drug dose did not cure intravaginal infections by the parasite. The implications of these findings with respect to the value of the model systems used and the potential of DFMO as an antitrichomonal drug are discussed. | Eflornithine |
BACKGROUND: Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a beta-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (beta(1) adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (alpha(2C) AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology. METHODOLOGY: In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of beta(1)389 and alpha(2C)322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for beta(1)389 AR variants was measured in human explanted left ventricles. PRINCIPAL FINDINGS: The combination of beta(1)389 Arg+alpha(2C)322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in beta(1)389 Arg homozygotes+alpha(2C)322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in beta(1)389 Arg vs. Gly ARs, which converts alpha(2C)Del minor allele-associated NE lowering from a therapeutic liability to a benefit. CONCLUSIONS: On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (beta(1)389 Arg homozygotes), intermediate (beta(1)389 Gly carriers+alpha(2C)322-325 Wt homozygotes), and no (beta(1)389 Gly carriers+alpha(2C)322-325 Del carriers) efficacy. | Receptors, Adrenergic, beta-1 |
BACKGROUND: Candidatus Nanohaloarchaeota, an archaeal phylum within the DPANN superphylum, is characterized by limited metabolic capabilities and limited phylogenetic diversity and until recently has been considered to exclusively inhabit hypersaline environments due to an obligate association with Halobacteria. Aside from hypersaline environments, Ca. Nanohaloarchaeota can also have been discovered from deep-subsurface marine sediments. RESULTS: Three metagenome-assembled genomes (MAGs) representing a new order within the Ca. Nanohaloarchaeota were reconstructed from a stratified salt crust and proposed to represent a novel order, Nucleotidisoterales. Genomic features reveal them to be anaerobes capable of catabolizing nucleotides by coupling nucleotide salvage pathways with lower glycolysis to yield free energy. Comparative genomics demonstrated that these and other Ca. Nanohaloarchaeota inhabiting saline habitats use a salt-in" strategy to maintain osmotic pressure based on the high proportion of acidic amino acids. In contrast, previously described Ca. Nanohaloarchaeota MAGs from geothermal environments were enriched with basic amino acids to counter heat stress. Evolutionary history reconstruction revealed that functional differentiation of energy conservation strategies drove diversification within Ca. Nanohaloarchaeota, further leading to shifts in the catabolic strategy from nucleotide degradation within deeper lineages to polysaccharide degradation within shallow lineages. CONCLUSIONS: This study provides deeper insight into the ecological functions and evolution of the expanded phylum Ca. Nanohaloarchaeota and further advances our understanding on the functional and genetic associations between potential symbionts and hosts. Video Abstract." | Amino Acids, Basic |
We report a 26-month-old child diagnosed with prune-belly syndrome and end-stage renal disease who received intraperitoneal implantation of an adult cadaveric renal graft which functioned very well for approximately 6 weeks. The patient then presented with acute renal failure which was proved to be secondary to torsion of the graft, twisting the artery and vein. The ureter was wrapped 360 degrees around the graft. These conditions resulted in loss of the graft and nephrectomy. Ours is the second report of such an occurrence; the first was from a living-related kidney donor. We believe the lack of abdominal wall tone contributes to graft mobility and risk of torsion of the kidney. We recommend that nephropexy be considered in these patients. In addition, the risk of torsion must be at the forefront of the differential diagnosis in a prune-belly renal transplant patient with acute onset of oliguria. Renal sonography with Doppler should be employed as soon as possible so that the graft can be saved. | Prune Belly Syndrome |
Perivascular adipose tissue (PVAT) is a source of factors affecting vasomotor tone with the potential to play a role in the performance of saphenous vein (SV) bypass grafts. As these factors have been described as having constrictor or relaxant effects, they may be considered either beneficial or detrimental. The close proximity of PVAT to the adventitia provides an environment whereby adipose tissue-derived factors may affect the vasa vasorum, a microvascular network providing the vessel wall with oxygen and nutrients. Since medial ischaemia promotes aspects of graft occlusion the involvement of the PVAT/vasa vasorum axis in vein graft patency should be considered. | Vasa Vasorum |
A 2.5-year-old boy was referred to the emergency room for a sudden onset of diffuse and increasing abdominal pain with lethargy, abdominal distension, and vomiting, all in the past 24 hours. A plain abdominal X-ray showed gastric distension. Two liters of gastric contents were evacuated by suction. The abdominal sonogram showed an unusual position of the spleen in the left-lower quadrant, with no splenic ischemia. The diagnosis of gastric volvulus associated with a wandering spleen was then evoked. Laparoscopic exploration revealed a nonischemic spleen, absence of normal supporting ligaments for the spleen, and gastric distension with flaccid gastric walls. The spleen was then easily moved in the left-under quadrant. A parietal peritoneal posterolateral incision was made, opposite the large gastric curve, up to the diaphragm (7 cm). This delimitated a sharp demarcation zone between the two edges of the incised peritoneum. The stomach was fixed to the peritoneal incision, covering and anchoring the spleen in a good position. Recovery was uneventful, and an abdominal sonogram performed 4 years after the surgery shows a viable spleen in its correct location. The rarity of gastric volvulus associated with a wandering spleen and its fast clinical improvement with medical treatment often delays the diagnosis and the surgical treatment. Laparoscopy in this case has a dual relevance: diagnosis and therapeutic management (splenectomy or gastropexy). Laparoscopic gastropexy for the treatment of gastric volvulus associated with a wandering spleen is an easy procedure and combines the advantages of all the surgical techniques previously described. | Wandering Spleen |
The natural variant of the cytochrome P450 enzyme CYP2D6.1, CYP2D6.17, is most common in African populations, has three amino acid substitutions (T107I, R296C, and S486T) compared to the wild-type, and is known to have a different ligand preference from CYP2D6.1. It is becoming increasingly important to understand differences in the metabolism of medicines in different ethnic groups in order to assess the relevance of clinical data from different countries. This study investigated differences in the inhibition profiles of drugs for CYP2D6 with respect to gene polymorphisms. Firstly, we used computer docking with six drugs to several CYP2D6.1 structures, sampled from the trajectory of MD simulations, and calculated MM-GB/SA scores representing binding free energies. We then used regression analysis to predict the potency with which drugs inhibited CYP2D6.1 based on MM-GB/SA scores. The pKi-values obtained were in good agreement with experimental values measured for the six drugs (r(2) = 0.81). We carried out the same analysis for CYP2D6.17 and the pKi-values calculated were also in good agreement with experimental values (r(2) = 0.92). Finally, we were able to successfully explain the different abilities of CYP2D6.1 and CYP2D6.17 to metabolize drugs in different ethnic groups with reference to their 3D-structures." | Cytochrome P-450 CYP2D6 Inhibitors |
