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pubmed_1086_10549 | BACKGROUND
To report our patient experience with squamous cell carcinoma of the anal margin and to evaluate the prognostic factors influencing outcome.
MATERIALS AND METHODS
Between 1980 and 2001, 26 patients with anal margin squamous cell carcinoma were treated in Lyon-Sud: 7 T1, 14 T2, 4 T3, and 1 T4 with 20 N0, 3 N1, and 3 N2. The anal canal was invaded in five patients. Treatment consisted of definitive external irradiation in 14 patients and adjuvant irradiation (after a local excision) in 12 patients. External irradiation was combined with chemotherapy in seven patients, brachytherapy in four patients, and both brachytherapy and chemotherapy in one patient.
RESULTS
The local control rate was initially 61.4%, and it was 80.8% after salvage treatment. The 5-year overall and specific survival rates were 71 and 88.3%, respectively. Three factors correlated with specific survival: cell differentiation (P=0.038) and T (P=0.001) and N category (P=0.0005). A salvage abdominoperineal resection was successfully employed in five of seven local recurrences. Four grade 3 and two grade 4 toxicities were observed. Sphincter preservation was possible in 66% of alive patients.
CONCLUSION
Our results confirm the dominating place of definitive irradiation and radiochemotherapy in the treatment of anal margin squamous cell carcinoma. The indications for abdominoperineal resection must be limited to local relapse. The prognosis of squamous cell carcinoma is correlated to T and N staging and cell differentiation. | 10.1007/s00384-006-0114-9 |
pubmed_325_2355 | BACKGROUND
Quantitative microbial risk assessment (QMRA), the current method of choice for evaluating human health risks associated with disease-causing microorganisms, is often constrained by issues such as availability of required data, and inability to incorporate the multitude of factors influencing risk. Bayesian networks (BNs), with their ability to handle data paucity, combine quantitative and qualitative information including expert opinions, and ability to offer a systems approach to characterisation of complexity, are increasingly recognised as a powerful, flexible tool that overcomes these limitations.
OBJECTIVES
We present a QMRA expressed as a Bayesian network (BN) in a wastewater reuse context, with the objective of demonstrating the utility of the BN method in health risk assessments, particularly for evaluating a range of exposure and risk mitigation scenarios. As a case study, we examine the risk of norovirus infection associated with wastewater-irrigated lettuce.
METHODS
A Bayesian network was developed following a QMRA approach, using published data, and reviewed by domain experts using a participatory process.
DISCUSSION
Employment of a BN facilitated rapid scenario evaluations, risk minimisation, and predictive comparisons. The BN supported exploration of conditions required for optimal outcomes, as well as investigation of the effect on the reporting nodes of changes in 'upstream' conditions. A significant finding was the indication that if maximum post-treatment risk mitigation measures were implemented, there was a high probability (0.84) of a low risk of infection regardless of fluctuations in other variables, including norovirus concentration in treated wastewater.
CONCLUSION
BNs are useful in situations where insufficient empirical data exist to satisfy QMRA requirements and they are exceptionally suited to the integration of risk assessment and risk management in the QMRA context. They allow a comprehensive visual appraisal of major influences in exposure pathways, and rapid interactive risk assessment in multifaceted water reuse scenarios. | 10.1016/j.scitotenv.2015.10.030 |
pubmed_197_9929 | Conjugated oligoelectrolytes (COEs) are being introduced into a variety of optical and electronic technologies, yet the dependence of their properties as a function of molecular structure remains poorly understood. In response, we designed, synthesized, and examined a new tetracationic COE, namely, 1,4-bis{9',9'-bis[6''-(N,N,N-trimethylammonium)hexyl]-2'-fluorenyl}-2,5-bis(trifluoromethyl)benzene tetrabromide (FPF-F6), which contains bulky electron-withdrawing trifluoromethyl groups, and compared its properties with the unsubstituted counterpart 1,4-bis{9',9'-bis[6''-(N,N,N-trimethylammonium)hexyl]-2'-fluorenyl}benzene tetrabromide (FPF). The ground-state geometry of FPF-F6 is primarily twisted with little electronic communication between the aromatic units, as confirmed by single-crystal X-ray diffraction studies of the neutral precursor. However, absorption and photoluminescence spectroscopies reveal that the excited state of FPF-F6 displays strong intramolecular charge-transfer characteristics. Solution AFM in aqueous media shows that introduction of trifluoromethyl groups changes the size and aspect ratio of supramolecular aggregates that are brought together as a result of hydrophobic interactions. Furthermore, addition of ssDNA to FPF-F6 leads to interoligoelectrolyte complexes wherein the backbone is more planar; the environment the chromophore experiences under these conditions is also considerably less polar. These findings provide considerable insight into the complex photophysics of electronically conjugated materials in aqueous media. | 10.1002/chem.201000885 |
pubmed_1011_12869 | The mouse hepatoma cell (Hepa-1) in tissue culture has been shown to synthesize and secrete three electrophoretically distinct transferrins. Each of these forms of transferrin has a molecular weight of 77,000, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The concentration of each form is indicated by its staining intensity, which is highest in the form with the fastest mobility and lowest in the form with the slowest mobility. The relative rate of transferrin synthesis has been determined in log-phase and stationary-phase cells; the data indicate that the relative rate of synthesis increases twofold in stationary-phase cells. When the incorporation of [3H]leucine into transferrin reaches steady state, the rate of secretion is equal to the rate of synthesis; the rate of secretion also increases twofold in stationary-phase cells. Our studies also show that transferrin synthesis accounts for 0.98% of the total protein synthesis in log-phase cells and for 1.8% in stationary-phase cells. This is the level of synthesis that has been determined by in vivo studies. We conclude that after continuous culture for several years these hepatoma cells have maintained one of the characteristics of the differentiated liver cell, namely, the ability to synthesize and secrete transferrin. | 10.1111/j.1432-0436.1978.tb00956.x |
pubmed_414_1488 | AIM
To explore the mechanism of topiramate-induced weight loss in epilepsy children by monitoring metabolism indices.
METHODS
Children with epilepsy were treated with topiramate at their first clinical visit. Metabolism indices including body mass index (BMI) and its SD scores, leptin, adiponectin, leptin/adiponectin (L/A), lipid profile-insulin and Homeostasis Model Assessments (HOMA) index were collected before and after treatment.
RESULTS
Topiramate treatment significantly reduced L/A (t = 2.156, p = 0.031), and markedly increased the serum level of adiponectin (t = 3.124, p = 0.002). Moreover, there were no relationships between the metabolism indices and dosages of topiramate (p > 0.05).
CONCLUSION
Our studies find that topiramate treatment in epilepsy children increases energy metabolism, resulting in weight loss. It has been demonstrated that adiponectin play a significant role in metabolic regulations. | 10.1111/j.1651-2227.2009.01349.x |
pubmed_165_6079 | Four cases of patients who described an unpleasant subjective experience of weakness and reduced muscle tone during treatment with clozapine are presented. An exacerbation of muscular dystrophy during clozapine treatment is also described. It is hypothesized that these adverse effects are related to the muscle relaxant properties of clozapine. The differential diagnosis of sedation, fatigue, asthenia, and reduced muscle tone is discussed. | 10.3109/10401239609147758 |
pubmed_916_14840 | Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies. | pubmed_916_14840 |
pubmed_1021_7621 | The authors sought to determine the analgesic activity of clomipramine (CMP) versus placebo, efficacy and side-effects according to the time of administration, long term clinical results and the relationship between plasma levels and analgesic effect. This double-blind randomised trial involved the infusion of 250 ml of glucose solution morning and evening versus placebo. CMP was administered at progressive doses for 8 days (maximum dosage 75 mg), either in the morning at 8 a.m. or in the evening at 6 p.m. Sixty eight patients accepted to be treated, all suffering from low back pain with or without sciatica. Maintenance treatment at the dose of 75 mg/day was then administered. CMP had a statistically significant analgesic action independent (rapidity of action) of its antidepressant activity. CMP was more effective and better tolerated (sedative and tranquilizer effect) in the evening. Long term results were poor (75% of cases). There was no link between plasma levels and clinical response. The authors noted that the analgesic activity of CMP was rapid, but for a duration limited to the short term and that this efficacy compared with the quite good results obtained with the placebo could be explained by a possible methodological bias (patients hospitalised and treated by intravenous infusions). The finding that CMP was better tolerated in the evening, without any loss of efficacy, is a positive feature (chronotherapeutic trial). Poor long term results could be partially explained by side-effects (66%). There was no relationship between analgesic effect and plasma levels. | pubmed_1021_7621 |
pubmed_629_13029 | The present study utilized microarray technology as a tool to elucidate the molecular signatures of soy-derived phytochemicals in the human androgen-responsive prostate cancer cell line LNCaP. Global gene expression pattern analysis of LNCaP cells exposed to 0, 1, 5, or 25 microM of the soy-derived phytochemicals equol and daidzein were conducted and compared. The data were further compared with previously generated data from exposure of LNCaP cells to the same doses of genistein, a soy isoflavone. Multidimensional scaling (MDS) analyses of the expression patterns suggest that these compounds exerted differential effects on gene expression in LNCaP cells. Further examination of specific gene changes revealed that these compounds differentially modulated genes in multiple cellular pathways, including the cell-cycle pathway genes. However, the three compounds also exerted similar effect on genes belonging to several other important cellular pathways. A universal effect of the three compounds on androgen-responsive genes, IGF-1 pathway gene, and MAP kinase-related pathway gene was observed. These results provide the foundation for establishing molecular signatures for equol, daidzein, and genistein. Moreover, these results also allow for the identification of candidate mechanism(s) by which soy phytochemicals and soy may act in prostate cancer cells. | 10.1002/mc.20247 |
pubmed_671_12222 | The effects of inhibitors of mitochondrial ATP synthesis and the calcium ionophore, A23187, on the capping of surface immunoglobulin, concanavalin A receptors and theta antigen on mouse spleen or thymus cells have been examined. (i) For all of these capping ligands and inhibitors, the cellular ATP level must be above 80% of the normal level in resting lymphocytes for 90% of maximal cap formation to occur. Below 50% of the normal ATP level, less than 10% of maximal capping occurs. There is, therefore, a common dependence for all three capping systems on the cellular ATP level, irrespective of the metabolic inhibitor used. (ii) Inhibition of cap formation by A23187 follows the same profile for ATP dependence as the mitochondrial inhibitors, but in contrast to those inhibitors, A23187 requires extracellular calcium to decrease the ATP level and inhibit capping. Other agents can affect cap formation without reducing the ATP level. For example, concanavalin A inhibits its own cap formation and cytochalasin B reduces the rate of cap formation at concentrations which do not alter the cellular ATP level. (iii) From these and other data we conclude that there are cellular functions essential for cap formation, other than the maintenance of ionic gradients, that require a high concentration of cellular ATP. The possibility that high levels of ATP are required for the function of the cytoskeleton in lymphocytes is discussed. | 10.1016/0005-2736(80)90334-x |
pubmed_484_2445 | While in bone marrow allogeneic transplantation the infusion of high doses of progenitor stem cells has a favourable impact on outcome, due to a faster hematopoietic and immune recovery, in the peripheral blood allo-setting the infusion of a high number of CD34 cells increases the risk of extensive chronic graft vs. host disease (cGVHD). This higher incidence of extensive cGVHD has an adverse impact on outcome due to a higher transplant related mortality, specially among patients receiving T-cell depleted allogeneic transplantation with myeloablative conditioning. By contrast, patients undergoing reduced intensity conditioning regimen may benefit from increasing higher CD34 + cell doses, especially those categorized as high risk according to disease status at transplant. Thus, the source of progenitors cells, type of conditioning and GVHD prophylaxis, among other factors, may influence the effect of the progenitor cell dose on outcome after allogeneic transplant. | 10.1080/10428190400014900 |
pubmed_656_1923 | Most reproductive biologists who study female gametes will agree with the 16th century anatomist William Harvey's doctrine: 'Ex Ovo Omnia'. This phrase, which literally translates to 'everything from the egg', recognizes the centrality of the egg in animal development. Eggs are most impressive cells, capable of supporting development of an entirely new organism following fertilization or parthenogenetic activation. Not so uniformly embraced in the field of reproductive biology is the nomenclature used to refer to the female germ cell. What is an oocyte? What is an egg? Are these terms the same, different, interchangeable? Here we provide functional definitions of the oocyte and egg, and how they can be used in the context of mammalian gamete biology and beyond. | 10.1093/molehr/gaaa066 |
pubmed_923_5731 | Membrane fusion mediated by interaction of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein with the human CD4 molecule generally requires that the CD4 be expressed on a human cell. The failure of murine or simian cells expressing human CD4 to form syncytia upon mixing with cells expressing envelope glycoprotein could not be corrected by expression of both molecules at extremely high surface levels using vaccinia virus expression vectors. Video fluorescence microscopic analysis of fluorescent dye transfer between fusing cells indicated that the block occurred at the level of membrane fusion between individual pairs of cells. To gain insight into the basis for this fusion block, we tested the ability of fluorescent probe cells expressing envelope glycoprotein to fuse with transient animal x human hybrid giant cells expressing human CD4. The hybrid giant cells were generated either by low-pH-induced fusion of vaccinia-infected cells or by CD4/HIV-1 envelope glycoprotein-mediated cell fusion. We observed that envelope glycoprotein-expressing probe cells efficiently fused with CD4-expressing animal x human hybrid giant cells, independent of whether the CD4 was originally expressed on the animal or on the human cell. Fusion did not occur with CD4-expressing giant cells derived from animal cells alone. These results indicate that the fusion block is not due to dominant inhibitory components in the animal cell. Rather, they suggest that human cells contain an additional component(s) which, when transferred to the CD4-bearing animal cell, confers the ability to undergo membrane fusion mediated by the HIV-1 envelope glycoprotein. | 10.1006/viro.1993.1151 |