Land surface albedo plays a crucial role in the land surface energy budget and climate. This paper identified the spatiotemporal variations of surface albedo on the Tibetan Plateau (TP) from 1982 to 2015, and quantified the relationships between the spatial and temporal patterns of the albedo and associated influencing factors (snow cover, vegetation, and soil moisture) on the seasonal and interannual basis using satellite products and reanalysis data. It was determined that the albedo presented a distinct spatial variability, with high values in mountainous areas and low values on the southeastern TP. Spatially, average albedo exhibited a positive correlation with snow cover and negative correlations with vegetation and soil moisture. Average albedo over the whole TP had a clear seasonal cycle with a peak in winter and a minimum value in summer, which is dictated by seasonal changes in snow and vegetation covers. Annual average albedo exhibited a weakly downward trend, which was mainly contributed by a significant decrease in summer, pointing to the important role in vegetation dynamics for temporal change of the albedo. On the regional basis, interannual variation of albedo was more responsive to snow cover over the snow- and vegetation-coexisting area than the snow-covered area, and to changes in Normalized Difference Vegetation Index (NDVI) over the vegetation-covered area than the snow- and vegetation-coexisting area; albedo had a weakly negative correlation with soil moisture over bare soil. Furthermore, our results indicated that snow cover was the dominant factor for albedo change on mountainous areas, and vegetation change predominated the variation of albedo on the eastern, southern, and northwestern TP. Specifically, variations in snow cover contributed more than those of vegetation to the interannual albedo variation over the Three Rivers Headwater Region. These results would be beneficial for better understanding the climate and eco-environment changes over the TP. | Snow |
INTRODUCTION: Hypophysitis is an inflammation of the pituitary gland and a rare case of hypopituitarism. Despite the expanding spectrum of histological variants and causative agents, its pathogenesis is far to be fully understood. The present review is focused on recent evidence concerning the pathogenesis of autoimmune hypophysitis by searching through online databases like MEDLINE and Scopus up to May 2021. AREAS COVERED: Hypophysitis frequently develops in the context of a strong autoimmune background, including a wide spectrum of subtypes ranging from the commonest form of lymphocytic hypophysitis to the newly described and less common IgG4-, anti-PIT-1, and ICI-induced forms. A peculiar combination of genetic predisposition, pituitary damage and immunological setting represents the pathogenetic basis of autoimmune hypophysitis, which is characterized by diffuse infiltration of the gland by lymphocytes and variable degrees of fibrosis followed by pituitary cell destruction. Anti-pituitary antibodies (APA) have been described in sera from patients suffering from autoimmune hypophysitis, though their pathophysiological significance remains largely unknown and their diagnostic value limited. EXPERT OPINION: In recent years hypophysitis has gained interest due to the increased number of new diagnoses and the recognition of novel subtypes. Further studies could lead to improvements in biochemical/immunological diagnosis and targeted treatments. | Pituitary Diseases |
The analgesic efficacy of two doses of conorphone (20 and 40 mg), a mixed agonist-antagonist analgesic, were compared to two doses of codeine for postoperative pain in the oral surgery model. Each subject received 2 of the 4 possible treatment at two separate sessions in an incomplete block, single crossover design. Both doses of conorphone and the 60 mg dose of codeine were superior to 30 mg of codeine for the various indices of analgesic activity. The 40 mg dose of conorphone resulted in a high incidence of side effects (25/30 subjects) such as drowsiness, dizziness, nausea and vomiting. The low dose of conorphone resulted in side effects similar to 60 mg of codeine with the exception of a greater incidence of drowsiness. These data suggest that while 40 mg of conorphone may not be well tolerated clinically, 20 mg of conorphone may be an alternative to 60 mg of codeine for postoperative pain. | Codeine |
As a screening study for anti-tumor promoters, 51 carotenoids with diverse structures were examined for their inhibitory effects on the Epstein-Barr virus activation activity of 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The results showed that most of the carotenoids exhibited inhibitory activity, and in general, no cytotoxicity on Raji cells was observed in the assay. Among the carotenoids, beta-cryptoxanthin, lutein, and lactucaxanthin showed the strongest inhibitory activity, superior to the well known anti-tumor promoter, beta-carotene. Heteroxanthin, peridinin, and halocynthiaxanthin showed cytotoxicity at the high concentration (1000 molar ratio per TPA), but indicated a strong inhibitory effect at the lower concentrations, which were only weakly toxic (500 and 100 molar ratios). Based on these results, the essential moiety for the activity of carotenoids was considered to be the 3-hydroxy-epsilon-end group. | Tetradecanoylphorbol Acetate |
Familial hypokalemic periodic paralysis is an autosomal dominant muscle disorder characterized by episodic attacks of muscle weakness, accompanied by a decrease in blood potassium levels. It is based on genetic mutations in the genes CACNA1S (most frequent, encoding the skeletal muscle calcium channel) and SCN4A (10% of cases, encoding the sodium channel). Few cases have been reported with cardiac dysrhythmia. We report a rare case of a patient with a novel SCN4A mutation who presented, on ECG, extreme bradycardia and syncopal sinus arrest that required a temporary pacemaker implant" | Paralysis, Hyperkalemic Periodic |
Balamuthia mandrillaris is a rare but increasingly recognized cause of amebic encephalitis, yet it remains poorly understood. The condition is almost universally fatal, and due to diagnostic difficulty, most cases are identified postmortem. The authors report a case of Balamuthia amebic encephalitis in a patient with combined variable immunodeficiency in which a rare antemortem diagnosis was made via brain biopsy. Despite broad-spectrum antimicrobial therapy, the outcome was fatal. Such presentations are challenging, and definitive diagnosis may require biopsy in consultation with a skilled neuropathologist. | Meningoencephalitis |