pubmed_183_20466 | Cathepsins (CTSs) are peptidases that have biological roles in degrading extracellular matrix, catabolism of intracellular proteins, and processing of pro-hormones. Cystatin C (CST3) is a secreted inhibitor of lysosomal cysteine proteases cathepsin B (CTSB) and CTSL. Our working hypothesis is that cathepsins and cystatins play important roles in implantation and placentation in sheep. Expression of CTSB, CTSD, CTSH, CTSK, CTSL, CTSS, CTSZ, and CST3 mRNAs was detected in ovine uteroplacental tissues with distinct temporal and/or spatial expression patterns between Days 40 and 120 of pregnancy. Of particular note, CTSB, CTSD, and CTSZ mRNAs were predominantly detected in the chorion of the placenta and were more abundant in the placentomes than the intercaruncular endometria. CTSL and CST3 mRNAs were abundant in the endometrial epithelia and chorion, whereas CTSK, CTSS and CTSH mRNAs were most abundant in the stratum compactum stroma of the intercaruncular endometrium. Consistent with localisation of mRNAs, immunoreactive CTSL and CST3 proteins were mainly observed in the intercaruncular endometrial glands and intercotyledonary placenta during later pregnancy. These results support the working hypothesis that CTS and CST3 in uteroplacental tissues are involved in endometrial remodelling and placentation in sheep. | 10.1016/j.placenta.2007.04.004 |
pubmed_351_4545 | Ninety-four urinary bladder cancer patients with locally advanced, recurrent or metastatic urinary bladder cancer were treated with external radiotherapy with the aim of palliating local disease. Conventional radical radiotherapy was inappropriate because of extensive disease, poor general condition or old age of the patients. The palliative course studied was 30 Gy (mid-point dose) in six fractions, two fractions a week. Eighty-two patients (87%) tolerated treatment as planned. Forty patients (43%) had complete palliation of initial symptoms. Thirty-eight patients (40%) had initial local control of the tumour, which was lasting in 25 cases (26%). Median disease-specific survival of the patients was 13.3 months. The estimated five-year survival was 13% and survival from bladder cancer 27%. | 10.3109/02841869209088288 |
pubmed_792_7965 | BACKGROUND
Ciprofloxacin (CIP) is a fluoroquinolone-antibiotic with a high antimicrobial activity against all pathogens causing bacterial endophthalmitis. After intravitreal injection, however, elimination half-life of this antibiotic is only 2.2 hours. To prolong intraocular bioavailability this study was performed to incorporate CIP into liposomes and to determine its clearance from the vitreous after intravitreal injection.
MATERIALS AND METHODS
CIP was incorporated into multilamellar vesicles by mechanical dispersion. 0.1 ml of this suspension (equiv. 273.6 micrograms CIP) was injected into the midvitreous of pigmented rabbit eyes (Chinchilla-bastards). One day, 3 and 14 days after the injection intravitreal concentration of CIP was determined by means of high-pressure-liquid-chromatography after dissolution of the liposomes by ultrasound. At the same intervals serum concentration of the antibiotic was examined as well.
RESULTS
Within 24 hours intravitreal concentration fell to 18.0 micrograms/ml. Three days after the injection the concentration of CIP was 6.9 micrograms/ml. This is still above the minimal inhibitory concentration (MIC90) of the most common ocular pathogens. At 14 days CIP was not detectable in the vitreous any more. The serum concentration was between 0.04 microgram/ml and 0.07 microgram/ml. 3 and 14 days after injection no CIP could be detected.
CONCLUSIONS
This study shows that the incorporation of CIP into liposomes can be achieved in sufficient doses by mechanical dispersion method. After intravitreal application the bioavailability of the antibiotic can be markedly improved. Even after 3 days the intravitreal levels were above the MIC90 of the most common endophthalmitis pathogens. | 10.1055/s-2008-1034989 |
pubmed_975_13097 | Serotonergic agents (uptake inhibitors, receptor ligands) cause significant craniofacial malformations in cultured mouse embryos suggesting that 5-hydroxytryptamine (serotonin) (5-HT) may be an important regulator of craniofacial development. To determine whether serotonergic regulation of cell migration might underly some of these effects, cranial neural crest (NC) explants from embryonic day 9 (E9) (plug day = E1) mouse embryos or dissociated mandibular mesenchyme cells (derived from NC) from E12 embryos were placed in a modified Boyden chamber to measure effects of serotonergic agents on cell migration. A dose-dependent effect of 5-HT on the migration of highly motile cranial NC cells was demonstrated, such that low concentrations of 5-HT stimulated migration, whereas this effect was progressively lost as the dose of 5-HT was increased. In contrast, most concentrations of 5-HT inhibited migration of less motile, mandibular mesenchyme cells. To investigate the possible involvement of specific 5-HT receptors in the stimulation of NC migration, several 5-HT subtype-selective antagonists were used to block the effects of the most stimulatory dose of 5-HT (0.01 microM). Only NAN-190 (a 5-HT1A antagonist) inhibited the effect of 5-HT, suggesting involvement of this receptor. Further evidence was obtained by using immunohistochemistry with 5-HT receptor antibodies, which revealed expression of the 5-HT1A receptor but not other subtypes by migrating NC cells in both embryos and cranial NC explants. These results suggest that by activating appropriate receptors 5-HT may regulate migration of cranial NC cells and their mesenchymal derivatives in the mouse embryo. | 10.1073/pnas.92.16.7182 |
pubmed_43_4117 | It is of great interest and potential to discover causal relationships between pairs of exposures and outcomes using genetic variants as instrumental variables (IVs) to deal with hidden confounding in observational studies. Two most popular approaches are Mendelian randomization (MR), which usually use independent genetic variants/SNPs across the genome, and transcriptome-wide association studies (TWAS) (or their generalizations) using cis-SNPs local to a gene (or some genome-wide and likely dependent SNPs), as IVs. In spite of their many promising applications, both approaches face a major challenge: the validity of their causal conclusions depends on three critical assumptions on valid IVs, and more generally on other modeling assumptions, which however may not hold in practice. The most likely as well as challenging situation is due to the wide-spread horizontal pleiotropy, leading to two of the three IV assumptions being violated and thus to biased statistical inference. More generally, we'd like to conduct a goodness-of-fit (GOF) test to check the model being used. Although some methods have been proposed as being robust to various degrees to the violation of some modeling assumptions, they often give different and even conflicting results due to their own modeling assumptions and possibly lower statistical efficiency, imposing difficulties to the practitioner in choosing and interpreting varying results across different methods. Hence, it would help to directly test whether any assumption is violated or not. In particular, there is a lack of such tests for TWAS. We propose a new and general GOF test, called TEDE (TEsting Direct Effects), applicable to both correlated and independent SNPs/IVs (as commonly used in TWAS and MR respectively). Through simulation studies and real data examples, we demonstrate high statistical power and advantages of our new method, while confirming the frequent violation of modeling (including valid IV) assumptions in practice and thus the importance of model checking by applying such a test in MR/TWAS analysis. | 10.1371/journal.pcbi.1009266 |
pubmed_1042_20190 | Mesoionic carbenes have found wide use as components of homogeneous catalysts. Recent discoveries have, however, shown that metal complexes of such ligands also have huge potential in photochemical research and in the activation of small molecules. We present here three ReI complexes with mesoionic pyridyl-carbene ligands. The complexes display reduction steps which were investigated via UV-vis-NIR-IR spectro-electrochemistry, and these results point toward an EC mechanism. The ReI compounds emit in the visible range in solution at room temperature with excited state lifetimes that are dependent on the substituents of the mesoionic carbenes. These complexes are also potent electrocatalysts for the selective reduction of CO2 to CO. Whereas the substituents on the carbenes have no influence on the reduction potentials, the electrocatalytic efficiency is strongly dependent on the substituents. This fact is likely a result of catalyst instability. The results presented here thus introduce mesoionic carbenes as new potent ligands for the generation of emissive ReI complexes and for electrocatalytic CO2 reduction. | 10.1021/acs.inorgchem.9b02591 |
pubmed_705_17595 | The renin-angiotensin system has a pivotal role in hypertension. The Tsukuba hypertensive mouse (THM; a transgenic mouse carrying human genes for both renin and angiotensinogen) was generated to allow further examination of the renin-angiotensin system in a variety of pathologic conditions. We evaluated the development of renal lesions in these mice and in controls by morphometric, immunohistochemical and ultrastructural methods. Blood pressure was significantly higher in THM than in control mice; 1 year after birth, it was approximately 40 mmHg higher. The kidney-to-body weight ratio was also higher in THM than in control. Morphometrical analysis revealed that the glomerular sclerosis index was significantly elevated in THM with 10% of the glomeruli sclerotic at 18 months. The grade of vascular lesion and the frequency of fibronoid arteritis of the kidney exhibited the same tendency as the glomerular sclerosis index. Murine renin was located exclusively in the juxtaglomerular apparatus, whereas human renin was expressed not only in the juxtaglomerular apparatus, but also in periarteriolar smooth muscle cells and in mesangial and epithelial cells of the glomeruli. Light and electron microscopy revealed significant fibrinoid arteritis of the kidney in THM and also "onion skinning", both pathognomonic for malignant nephrosclerosis. THM may be an excellent model of human malignant hypertension. | 10.1007/s004280050152 |
pubmed_476_3365 | The bacterial pathogen Shigella flexneri causes 270 million cases of bacillary dysentery worldwide every year, resulting in more than 200,000 deaths. S. flexneri pathogenic properties rely on its ability to invade epithelial cells and spread from cell to cell within the colonic epithelium. This dissemination process relies on actin-based motility in the cytosol of infected cells and formation of membrane protrusions that project into adjacent cells and resolve into double-membrane vacuoles (DMVs) from which the pathogen escapes, thereby achieving cell-to-cell spread. S. flexneri dissemination is facilitated by the type 3 secretion system (T3SS) through poorly understood mechanisms. Here, we show that the T3SS effector IpgD facilitates the resolution of membrane protrusions into DMVs during S. flexneri dissemination. The phosphatidylinositol 4-phosphatase activity of IpgD decreases PtdIns(4,5)P2 levels in membrane protrusions, thereby counteracting de novo cortical actin formation in protrusions, a process that restricts the resolution of protrusions into DMVs. Finally, using an infant rabbit model of shigellosis, we show that IpgD is required for efficient cell-to-cell spread in vivo and contributes to the severity of dysentery. | 10.1371/journal.ppat.1010324 |
pubmed_144_880 | The neural mechanisms controlling sexual behavior are sexually differentiated by perinatal actions of gonadal hormones. We recently observed using female mice deficient in alpha-fetoprotein (AFP-KO) and which lack the protective actions of AFP against maternal estrogens, that exposure to prenatal estrogens completely defeminized their potential to show lordosis behavior in adulthood. Therefore, we determined here whether mate preferences were also affected in female AFP-KO mice. We observed a robust preference for an estrous female over an intact male in female AFP-KO mice, which were ovariectomized in adulthood and subsequently treated with estradiol and progesterone, whereas similarly treated WT females preferred the intact male over the estrous female. Gonadally intact WT males preferred the estrous female over the male, but only when visual cues were blocked by placing stimulus animals behind opaque partitions. Furthermore, when given the choice between an intact male and a castrated male, WT females preferred the intact male, whereas AFP-KO females showed no preference. Finally when given the choice between an estrous female and an ovariectomized female, WT males preferred the estrous female whereas AFP-KO females preferred the ovariectomized female or showed no preference depending on whether they could see the stimulus animals or not. Taken together, when AFP-KO females are tested under estrous conditions, they do not show any male-directed preferences, indicating a reduced sexual motivation to seek out the male in these females. However, they do not completely resemble males in their mate preferences suggesting that the male-typical pattern of mate preferences is not solely organized by prenatal estrogens. | 10.1016/j.yhbeh.2010.10.012 |
pubmed_77_9102 | This study investigates the causes of the apparent differences between the optical diffraction pattern of a micrograph of a Tobacco Mosaic Virus (TMV) particle, the optical diffraction pattern of a ten-fold photographically averaged image, and the computed diffraction pattern of the original micrograph. Peak intensities along the layer lines in the transform of the averaged image appear to be quite unlike those in the diffraction pattern of the original micrograph, and the diffraction intensities for the averaged image extend to unexpectedly high resolution. A carefully controlled, quantitative comparison reveals, however, that the optical diffraction pattern of the original micrograph and that of the ten-fold averaged image are essentially equivalent. Using computer-based image processing, we discovered that the peak intensities on the 6th layer line have values very similar in magnitude to the neighboring noise, in contrast to what was expected from the optical diffraction pattern of the original micrograph. This discrepancy was resolved by recording a series of optical diffraction patterns when the original micrograph was immersed in oil. These patterns revealed the presence of a substantial phase grating effect, which exaggerated the peak intensities on the 6th layer line, causing an erroneous impression that the high resolution features possessed a good signal-to-noise ratio. This study thus reveals some pitfalls and misleading results that can be encountered when using optical diffraction patterns to evaluate image quality. | 10.1016/0304-3991(83)90050-5 |
pubmed_1111_21599 | BACKGROUND
The lung is one of the sites of granulomatous responses, which are characterized by the recruitment and organization of activated macrophages and lymphocytes. There have been several reports that have shown that some pulmonary granulomatous diseases, such as sarcoidosis and nontuberculous mycobacterial disease, are likely to be characterized by a preponderance in postmenopausal females. Although sex hormones have been shown to play an important role in the regulation of the immune system, the influence of sex hormones on pulmonary granuloma formation is still unclear.
OBJECTIVES
The purpose of this study was to assess whether sex hormones are involved in granulomatous inflammation and to evaluate how sex hormones modulate this response in the lung.