In the field of correlative microscopy, light and electron microscopy form a powerful combination for morphological analyses in zoology. Due to sample thickness limitations, these imaging techniques often require sectioning to investigate small animals and thereby suffer from various artefacts. A recently introduced nanoscopic X-ray computed tomography (NanoCT) setup has been used to image several biological objects, none that were, however, embedded into resin, which is prerequisite for a multitude of correlative applications. In this study, we assess the value of this NanoCT for correlative microscopy. For this purpose, we imaged a resin-embedded, meiofaunal sea cucumber with an approximate length of 1 mm, where microCT would yield only little information about the internal anatomy. The resulting NanoCT data exhibits isotropic 3D resolution, offers deeper insights into the 3D microstructure, and thereby allows for a complete morphological characterization. For comparative purposes, the specimen was sectioned subsequently to evaluate the NanoCT data versus serial sectioning light microscopy (ss-LM). To correct for mechanical instabilities and drift artefacts, we applied an alternative alignment procedure for CT reconstruction. We thereby achieve a level of detail on the subcellular scale comparable to ss-LM images in the sectioning plane. | X-Ray Microtomography |
Modern period of psychopharmacology development is characterized by seven main features: changes in both clinical picture and course of psychic diseases; the use of psychotropic drug in general medicine; some new nosologic entities in ICD-10 which require of more accurate definition of the methods of therapy; progress in the study of biologic mechanisms of psychotropic drugs' action; appearance of numerous little-known preparations; discovery of some new aspects in action of well-known drugs; increase of the number of patients resistent to psychopharmacotherapy. Traditional and original classifications of psychotropic drugs are presented. Clinical analysis revealed that clear limits between separate groups of drugs are relative. Between the separate classes transitional" drugs exist with distinct properties of both groups. Such drugs are thymoneuroleptics, thymotranquilizers, antidepressants with nootropic and neuroleptic properties, tranquilonootrops, etc. In accordance with the conception of "ideal" drug each class of psychotropic drugs was analyzed in terms of main advantages and defects. The advantages of some new drugs are considered." | Psychopharmacology |
A 26 year old nulligravida presented at 24 weeks gestation for the second opinion of abnormal fetal profile and mid-face views on ultrasound at another institution. A detailed fetal anatomic ultrasound at our facility revealed the absence of fetal lens and globes bilaterally consistent with bilateral anophthalmia (HP: 0000528) without other anomalies. Karyotype and chromosomal microarray analysis were completed from amniocentesis sample. After these results, duo exome testing with paternal sequencing was completed from proband amniotic fluid sample and parental blood samples. A pathogenic variant in SOX2 (NM_003106.3: c.513C>G p.(Tyr171*Ter)) with heterozygous autosomal dominant inheritance resulted. On duo exome testing with paternal segregation analysis, the variant was found to be consistent with likely sporadic de novo inheritance. The SOX2 variant reported is consistent with the fetal phenotype in this case. While germline mosaicism could exist, this identified variant provided the family with a likely explanation for this proband's finding. This ultrasound and genetic testing allowed the family to make decisions related to planning in current and future pregnancies. | Anophthalmos |
While most bark beetles attack only dead or weakened trees, many species in the genus Dendroctonus have the ability to kill healthy conifers through mass attack of the host tree, and can exhibit devastating outbreaks. Other species in this group are able to successfully colonize trees in small numbers without killing the host. We reconstruct the evolution of these ecological and life history traits, first classifying the extant Dendroctonus species by attack type (mass or few), outbreaks (yes or no), host genus (Pinus and others), location of attacks on the tree (bole, base, etc.), whether the host is killed (yes or no), and if the larvae are gregarious or have individual galleries (yes or no). We then estimated a molecular phylogeny for a data set of cytochrome oxidase I sequences sampled from nearly all Dendroctonus species, and used this phylogeny to reconstruct the ancestral state at various nodes on the tree, employing maximum parsimony, maximum likelihood, and Bayesian methods. Our reconstructions suggest that extant Dendroctonus species likely evolved from an ancestor that killed host pines through mass attack of the bole, had individual larvae, and exhibited outbreaks. The ability to colonize a host tree in small numbers (as well as gregarious larvae and attacks at the tree base) apparently evolved later, possibly as two separate events in different clades. It is likely that tree mortality and outbreaks have been continuing features of the interaction between conifers and Dendroctonus bark beetles. | Weevils |
During non-clinical and clinical development of a new molecular entity (NME), modeling and simulation (M&S) are routinely used to predict the exposure and pharmacokinetics (PK) of the drug compound in humans. The basic methodology and output are generally understood across all functional disciplines. However, this understanding is mostly restricted to traditional methods such as those in simplified kinetic models and void of adequate mechanistic foundation to address questions beyond the observed clinical data. In the past two decades, alternative and more mechanistic methods, particularly for describing absorption, distribution, excretion and metabolism (ADME) of drugs have been developed and applied under the general umbrella of physiologically-based pharmacokinetic (PBPK) methods. Their mechanistic nature gives the ability to ask many other questions which were not traditionally asked and provide some logically and evidenced-based potential answers. Whilst traditional PK methods are mainstream and understood by most scientists, mechanistic absorption models alongside other PBPK approaches are still deemed eclectic, despite making significant strides in the fundamental science as well as regulatory acceptance. On November 3rd, a short course was held at the annual American Association of Pharmaceutical Scientists (AAPS) meeting in San Antonio, Texas. The different talks were tailored to provide a basis or rationale for the subject, introduction to fundamental principles with historical perspective, a critique of the state-of-the-art, examples of successful application of the methods across different phases of the drug development process and the specific standards these mechanistic models should meet to be fully reliable from a regulatory perspective. | Pharmacokinetics |
Fatty acid photodecarboxylases (FAP) are a recently discovered family of FAD-containing, light-activated enzymes, which convert fatty acids to n-alkanes/alkenes with potential applications in the manufacture of fine and speciality chemicals and fuels. Poor catalytic stability of FAPs is however a major limitation. Here, we describe a methodology to purify catalytically stable and homogeneous samples of recombinant Chlorella variabilis NC64A FAP (CvFAP) from Escherichia coli. We demonstrate however that blue light-exposure, which is required for photodecarboxylase activity, also leads to irreversible inactivation of the enzyme, especially in the absence of palmitate substrate. Photoinactivation is attributed to formation of protein based organic radicals, which were observed by EPR spectroscopy. To suppress photoinactivation, we prepared stable and catalytically active FAP in the dark. The steady-state kinetic parameters of CvFAP (k(cat): 0.31 +/- 0.06 s(-1) and K(M): 98.8 +/- 53.3 muM) for conversion of palmitic acid to pentadecane were determined using gas chromatography. Methods described here should now enable studies of the catalytic mechanism and exploitation of FAPs in biotechnology. | Carboxy-Lyases |