METHODS
Ovariectomized rats were used as an experimental postmenopausal model in which chronic pulmonary granulomatous inflammation was induced by intravenous injection of complete Freund's adjuvant.
RESULTS
Histological analysis of lung tissues demonstrated enhancement of granuloma formation in the ovariectomized group. Such enhanced granuloma formation was significantly associated with generalized Th1-biased cytokine production in the bronchoalveolar lavage fluid.
CONCLUSION
These results indicate that sex hormones play an important role in pulmonary granuloma formation by altering the Th1 responses. | 10.1159/000324295 |
pubmed_83_16654 | INTRODUCTION
The COVID-19 pandemic has resulted in cancellation of medical peer meetings. The Chest Wall Injury Society Annual Summit was scheduled for April 2020. Due to safety concerns, the Society altered the meeting to an online format. The purpose of this paper is to describe how this was accomplished and also to highlight its outcomes.
METHODS
An online survey of participants was carried out to assess their views on the educational yield and technical difficulties encountered as compared to in-person meetings.
RESULTS
Sixty two of 275 (23%) registered participants filled out the survey. Eighty four percent felt that the educational quality was excellent/good. Seventy five percent and 95% felt in-person meetings are better for education and for networking, respectively. Eighty seven percent preferred in-person meetings in the future but would attend a virtual meeting again. Thirteen percent had technical difficulties accessing the meeting.
CONCLUSION
Online meetings are feasible but in-person meetings have more educational and networking value. | 10.1016/j.jsurg.2020.09.004 |
pubmed_32_18256 | With the additional ability to rotate the image around the axis of the centerline of the sector, multiplane transesophageal echocardiography (TEE) improves over single or biplane TEE in ease of use and diagnostic accuracy. This article reviews the anatomic, physiological, and topographic considerations that affect the use of multiplane TEE in evaluation of patients with mitral valve disease. The optimum mitral valve examination includes a true "short-axis" view, obtained by a transverse (zero-degree angle) transgastric image orientation with the probe tip flexed anteriorly, and several "long-axis" views, obtained from various rotations of the basilar multiplane TEE image planes. This provides a useful and accurate means to determine the mechanism of mitral regurgitation, which is useful in planning and timing, determining the likelihood, and predicting the surgical techniques that will be required for mitral valve repair. The postcardiopulmonary bypass (postpump) TEE examination in a patient with mitral regurgitation is a second important component of the process of repair, to determine the presence and severity of residual mitral regurgitation, and identify any complications of surgery. Of 1,550 mitral repair operations studied with postpump echocardiography at our hospital since 1987, a total of 105 (7%) have had second pump runs. Multiplane TEE is also useful to pinpoint the exact site of periprosthetic regurgitation around a mitral prosthesis, enabling direct surgical closure in some cases. Understanding special technical features of multiplane TEE is an important component for optimum utilization of this powerful diagnostic modality. | pubmed_32_18256 |
pubmed_897_14061 | BACKGROUND
Differences in the determinants of Chlamydia trachomatis ('chlamydia') and Mycoplasma genitalium (MG) genital infection in women are not well understood.
METHODS
A cohort study of 16 to 25 year old Australian women recruited from primary health care clinics, aimed to determine chlamydia and MG prevalence and incidence. Vaginal swabs collected at recruitment were used to measure chlamydia and MG prevalence, organism-load and chlamydia-serovar a cross-sectional analysis undertaken on the baseline results is presented here.
RESULTS
Of 1116 participants, chlamydia prevalence was 4.9% (95% CI: 2.9, 7.0) (n = 55) and MG prevalence was 2.4% (95% CI: 1.5, 3.3) (n = 27). Differences in the determinants were found - chlamydia not MG, was associated with younger age [AOR:0.9 (95% CI: 0.8, 1.0)] and recent antibiotic use [AOR:0.4 (95% CI: 0.2, 1.0)], and MG not chlamydia was associated with symptoms [AOR:2.1 (95% CI: 1.1, 4.0)]. Having two or more partners in last 12 months was more strongly associated with chlamydia [AOR:6.4 (95% CI: 3.6, 11.3)] than MG [AOR:2.2 (95% CI: 1.0, 4.6)] but unprotected sex with three or more partners was less strongly associated with chlamydia [AOR:3.1 (95%CI: 1.0, 9.5)] than MG [AOR:16.6 (95%CI: 2.0, 138.0)]. Median organism load for MG was 100 times lower (5.7 × 104/swab) than chlamydia (5.6 × 106/swab) (p < 0.01) and not associated with age or symptoms for chlamydia or MG.
CONCLUSIONS
These results demonstrate significant chlamydia and MG prevalence in Australian women, and suggest that the differences in strengths of association between numbers of sexual partners and unprotected sex and chlamydia and MG might be due to differences in the transmission dynamics between these infections. | 10.1186/1471-2334-11-35 |
pubmed_963_18071 | It has been reported that coronary endothelial dysfunction is associated with the pathogenesis of coronary spasm, and that endothelial nitric oxide (NO) mediated vasodilatation was decreased in coronary epicardial arteries in patients with coronary spastic angina (CSA). However, there are few reports about the endothelial function in peripheral resistance vessels of patients with CSA, so the present study investigated the role of NO in forearm resistance vessels in such patients. The responses of forearm blood flow to acetylcholine (ACh; 8-24 microg/min) and sodium nitroprusside (SNP; 0.4-1.2 microg/ml) infusions was examined using plethysmography, and subsequently the responses to ACh after an infusion of N(G)-monomethyl-L-arginine (L-NMMA; 4 micromol/min, for 5 min) in 17 patients with CSA and 17 age- and sex- matched controls. The vasodilator responses to ACh and SNP were comparable between the 2 groups (p=NS). L-NMMA significantly suppressed the vasodilator responses to ACh in controls (p<0.05), but there was no significant difference in the responses to ACh before and after infusion of L-NMMA in patients with CSA (p=NS). These results indicate that endothelial NO-mediated vasodilatation is decreased in the forearm resistance vessels of patients with CSA. | 10.1253/jcj.65.81 |
pubmed_791_2239 | A growing body of evidence suggests that the lip products are polluted by heavy metals, which would inevitably cause safety problems with long-term exposure, but few studies have focused on their deeper health risk assessments. This study sets out to identify the lip cosmetics in good sale from Chinese e-commerce market utilizing Python crawler and then explore the probabilistic health risks caused by 6 trace elements in 34 most popular lip cosmetics with Monte Carlo simulation. The results found that there was no obvious non-carcinogenic risk to humans. As for high users, the carcinogenic risk levels of Cr exceeded the acceptable risk recommended by USEPA, approximately 10% and 25% for lipsticks and lip glosses, respectively. Cr was regarded as the priority metal for risk control in the present study. Finally, it was recommended that the minimum use period limit for using up one lip product ranged from 0.54 months to 5.74 months. Overall, this study appears to be the first to conduct a probabilistic health risk assessment of trace elements in lip products, which would be of significance for policy makers to take effective strategies to minimize exposure health risk and contamination. | 10.1016/j.jhazmat.2020.124279 |
pubmed_424_20942 | This work has been conducted on 162 subjects, aged over 60 years, living in Senegal, investigated in the Departement of Biophysics and Nuclear Medecine of Dakar for suspicion of dysthyroidism. The levels of T3, T4 and TSH US hormones were determined by a radio-immunological method. This technique, exhibiting good functionnal sensitivity and its high specificity, is likely to be beneficial to the diagnosis of dysthyroidisms. Besides, this experiment leads us to consider that the dosage of TSH remains an useful first intention examination for the old patients and could notably improve the screening of dysthyroidisms with a decrease in the cost of the investigation. However, because of the therapeutical implications, some biological profiles schould be interpreted cautiously. The equipment for the determination of the free fractions (T3 and T4) with the brought additional accuracy could allow to dismiss some diagnostci uncertainties. | pubmed_424_20942 |
pubmed_541_9706 | Thermal decomposition by the azo initiator 2,2' azobis(2-amidinopropane) dihydrochloride (AAPH) has been widely used as a water-soluble source of free radical initiators capable of inducing lipid peroxidation and protein damage. Here, in a lipid-free system, AAPH alone (40 mM) rapidly induced protein modification and inactivation of the enzyme catalase (EC 1.11.1.6). Using SDS-PAGE, it was shown that protein band intensity is dramatically reduced after 4 h of incubation with AAPH, leading to protein aggregation. Several antioxidants including melatonin, glutathione (GSH) and trolox prevented catalase modification when used at a 250 microM concentration whereas ascorbate was only effective at 1 mM concentration. All the antioxidants tested reduced carbonyl formation although melatonin was the most effective in this regard. Enzyme inactivation caused by AAPH was also significantly reduced by the antioxidants and again melatonin was more efficient than the other antioxidants used in this study. Results shown here demonstrate that alkyl peroxyl radicals inactivate catalase and reduce the effectiveness of cells to defend against free radical damage; the damage to catalase can be prevented by antioxidants, especially melatonin. | 10.1080/1071576031000083206 |
pubmed_841_3101 | The requirements for day-case a-v fistula surgery are an effective out-patient clinic, adequate surgical and anaesthesiological equipment and a thorough patient selection for the planned operation. For surgical reasons, only 87 cases (8.1%) out of the 1068 a-v fistula operations carried out had to be admitted to a ward. Nevertheless 35% of the patients were on a ward at the time of the operation for medical reasons. In case of an ideal co laboration between nephrologists and surgeons there should not be more than 10-25% of the dialysis patients in hospital at the time of a-v fistula surgery depending on the severity of their disease and the planned operation. | pubmed_841_3101 |
pubmed_469_15424 | Increasing evidence supports the notion that filamentous actin (F-actin) and globular actin exist in the nuclei of somatic cells, and are involved in chromatin remodeling, gene transcription regulation and DNA damage repair. However, the underlying mechanisms of how nuclear F-actin are polymerized in cells remain incompletely understood. Here, we identify potential kinase targets that participate in nuclear F-actin polymerization in ovarian cancer cells using small-molecule inhibitor library screening in combination with a deep learning approach. The analysis of the targets of the inhibitors used in this study suggest that the PI3K-AKT pathway are involved in regulating nuclear F-actin organization in ovarian cancer cells. Our work lays the foundation for uncovering the important roles of nuclear F-actin in the context of ovarian cancer, and for understanding how nuclear F-actin structures are organized. | 10.3389/fcell.2022.869531 |
pubmed_159_8967 | CD44, a surface marker for cancer stem cells, interacts with PKM2, a key regulator of aerobic glycolysis, and enhances the glycolytic phenotype of cancer cells leading to antioxidant protection and macromolecules' synthesis. To clarify the clinical importance of this "cross-talk" as a mechanism of drug resistance, we assessed the expression both of PKM2 and of CD44 in cancer cells of patients with epithelial ovarian cancer (EOC) treated with platinum-based treatment. One hundred and seventy-one patients with EOC were assessed for PKM2mRNA expression and PKM2 and CD44 proteins detection. Associations with progression-free survival (PFS) and overall survival (OS) were assessed with Kaplan-Meier and adjusted Cox regression models. PKM2mRNA and protein as well as CD44 protein were detectable in the majority of patients. Positive correlation between PKM2 and CD44 protein expression was observed (Spearman rho = 0.2, p = 0.015). When we used the median to group patients into high versus low expression, high PKM2mRNA and protein levels were significantly associated with lower progression-free survival (PFS; p = 0.003 and p = 0.002, respectively) and shorter overall survival (OS; p ≤ 0.001 and p = 0.001, respectively). However, high CD44 protein expression was significantly correlated only with shorter OS (p = 0.004). Moreover, patients with both high PKM2 and CD44 protein levels experienced shorter PFS and OS (p = 0.007 and p = 0.003, respectively) compared to patients with low expression of both proteins. Finally, higher PKM2mRNA and protein expression as well as CD44 protein expression (HR: 2.16; HR: 1.82; HR: 1.01, respectively) were independent prognostic factors for decreased median OS (mOS), whereas only PKM2 protein expression (HR: 1.95) was an independent prognostic factor for decreased median PFS (mPFS). In conclusion, PKM2 expression is a negative prognostic factor in EOC patients, but the interaction between CD44 and PKM2 that may be implicated in EOC platinum-resistance needs further investigation. | 10.3390/cancers12041013 |
pubmed_987_5991 | Major histocompatibility complex (MHC) tetramers can work as diagnostic tools to identify antigen-specific T cells in immunological research and monitoring. Here, we provide a general protocol for the production of MHC tetramer. We obtain highly pure N-terminal His-tagged HLA-A2 α chain and β2-microglobulin (β2m) to fold a monomer with a photocleavable peptide, which can exchange with an HLA-A2 presented peptide derived from influenza A virus. Further those monomers compose tetramer to stain antigen-specific CD8+ T cells. For complete details on the use and execution of this protocol, please refer to Xiao C.C. et al. (2021). | 10.1016/j.xpro.2022.101206 |
pubmed_454_6874 | BACKGROUND
Several studies have suggested a greater risk of suicide in Huntington disease (HD); however, unique risk factors for suicide in HD are not established.
OBJECTIVE
We sought to determine risk factors for suicidal behavior, defined as suicide or attempted suicide, in prodromal HD.
METHODS
From the prospective PREDICT-HD cohort, we identified 735 cases with HD gene expansion but no manifest symptoms of HD and 194 non-gene-expanded controls. In survival analysis, a number of potential risk factors for suicidal behavior were assessed, including symptoms of depression, hopelessness, substance abuse, marital status, gender, and psychiatric history.