Humoral and cellular immunity were evaluated in 10 patients with Darier's disease. The mean levels of serum immunoglobulins, serum complement, peripheral macrophages, and peripheral B and T lymphocytes were within normal limits. Secretory IgA was present in all patients studied. Skin tests for delayed hypersensitivity revealed complete anergy in one of the eight patients tested. Lymphocyte transformation tests revealed statistically significant enhanced responsiveness to both PHA and ConA mitogens in several concentrations studied. These findings may suggest either the existence of alterations in immunoregulation of lymphocyte subpopulations in Darier's disease or may be limited to alterations in membrane functions of certain lymphocyte subpopulations which can be detected only in vitro. The role that such immunologic aberrations may play in the pathogenesis of Darier's disease is still obscure. | Darier Disease |
Hypophosphatasia (HPP) is the inborn-error-of-metabolism that features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia) caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of ALP (TNSALP). Autosomal recessive or autosomal dominant inheritance from among >300 TNSALP (ALPL) mutations largely explains HPP's remarkably broad-ranging severity. TNSALP is a cell-surface homodimeric phosphohydrolase richly expressed in the skeleton, liver, kidney, and developing teeth. In HPP, TNSALP substrates accumulate extracellularly. Among them is inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Superabundance of extracellular PPi explains the hard tissue complications of HPP that feature premature loss of deciduous teeth and often rickets or osteomalacia as well as calcific arthropathies in some affected adults. In infants with severe HPP, blocked entry of minerals into the skeleton can cause hypercalcemia, and insufficient hydrolysis of pyridoxal 5'-phosphate (PLP), the major circulating form of vitamin B(6), can cause pyridoxine-dependent seizures. Elevated circulating PLP is a sensitive and specific biochemical marker for HPP. Also, the TNSALP substrate phosphoethanolamine (PEA) is usually elevated in serum and urine in HPP, though less reliably for diagnosis. Pathognomonic radiographic changes occur in pediatric HPP when the skeletal disease is severe. TNSALP mutation analysis is essential for recurrence risk assessment for HPP in future pregnancies and for prenatal diagnosis. HPP was the final rickets/osteomalacia to have a medical treatment. Now, significant successes using asfotase alfa, a mineral-targeted recombinant TNSALP, are published concerning severely affected newborns, infants, and children. Asfotase alfa was approved by regulatory agencies multinationally in 2015 typically for pediatric-onset HPP. | Hypophosphatasia |
Cerebral achromatopsia is an acquired colour perception impairment caused by brain injury, and is generally considered to be rare. Both hemispheres are thought to contribute to colour perception, but most published cases have had bilateral or right hemisphere lesions. In contrast to congenital colour blindness that affects the discrimination between specific hues, cerebral achromatopsia is often described as affecting perception across all colours. Most studies of cerebral achromatopsia have been single cases or case series of patients with colour perception deficits. Here, we explore colour perception deficits in an unbiased sample of patients with stroke affecting the posterior cerebral artery (N = 63) from the Back of the Brain project. Patients were selected based on lesion location only, and not on the presence of a given symptom. All patients were tested with the Farnsworth D-15 Dichotomous Colour Blindness Test and performance compared to matched controls (N = 45) using single case statistics. In patients with abnormal performance, the patterns of colour difficulties were qualitatively analysed. 22% of the patients showed significant problems with colour discrimination (44% of patients with bilateral lesions, 28% with left hemisphere lesions and 5% with right hemisphere lesions). Lesion analyses identified two regions in ventral occipital temporal areas in the left hemisphere as particularly strongly related to impaired performance in colour perception, but also indicated that bilateral lesions are more strongly associated with impaired performance that unilateral lesions. While some patients only had mild deficits, colour perception impairments were in many cases severe. Many patients had selective deficits only affecting the perception of some hues. The results suggest that colour perception difficulties following PCA stroke are common, and that they vary in severity and expression. In addition, the results point towards bilateral processing of colour perception with a left hemispheric domination, contradicting previous reports. | Cone Dystrophy |
PURPOSE: A first-pass, direct aspiration technique and stent retrieval with a balloon guide catheter represent advanced thrombectomy techniques that are increasingly being used in the clinical routine. The purpose of this experimental study was to evaluate whether the techniques' effectiveness depended on the clot composition and to visualize the interaction between the devices and the clot. MATERIALS AND METHODS: Erythrocyte-rich (red) and fibrin-rich (white) clots were placed into the M1-segment of the middle cerebral artery in a transparent vascular phantom with physiological architecture. Physiological hemodynamic conditions were maintained with a programmable pump. On the one hand direct aspiration with a 5F aspiration catheter (ADAPT) and on the other hand stent retrieval with a balloon guide catheter (flow arrest/reversal) was performed. The experiments were made under direct visual control to observe the interaction between the devices and the clot. The primary end points were the number of passes/maneuvers and the occurrence of distal emboli and emboli in a new territory (anterior cerebral artery), until full recanalization was achieved. The experiment was filmed with a full high-definition camera identifying emboli. RESULTS: Six experiments were conducted for each technique and clot model. Red clots were retrieved by ADAPT with fewer passes and distal emboli, and could usually be aspirated directly at the occlusion site. White clots clogged the tip of the 5F aspiration catheter in every experiment. The catheter had to be pulled back into the long sheath in the cervical internal carotid artery, producing distal emboli. White clots were retrieved by the stent retriever and balloon guide catheter with fewer distal emboli. There was no difference in the number of passes. The stent-thrombus interaction was superficial in both clot models. Successful retrieval was granted by the flow arrest and proximal aspiration/flow reversal. One embolus in a new territory developed when using each technique in white clots. CONCLUSION: This experimental study showed that the efficacy of advanced thrombectomy techniques might depend on clot composition. Identifying the right technique for the right clot might improve the results of thrombectomy. In a clinical setting the thrombus morphology in non-enhanced CT could be used as a marker for patient selection. KEY POINTS: . The efficacy of thrombectomy seems to depend on thrombus composition.. . ADAPT might be more effective for rbc-rich clots.. . Thrombectomy with BGC might be more effective for fibrin-rich clots.. CITATION FORMAT: . Madjidyar J, Pineda Vidal L, Larsen N et al. Influence of Thrombus Composition on Thrombectomy: ADAPT vs. Balloon Guide Catheter and Stent Retriever in a Flow Model. Fortschr Rontgenstr 2020; 192: 257 - 263. | Balloon Embolectomy |