RESULTS
During a mean of 3.7 years of prospective follow-up, 12 cases (1.6%) attempted suicide and 1 completed suicide (0.1%). No suicides were observed among controls. In univariate Cox proportional hazards regression models, a history of suicide attempts (HR 8.5, 95% CI 2.8-26.1, p < 0.0002) and a Beck Depression Inventory II score >13 (HR 7.2, 95% CI 2.3-22.0, p < 0.0006) were associated with suicidal behavior. These risk factors had independent effects in multivariate models. A history of incarceration in the past 2 years was also associated (HR 12.5, 95% CI 2.7-56.6, p < 0.002), though uncommon. No further risk factors were identified.
CONCLUSION
A history of suicide attempts and the presence of depression are strongly predictive of suicidal behavior in prodromal HD. As these risk factors are among the most robust risk factors for suicide, established suicide risk factors appear applicable to those with prodromal HD. | 10.1159/000327754 |
pubmed_357_1491 | Alternatives to protect crops against diseases are desperately needed to secure world food production and make agriculture more sustainable. Genetic resistance to pathogens utilized so far is mostly based on single dominant resistance genes that mediate specific recognition of invaders and that is often rapidly broken by pathogen variants. Perturbation of plant susceptibility (S) genes offers an alternative providing plants with recessive resistance that is proposed to be more durable. S genes enable the establishment of plant disease, and their inactivation provides opportunities for resistance breeding of crops. However, loss of S gene function can have pleiotropic effects. Developments in genome editing technology promise to provide powerful methods to precisely interfere with crop S gene functions and reduce tradeoffs. | 10.1016/j.copbio.2021.05.005 |
pubmed_220_14316 | PURPOSE
To identify older adults' knowledge of acquired immune deficiency syndrome (AIDS), perceptions of their risk of AIDS, and at-risk behaviors by using a questionnaire derived from the health belief model.
DATA SOURCES
A descriptive correlation design was used to survey persons 50 years of age and older who participate in university-based senior programs. The sample of 166 persons (55% return rate) had a mean age of 71 years and included 33% males. The sample is representative of the participants in these programs.
CONCLUSIONS
Five hypotheses based on the health belief model were tested. Statistical analyses showed significant predictors of the likelihood of using recommended safe sexual practices were gender, knowledge of AIDS, perceived susceptibility to AIDS, and perceived threat of AIDS. The results indicated the respondents were knowledgeable about human immunodeficiency virus (HIV) transmission through casual contact and medical aspects of AIDS. Although the respondents recognized the seriousness of AIDS, they generally did not believe that they were susceptible to this disease, even though about 10% indicated sexual activity outside of a long-term relationship.
IMPLICATIONS FOR PRACTICE
The study findings support the need for nurse practitioners to assess sexual behaviors in and provide information about safe sex practices to older clients because of the documented rising incidence of AIDS in persons over 50 years of age. | 10.1111/j.1745-7599.2003.tb00340.x |
pubmed_894_6399 | The authors report a case of pulmonary tumor embolism during a hepatectomy for hepatoma, leading to a fatal cardiac arrest. This cause of cardiac arrest during operation has never been reported in the literature, but systematic autopsies of patients dying from liver cancer, especially primary or metastatic tumors, shows that the incidence of these embolisms is frequently underestimated. Any anomaly of the hepatic vein appearing in the X-rays implies a danger of intra- or post-operative embolism. Allowance must therefore be made for this in the surgical technique, which should include complete or partial cross-clamping of the vena cava. | pubmed_894_6399 |
pubmed_1086_14780 | This case report presents the dental management of a 13-year-old girl with mosaic trisomy 9. She had: (1) severe psychomotor retardation; (2) short stature; (3) progressive microcephaly; (4) flat feet; (5) genu valgum; and (6) severe kyphoscoliosis. Dysmorphic facial features included: (1) maxillary prognathism; (2) narrow high-arched palate; (3) short philtrum; (4) small low posterior dysplastic ears; and (5) down slanting palpebral fissures with right eye ptosis. The case report describes initial treatment under general anesthesia and further treatments using conscious sedation. Emphasis was placed on the need to adjust the treatment to patient's skeletal malformations and respiratory problems by adjusting her ability to sit in the dental chair in an upright position. Supernumerary premolars and opalescent changes of the maxillary incisors might be part of the clinical features related to trisomy 9 mosaic syndrome. | pubmed_1086_14780 |
pubmed_487_4532 | Although arsenic (As) contamination of groundwater in the Bengal Basin has received wide attention over the past decade, comparative studies of hydrogeochemistry in geologically different sub-basins within the basin have been lacking. Groundwater samples were collected from sub-basins in the western margin (River Bhagirathi sub-basin, Nadia, India; 90 samples) and eastern margin (River Meghna sub-basin; Brahmanbaria, Bangladesh; 35 samples) of the Bengal Basin. Groundwater in the western site (Nadia) has mostly Ca-HCO(3) water while that in the eastern site (Brahmanbaria) is much more variable consisting of at least six different facies. The two sites show differences in major and minor solute trends indicating varying pathways of hydrogeochemical evolution However, both sites have similar reducing, postoxic environments (p(e): +5 to -2) with high concentrations of dissolved organic carbon, indicating dominantly metal-reducing processes and similarity in As mobilization mechanism. The trends of various redox-sensitive solutes (e.g. As, CH(4), Fe, Mn, NO(3)(-), NH(4)(+), SO(4)(2-)) indicate overlapping redox zones, leading to partial redox equilibrium conditions where As, once liberated from source minerals, would tend to remain in solution because of the complex interplay among the electron acceptors. | 10.1016/j.jconhyd.2007.10.005 |
pubmed_429_9125 | Chloroquine splits autoantibodies from erythrocytes of patients with autoimmune haemolytic anaemia in vitro. After the removal of chloroquine from the samples the autoantibodies can be identified in the eluates. With one exception the autoantibodies of patients with idiopathic autoimmune haemolytic anaemia (AIHA) and severe haemolysis were completely split from the cells, whereas the autoantibodies of patients with symptomatic AIHA and moderate anaemia, of patients with diseases unrelated to haemolysis, and of healthy persons, were not completely split from the erythrocytes. In general, autoantibodies, which are associated with severe haemolysis, were more easily split from the red cells by chloroquine. The eluted IgG incomplete warm autoantibodies were only in part specific to Rh antigens. The Rh specificity does not correlate with the absence of presence of increased haemolysis. The inhibition of the autoantibodies and the splitting or 'loosening' of the antigen-antibody linkage with the immunocomplex by chloroquine could be responsible of a longer survival of autoantibody-coated red cells in patients with AIHA. | 10.1111/j.1423-0410.1976.tb02851.x |