Three neo-clerodane diterpenoids, inermes A, B and 14,15-dihydro-15 beta-methoxy-3-epicaryoptin, have been isolated from the hexane extract of the leaves of Clerodendrum inerme in addition to an epimeric mixture of 14,15-dihydro-15-hydroxy-3-epicaryoptin. Structures of these compounds have been elucidated on the basis of spectral studies. | Diterpenes, Clerodane |
Preparations of Harpagophytum procumbens and of Salix species are successfully used for the treatment of degenerative rheumatism and painful arthrosis. For the quality control of both drugs, rapid methods of quantification are desirable. Here we report the development of two HPTLC methods enabling the determination of harpagoside in Harpagophyti radix and of salicin in Salicis cortex. We focused on a standardized methodology and thorough validation including two laboratories. The methods allow the analyses of up to 16 samples in parallel demonstrating the proposed methods as very rapid and cost efficient. | Harpagophytum |
Omega-3 polyunsaturated fatty acids (PUFA) are produced in some unicellular organisms, such as marine gammaproteobacteria, myxobacteria, and thraustochytrids, by large enzyme complexes called PUFA synthases. These enzymatic complexes resemble bacterial antibiotic-producing proteins known as polyketide synthases (PKS). One of the PUFA synthase subunits is a conserved large protein (PfaA in marine proteobacteria) that contains three to nine tandem acyl carrier protein (ACP) domains as well as condensation and modification domains. In this work, a study of the PfaA architecture and its ability to initiate the synthesis by selecting malonyl units has been carried out. As a result, we have observed a self-acylation ability in tandem ACPs whose biochemical mechanism differ from the previously described for type II PKS. The acyltransferase domain of PfaA showed a high selectivity for malonyl-CoA that efficiently loads onto the ACPs domains. These results, together with the structural organization predicted for PfaA, suggest that this protein plays a key role at early stages of the anaerobic pathway of PUFA synthesis." | Acyl-Carrier Protein S-Acetyltransferase |
We aim to establish that accelerated aging and premature cellular senescence seen in individuals with Down syndrome is related to reduced DNA polymerasebeta. We report here that primary fibroblasts from Down syndrome individuals exhibit greater SA-beta-gal staining (fourfold increase, P < 0.001), increased p16 transcript abundance (threefold increase, P < 0.01), and reduced HMGB1 nuclear localization (1.5-fold lower, P < 0.01). We also find that DNA polymerase beta expression is significantly reduced in Down syndrome primary fibroblasts (53% decline, P < 0.01). To evaluate whether DNA polymerase beta might be causative in senescence induction, we evaluated the impact of murine DNA polymerase beta nullizygosity on senescence. We find that unexposed DNA polymerase beta -null primary fibroblasts exhibit a robust increase in the number of senescent cells compared to wild-type (11-fold, P < 0.001), demonstrating that loss DNA polymerase beta is sufficient to induce senescence. We also see an additional increase in response to hydroxyurea (threefold greater than WT-HU, P < 0.05). These data demonstrate that loss of DNA polymerase beta is sufficient to induce senescence. Additionally, we report a significant induction in spontaneous DNA double strand breaks in DNA polymerase beta null MEFs (fivefold increase from wild-type, P < 0.0001). Our findings strongly suggest that DNA polymerase beta is causative in senescence induction, reasonably pointing to DNA polymerase beta as a likely factor driving the premature senescence in Down syndrome. Environ. Mol. Mutagen. 59:603-612, 2018. (c) 2018 Wiley Periodicals, Inc. | DNA Polymerase beta |
Unfractionated heparin (UFH), which has been available commercially for over half a century, has been the most widely used agent for quickly suppressing thrombosis. When given intravenously, UFH quickly binds to and activates antithrombin, which then inhibits several activated factors in the clotting cascade. For decades, UFH was invaluable for treating arterial and venous thrombosis, and no alternative was available. The short half-life of UFH and the fact that its action could be reversed readily with protamine made it an almost ideal antithrombotic agent. However, variable pharmacokinetics, together with problems of inaccuracy and unreliability of the activated partial thromboplastin time, have made it difficult to use this drug optimally. In addition, side effects such as osteoporosis, heparin-induced thrombocytopenia (HIT), and delayed HIT have led to increased concerns about the use of UFH in view of the advantages offered by newer agents. Fractionating heparin into low-molecular-weight heparins that still retain the pentasaccharide active site provided a way to achieve the same type of therapeutic effect with more predictable dosing and fewer adverse effects. Similarly, a pentasaccharide has been synthesized and marketed as fondaparinux. Although these advances have improved our therapeutic options, continued advances on the horizon raise the question of whether the use of UFH will soon be abandoned. | Fibrin Modulating Agents |
Perception of acoustic stimuli is modulated by the temporal and spectral relationship between sound components. Forward masking experiments show that the perception threshold for a probe tone is significantly impaired by a preceding masker stimulus. Forward masking has been systematically studied at the level of the auditory nerve, cochlear nucleus, inferior colliculus and auditory cortex, but not yet in the superior olivary complex. The medial nucleus of the trapezoid body (MNTB), a principal cell group of the superior olive, plays an essential role in sound localization. The MNTB receives excitatory input from the contralateral cochlear nucleus via the calyces of Held and innervates the ipsilateral lateral and medial superior olives, as well as the superior paraolivary nucleus. Here, we performed single-unit extracellular recordings in the MNTB of rats. Using a forward masking paradigm previously employed in studies of the inferior colliculus and auditory nerve, we determined response thresholds for a 20-ms characteristic frequency pure tone (the probe), and then presented it in conjunction with another tone (the masker) that was varied in intensity, duration, and frequency; we also systematically varied the masker-to-probe delay. Probe response thresholds increased and response magnitudes decreased when a masker was presented. The forward suppression effects were greater when masker level and masker duration were increased, when the masker frequency approached the MNTB unit's characteristic frequency, and as the masker-to-probe delay was shortened. Probe threshold shifts showed an exponential decay as the masker-to-probe delay increased. | Trapezoid Body |
Nurse leaders must use behaviors that foster effective teams. The purpose of this study was to determine the behavioral style by 3,396 nurse leaders who attended leadership and communication continuing education courses. Sessions included identifying behavioral style preferences using the DiSC((R)) Personal Profile Instrument. Of the four behavioral dimensions, Dominance, Influence, Steadiness, and Conscientiousness, 73% scored highest in Dominance and Conscientiousness. The remaining 27% scored highest in preferences for Influence and Steadiness. Nursing leaders may benefit from awareness of differences in behavioral style preferences to enhance communication and team effectiveness, as well as improve satisfaction among team members. | Type B Personality |
The 5-HT(2A) receptor (5-HT(2A)R) plays an important role in various neuropsychiatric disorders, including substance use disorder and schizophrenia. Homodimerization of this receptor has been suggested, but tools that allow direct assessment of the relevance of the 5-HT(2A)R:5-HT(2A)R homodimer in these disorders are necessary. We chemically modified the selective 5-HT(2A)R antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools for probing 5-HT(2A)R:5-HT(2A)R homodimer function. We tested these molecules for 5-HT(2A)R antagonist activity in a cell line stably expressing the functional 5-HT(2A)R and quantified a downstream signaling target, activation (phosphorylation) of extracellular regulated kinases 1/2 (ERK(1/2)), in comparison to in vivo efficacy of altering spontaneous or cocaine-evoked locomotor activity in rats. All of the synthetic compounds inhibited 5-HT-mediated phosphorylation of ERK(1/2) in the cellular signaling assay; the potency of the bivalent ligands varied as a function of linker length, with the intermediate linker lengths being the most potent. The K(i) values for the binding of bivalent ligands to 5-HT(2A)R were only slightly lower than the values for the parent (+)-M100907 compound, but significant selectivity for 5-HT(2A)R over 5-HT(2B)R or 5-HT(2C)R binding was retained. In addition, the 11-atom-linked bivalent 5-HT(2A)R antagonist (2 mg/kg, intraperitoneally) demonstrated efficacy on par with that of (+)-M100907 in inhibiting cocaine-evoked hyperactivity. As we develop further strategies for ligand-evoked receptor assembly and analyses of diverse signaling and functional roles, these novel homobivalent 5-HT(2A)R antagonist ligands will serve as useful in vitro and in vivo probes of 5-HT(2A)R structure and function. | Receptor, Serotonin, 5-HT2A |
The natural alkaloid gramine has attracted significant attention in both academic and industrial circles because of its potential and diverse biological activities, including antiviral, antibacterial, antifungal, anti-inflammatory and antitumor activities; application in therapy for Alzheimer's disease; serotonin-receptor-related activity; insecticidal activity; and application as an algicide. In this review, we focus on the research advances that have been made for gramine-based molecules since their discovery, providing key information on their extraction and separation, chemical synthesis and diverse biological activities. Data regarding their mechanisms of action are also presented. This comprehensive and critical review will serve as a guide for developing more drug candidates based on gramine skeletons. | Alkaloids |
Both sporadic and autosomal dominant forms of Parkinson's disease (PD) have been causally linked to mutations in leucine-rich repeat kinase 2 (LRRK2), a large protein with multiple domains. The kinase domain plays an important role in LRRK2-mediated toxicity. Although a number of investigations have focused on LRRK2 kinase activity, less is known about the GTPase function of LRRK2. The activity of GTPases is regulated by GTPase activating proteins (GAPs) and GTP exchange factors. Here, we identify ArfGAP1 as the first GAP for LRRK2. ArfGAP1 binds LRRK2 predominantly via the WD40 and kinase domain of LRRK2, and it increases LRRK2 GTPase activity and regulates LRRK2 toxicity both in vitro and in vivo in Drosophila melanogaster. Unexpectedly, ArfGAP1 is an LRRK2 kinase substrate whose GAP activity is inhibited by LRRK2, whereas wild-type and G2019S LRRK2 autophosphorylation and kinase activity are significantly reduced in the presence of ArfGAP1. Overexpressed ArfGAP1 exhibits toxicity that is reduced by LRRK2 both in vitro and in vivo. Delta64-ArfGAP1, a dominant-negative ArfGAP1, and shRNA knockdown of ArfGAP1 reduce LRRK2 toxicity. Thus, LRRK2 and ArfGAP1 reciprocally regulate the activity of each other. Our results provide insight into the basic pathobiology of LRRK2 and indicate an important role for the GTPase domain and ArfGAP1 in LRRK2-mediated toxicity. These data suggest that agents targeted toward regulation of LRRK2 GTP hydrolysis might be therapeutic agents for the treatment of PD. | GTPase-Activating Proteins |
An enantioselective two-step route to substituted benzo[a]- and indolo[2,3-a]quinolizidines has been developed. It consists of (i) a stereoselective cyclocondensation of a racemic or prochiral delta-oxo(di)ester with either (S)-(3,4-dimethoxyphenyl)alaninol or (S)-tryptophanol in a process involving a dynamic kinetic resolution and/or the differentiation of enantiotopic or diastereotopic ester groups, and (ii) a subsequent stereocontrolled cyclization on the aromatic ring taking advantage of the masked N-acyl iminium ion present in the resulting oxazolopiperidone lactams. | Quinolizines |
An effort with the goal of discovering single-dose, long-lasting (>6â¯months) injectable contraceptives began using levonorgestrel (LNG)-17-beta esters linked to a sulfonamide function purposed as human carbonic anhydrase II (hCA 2) ligands. One single analog from this first series showed noticeably superior anti-ovulatory activity in murine models, and a subsequent structure-activity relationship (SAR, the relationship between a compound's molecular structure and its biological activity) study based on this compound identified a LNG-phenoxyacetic acid ester analog exhibiting longer anti-ovulatory properties using the murine model at 2 and 4â¯mg dose than medroxyprogesterone acetate (MPA). The same ester function linked to etonogestrel (ENG) furnished a compound which inhibited ovulation at 2â¯mg for 60â¯days, the longest duration of all compounds tested at these doses. By comparison, MPA at the same dose inhibited ovulation for 32â¯days. | Norpregnanes |
INTRODUCTION: The epidermodysplasia verruciformis is a rare, autosomic, recessive, genodermatose characterized by a chronic, disseminated, cutaneous infection with human papillomavirus. The majority of these patients have a genetic or acquired immunodeficiency. PATIENTS AND METHODS: This retrospective study was conducted on the records of all patients who presented in our dermatology department with an epidermodysplasia verruciformis in a 13 years and 6 months period, from January 1st, 1992 to June 30th, 2005. RESULTS: We have collected 45 cases of epidermodysplasia verruciformis. They were aged from 3 to 57 years, with a mean of 24.6 years. The most concerned age bracket was that from zero to 9 years. They were 29 women (64.4%) and 16 men (35.6%). The eruption presented as papules of 2 to 3 mm size, associated with hypochromic, finely squamous macules with the same size. We noted three cases of itching. We found 37.7% of family cases. We observed 14 cases of HIV positive patients and one case of cancer. CONCLUSION: This study confirmed that the epidermodysplasia verruciformis was rare. Genetic factors or immunodeficiency would support the appearance of the disease." | Epidermodysplasia Verruciformis |
The regulatory role of circRNAs in cancer metastasis has become a focused issue in recent years. To date, however, the discovery of novel functional circRNAs and their regulatory mechanisms via binding with RBPs in bladder cancer (BC) are still lacking. Here, we screened out circSLC38A1 based on our sequencing data and followed validation with clinical tissue samples and cell lines. Functional assays showed that circSLC38A1 promoted BC cell invasion in vitro and lung metastasis of mice in vivo. By conducting RNA pull-down, mass spectrum, and RIP assays, circSLC38A1 was found to interact with Interleukin enhancer-binding factor 3 (ILF3), and stabilize ILF3 protein via modulating the ubiquitination process. By integrating our CUT&Tag-seq and RNA-seq data, TGF-beta2 was identified as the functional target of the circSLC38A1-ILF3 complex. In addition, m6A methylation was enriched in circSLC38A1 and contributed to its upregulation. Clinically, circSLC38A1 was identified in serum exosomes of BC patients and could distinguish BC patients from healthy individuals with a diagnostic accuracy of 0.878. Thus, our study revealed an essential role and clinical significance of circSLC38A1 in BC via activating the transcription of TGF-beta2 in an ILF3-dependent manner, extending the understanding of the importance of circRNA-mediated transcriptional regulation in BC metastasis." | Transforming Growth Factor beta2 |
We communicate a versatile synthetic approach to C-3 disubstituted 2-oxa-5-azabicyclo[2.2.1]heptanes as carbon-atom bridged morpholines, starting with 4R-hydroxy-l-proline as a chiron. Attaching an acetic acid moiety on the C-3 carbon of the 2-oxa-5-azabicyclo[2.2.1]heptane core reveals the framework of an embedded gamma-amino butyric acid (GABA). Variations in the nature of the substituent on the tertiary C-3 atom with different alkyls or aryls led to backbone-constrained analogues of the U.S. Food and Drug Administration-approved drugs baclofen and pregabalin. | Heptanes |
OBJECTIVES: To investigate the effects of magnesium sulphate on succinylcholine-induced fasciculation in patients during the induction of general anaesthesia. METHODS: The double-blind randomised clinical trial was conducted in 2012 at Tohid and Besat Hospitals in Sanandaj, Iran, on patients who were candidates for surgery under general anaesthesia. Patients were selected and divided into two equal groups of cases and controls using block randomisation. The cases received magnesium sulphate, while the controls received normal saline. SPSS 18 was used for statistical analysis. RESULTS: Of the 100 subjects in the study, 49 (49%) were men and 51 (51%) were women (p < 0.072). The mean age of the two groups were 37.5 +/- 12.2 years and 37.7 +/- 12 years (p < 0.9). There was significant difference between the two groups in terms of the degree of fasciculation and muscle fasciculation (p< 0.001). The difference between potassium levels in the two groups was not significant before anaesthesia (p > 0.05), but it was significant after anaesthesia (p < 0.001). CONCLUSIONS: Magnesium sulphate can prevent and reduce the degree of fasciculation after anaesthesia. Therefore it can be used to prevent fasciculation. | Fasciculation |
Following topical administration to albino rabbits, bunolol hydrochloride, a beta 1- and beta 2-adrenoceptor antagonist, was rapidly absorbed and distributed in ocular tissues, and transformed intraocularly to a single metabolite, dihydrobunolol. The half-life of bunolol was approximately 1.26 hours in the aqueous humor and 1.63 hours in the ciliary body. There was no significant accumulation of bunolol during a four-day period of twice-daily dosing. Most of the drug was excreted in the urine following ocular or intravenous administration. | Bunolol |
Oxynitrilase containing 2-thioFAD [C(2) = S] in place of FAD exhibits catalytic activity similar to that of native enzyme. Reaction of methyl methanethiolsulfonate with 2-thioFAD bound to oxynitrilase results in the formation of the corresponding flavin disulfide [C(2)-SSCH3]. Normal flavin [C(2) = O] is formed by reacting 2-thioFAD oxynitrilase with m-chloroperoxybenzoate or H2O2. Both reactions proceed via a spectrally detectable flavin 2-S-oxide intermediate [C(2) = S+-O-], but sizable amounts of this intermediate accumulate only in the m-chloroperoxybenzoate reaction (about 40%). While similar reactions have been reported with free 2-thioflavin, kinetic and other data indicate that the oxynitrilase reactions occur with intact enzyme. This shows that the 2-position of the pyrimidine ring in the bound coenzyme is accessible to solvent. The data are consistent with previous studies on the reaction of peroxides with oxynitrilase-bound 5-deazaFAD which show that the pyrimidine ring is accessible at position 4. Analogous studies indicate that the pyrimidine ring is buried in the case of flavin bound to lactate oxidase, since the data indicate that both positions 2 and 4 are inaccessible to solvent. | Flavin-Adenine Dinucleotide |
As the resident immune cells in the central nervous system (CNS), microglia orchestrate immune responses and dynamically sculpt neural circuits in the CNS. Microglial dysfunction and mutations of microglia-specific genes have been implicated in many diseases of the CNS. Developing effective and safe vehicles for transgene delivery into microglia will facilitate the studies of microglia biology and microglia-associated disease mechanisms. Here, we report the discovery of adeno-associated virus (AAV) variants that mediate efficient in vitro and in vivo microglial transduction via directed evolution of the AAV capsid protein. These AAV-cMG and AAV-MG variants are capable of delivering various genetic payloads into microglia with high efficiency, and enable sufficient transgene expression to support fluorescent labeling, Ca(2+) and neurotransmitter imaging and genome editing in microglia in vivo. Furthermore, single-cell RNA sequencing shows that the AAV-MG variants mediate in vivo transgene delivery without inducing microglia immune activation. These AAV variants should facilitate the use of various genetically encoded sensors and effectors in the study of microglia-related biology. | Gene Transfer Techniques |
OBJECTIVE: We aimed to present the radiographic and functional outcomes of anatomical reduction and fixation of anterior inferior tibiofibular ligament (AITFL) avulsion fracture without syndesmotic screw fixation in rotational ankle fracture. METHODS: We retrospectively reviewed 66 consecutive patients with displaced malleolar fracture combined with AITFL avulsion fracture. We performed reduction and fixation for the AITFL avulsion fracture when syndesmotic instability was present after malleolar fracture fixation. A syndesmotic screw was inserted only when residual syndesmotic instability was present even after AITFL avulsion fracture fixation. The radiographic parameters were compared with those of the contralateral uninjured ankles. The American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scores were assessed 1 year postoperatively. RESULTS: Fifty-four patients showed syndesmotic instability after malleolar fracture fixation and underwent reduction and fixation for AITFL avulsion fracture. Among them, 45 (83.3%) patients achieved syndesmotic stability, while 9 (16.7%) patients with residual syndesmotic instability needed additional syndesmotic screw fixation. The postoperative radiographic parameters were not significantly different from those of the uninjured ankles. The mean AOFAS score was 94. CONCLUSION: Reduction and fixation of AITFL avulsion fracture obviated the need for syndesmotic screw fixation in more than 80% of patients with AITFL avulsion fracture and syndesmotic instability. | Fractures, Avulsion |
The three major causes of anemia in neonates are blood loss, decreased red blood cell production, and increased degradation of erythrocytes. Establishing the cause of anemia in a neonate born prematurely can be challenging. Clinically, fetomaternal hemorrhage (FMH) can be difficult to diagnose-the condition often presents only after the manifestation of severe fetal anemia. FMH can be confirmed by determining the fetal hemoglobin F fraction in the mother, which is traditionally performed using the Kleihauer-Betke test (KBT). Herein, we present a case study of a newborn baby boy of Dutch ethnicity with massive FMH and negative KBT result. The KBT result appeared to be false-negative due to AO antagonism. However, the results of an additional marker alpha-fetoprotein (AFP) test confirmed the diagnosis of massive FMH. Therefore, measuring AFP in maternal blood can be helpful in confirming FMH in unexplained anemia of the neonate. | Fetomaternal Transfusion |
One-step direct patterning of high definition conductive tracks in textiles is realized through laser direct writing in combination with a silver organometallic ink developed in-house. Photoreduction, nano-crystallization, and sintering are accomplished in one pass under the irradiation of a CW green laser light (lambda = 532 nm) at moderate intensities (I >/= 95 mW/mm(2)). By tailoring the surface tension and viscosity of the ink, high-definition conductive tracks are formed in weft-knitted polyester-Spandex composite fabrics, well-following the laser's profile with negligible coffee stain effect. Length resistance as low as 4 Omega/cm is measured and anisotropy of the gauge factor as high as 25 is achieved. The metallized fabric exhibits reversible and hysteresis-free electromechanical responses subject to high strains. Durability assessment qualifies that the as-metallized strain sensors are able to sustain their performance for over 5000 stretch/release cycles, demonstrating its potential applications in biaxial strain sensing and interactive smart textiles. | Polyurethanes |
BACKGROUND: Osteoarthritis (OA) is an intractable degenerative disease of the whole joint, which is characterized by synovitis inflammation, cartilage damage, and chronic pain. Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) performs an important role in OA. PURPOSE: We aim to investigate avicularin to protect cartilage extracellular matrix degradation (ECM) and suppresses inflammation both in rat and human chondrocytes. METHODS: 5-Ethynyl-2'-deoxyuridine (EdU) staining, Quantitative real-time PCR, TRAF6 plasmid transfection, Western blot, Measurement of nitric oxide (NO), ROS detection and Immunofluorescence were utilized in vitro. micro-CT scanning, Safranin O-Fast Green, toluidine blue and immunohistochemistry staining were performed in vivo. RESULTS: In vitro, avicularin attenuates the degradation of ECM and inflammation, which could inhibit the activation of TRAF6/MAPK pathway via targeting TRAF6. Increased MMP3 and MMP13 expressions and decreased Aggrecan and Collagen âÂ
¡ levels were observed in anterior cruciate ligament transection (ACLT) induced osteoarthritic rats. Interestingly, intra-articular injection of avicularin attenuates this phenomenon. CONCLUSIONS: Taken together, our results indicate that avicularin suppresses cartilage extracellular matrix degradation and inflammation via TRAF6/MAPK activation by targeting TRAF6. These observations identify TRAF6 as a relevant drug target, and avicularin may as a potential therapeutic agent in osteoarthritis." | TNF Receptor-Associated Factor 6 |
The discovery of the RNA self-splicing group I intron provided the first demonstration that not all enzymes are proteins. Here we report the X-ray crystal structure (3.1-A resolution) of a complete group I bacterial intron in complex with both the 5'- and the 3'-exons. This complex corresponds to the splicing intermediate before the exon ligation step. It reveals how the intron uses structurally unprecedented RNA motifs to select the 5'- and 3'-splice sites. The 5'-exon's 3'-OH is positioned for inline nucleophilic attack on the conformationally constrained scissile phosphate at the intron-3'-exon junction. Six phosphates from three disparate RNA strands converge to coordinate two metal ions that are asymmetrically positioned on opposing sides of the reactive phosphate. This structure represents the first splicing complex to include a complete intron, both exons and an organized active site occupied with metal ions. | Azoarcus |
Cognitive and mood changes are frequently mentioned as complaints before, during and after menopausal transition. There is substantial biological evidence for such associations to occur, as there are many mechanisms through which oestrogens can affect the brain: by regulating metabolism, increasing cerebral blood flow and dendritic outgrowth, by acting on nerve growth factors through the co-localisation of receptors via neurotransmitter synthesis and turnover and many more. However, the evidence for objective and longer-term changes in cognitive function and mental health over the menopausal transition and beyond is less clear. While hormone treatment (HT) including oestrogens could potentially reverse these psychological issues, the evidence of long-term benefit is also inconclusive. However, for women with severe menopausal complaints, and particularly for those who undergo early menopause, including women with premature ovarian insufficiency, personalised HT at least up to the natural age of menopause around 50 should be considered, which is probably safe up to 10 years of treatment, unless contraindicated. This paper reviews the evidence for changes in psychological health related to menopausal transition and HTs. | Menopause |
The application of a novel modified planetary mill, with the capacity to process 48 samples in parallel, to the rapid screening of pharmaceutical cocrystals via grinding is demonstrated for carbamazepine/saccharin, caffeine/oxalic acid, and caffeine/maleic acid cocrystals. Milling is performed directly in standard glass vials therefore no vessel decontamination is needed or sample loss occurs. Furthermore, successive sample processing can be employed without the need for additional material, making the system suitable for screening compounds of limited availability. Use of the system in an automated screening workflow of dispensing, milling, and analysis with high-throughput is also discussed. | Pharmaceutical Vehicles |
This study shows that, in a population of microstrabic patients (N = 76), a regain of a normal stereoscopy was possible in 19.6 of the cases (14 cases). Of these patients, 14 were hyperopic. With the full hyperopic correction, the angle of deviation on the alternate cover test was 0.45 PD (range: 0 to 3 PD). Without correction the deviation increased to between 3 PD and 10 PD (mean: 6.3 PD). Ten patients presented an anisometropia between 0.75 D to 2.50 D. (mean: 1.4 D). All anisometropic patients were hyperopic and hyperopia was higher in the dominated eye in all these cases. These results demonstrate the interest of the definition of microtropia as a specific strabismological entity, which can be congenital or acquired and be influenced by accommodative factors. The incidence of anisometropia, as a consequence rather than a cause of the pathological dominance is discussed. | Hyperopia |
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