pubmed_824_14694 | Rates of thiocyanate degradation were measured in waters and sediments of marine and limnic systems under various redox conditions, oxic, anoxic (nonsulfidic, nonferruginous, nonmanganous), ferruginous, sulfidic, and manganous, for up to 200-day period at micromolar concentrations of thiocyanate. The decomposition rates in natural aquatic systems were found to be controlled by microbial processes under both oxic and anoxic conditions. The Michaelis-Menten model was applied for description of the decomposition kinetics. The decomposition rate in the sediments was found to be higher than in the water samples. Under oxic conditions, thiocyanate degradation was faster than under anaerobic conditions. In the presence of hydrogen sulfide, the decomposition rate increased compared to anoxic nonsulfidic conditions, whereas in the presence of iron(II) or manganese(II), the rate decreased. Depending on environmental conditions, half-lives of thiocyanate in sediments and water columns were in the ranges of hours to few dozens of days, and from days to years, respectively. Application of kinetic parameters presented in this research allows estimation of rates of thiocyanate cycling and its concentrations in the Archean ocean. | 10.1021/acs.est.7b04723 |
pubmed_49_9370 | A yeast cDNA genetic library in a bacteriophage expression vector was screened using an antiserum reacting with fructose 1,6-bisphosphate aldolase from Saccharomyces cerevisiae. Radio-labelled probes of selected immunopositive clones were used for screening of a yeast genomic library. From the genomic clones a yeast/Escherichia coli shuttle plasmid was constructed containing on a 1990-base-pair fragment the entire structural gene FBA1 coding for yeast aldolase. The primary structure of the FBA1 gene was determined. An open reading frame comprises 1077 base pairs coding for a protein of 359 amino acids with a predicted molecular mass of 39,608 Da. As observed for other strongly expressed yeast genes, codon usage is extremely biased. The 810 base pairs at the 5' end and the 90 base pairs at the 3' end of the coding region of the cloned FBA1 gene are sufficient for normal expression and show characteristic elements present in the noncoding sequences of other yeast genes. Aldolase is the major protein in yeast cells transformed with a high-copy-number plasmid containing the FBA1 gene. The aldolase gene was disrupted by insertion of the yeast URA3 gene into the coding region of one FBA1 allele in a homozygous diploid ura3 strain. The haploid offsprings with the defective aldolase allele fba1::URA3 lack aldolase enzymatic activity and fail to grow in media containing as a carbon source metabolites of only one side of the aldolase reaction. | 10.1111/j.1432-1033.1989.tb14648.x |
pubmed_13_8704 | The overexpression of AXL kinase has been described in many types of cancer. Due to its role in proliferation, survival, migration, and resistance, AXL represents a promising target in the treatment of the disease. In this study we present a novel compound family that successfully targets the AXL kinase. Through optimization and detailed SAR studies we developed low nanomolar inhibitors, and after further biological characterization we identified a potent AXL kinase inhibitor with favorable pharmacokinetic profile. The antitumor activity was determined in xenograft models, and the lead compounds reduced the tumor size by 40% with no observed toxicity as well as lung metastasis formation by 66% when compared to vehicle control. | 10.1021/acs.jmedchem.8b00672 |
pubmed_688_4105 | An electron microscopic study has been made of the tip of the growing pyramidal tract in the rat. This part of the developing bundle, designated as the growth-zone, has been examined at the levels of the medulla oblongata and the third spinal segment at embryonic day 20 and on the day of birth, respectively. The tip of the pyramidal tract contains, apart from axons, numerous larger profiles. An analysis of serial sections revealed that these represent either growth cones or preterminal periodic varicosities. In the growth cones of the corticospinal axons three zones can be distinguished: a proximal "tubular", an intermediate "vesicular-reticular" and a distal "fine-granular" zone. As distinct from the classical descriptions the corticospinal growth cones end in a single or, less frequently, in two more or less parallel filopodia. None of the growth cones analyzed in this study showed multiple filopodia radiating from the terminal expansion as observed at the end of growing axons in tissue cultures and in developing spinal fibre tracts of nonmammalian vertebrates. As regards the varicosities, most of these structures are characterized by a light cytoplasmic density. Others, however, contain a denser cytoplasm, closely resembling that of the vesiculo-reticular part of growth cones. | 10.1007/BF00319602 |
pubmed_1072_14092 | Importance
Robotic rectal cancer surgery is gaining popularity, but limited data are available regarding safety and efficacy.
Objective
To compare robotic-assisted vs conventional laparoscopic surgery for risk of conversion to open laparotomy among patients undergoing resection for rectal cancer.
Design, Setting, and Participants
Randomized clinical trial comparing robotic-assisted vs conventional laparoscopic surgery among 471 patients with rectal adenocarcinoma suitable for curative resection conducted at 29 sites across 10 countries, including 40 surgeons. Recruitment of patients was from January 7, 2011, to September 30, 2014, follow-up was conducted at 30 days and 6 months, and final follow-up was on June 16, 2015.
Interventions
Patients were randomized to robotic-assisted (n = 237) or conventional (n = 234) laparoscopic rectal cancer resection, performed by either high (upper rectum) or low (total rectum) anterior resection or abdominoperineal resection (rectum and perineum).
Main Outcomes and Measures
The primary outcome was conversion to open laparotomy. Secondary end points included intraoperative and postoperative complications, circumferential resection margin positivity (CRM+) and other pathological outcomes, quality of life (36-Item Short Form Survey and 20-item Multidimensional Fatigue Inventory), bladder and sexual dysfunction (International Prostate Symptom Score, International Index of Erectile Function, and Female Sexual Function Index), and oncological outcomes.
Results
Among 471 randomized patients (mean [SD] age, 64.9 [11.0] years; 320 [67.9%] men), 466 (98.9%) completed the study. The overall rate of conversion to open laparotomy was 10.1%: 19 of 236 patients (8.1%) in the robotic-assisted laparoscopic group and 28 of 230 patients (12.2%) in the conventional laparoscopic group (unadjusted risk difference = 4.1% [95% CI, -1.4% to 9.6%]; adjusted odds ratio = 0.61 [95% CI, 0.31 to 1.21]; P = .16). The overall CRM+ rate was 5.7%; CRM+ occurred in 14 (6.3%) of 224 patients in the conventional laparoscopic group and 12 (5.1%) of 235 patients in the robotic-assisted laparoscopic group (unadjusted risk difference = 1.1% [95% CI, -3.1% to 5.4%]; adjusted odds ratio = 0.78 [95% CI, 0.35 to 1.76]; P = .56). Of the other 8 reported prespecified secondary end points, including intraoperative complications, postoperative complications, plane of surgery, 30-day mortality, bladder dysfunction, and sexual dysfunction, none showed a statistically significant difference between groups.
Conclusions and Relevance
Among patients with rectal adenocarcinoma suitable for curative resection, robotic-assisted laparoscopic surgery, as compared with conventional laparoscopic surgery, did not significantly reduce the risk of conversion to open laparotomy. These findings suggest that robotic-assisted laparoscopic surgery, when performed by surgeons with varying experience with robotic surgery, does not confer an advantage in rectal cancer resection.
Trial Registration
isrctn.org Identifier: ISRCTN80500123. | 10.1001/jama.2017.7219 |
pubmed_749_6798 | The intensity and duration of TGF-β signaling determine the cellular biological response. How this is negatively regulated is not well understood. Here, we identified a novel negative regulator of TGF-β signaling, transmembrane p24-trafficking protein 10 (TMED10). TMED10 disrupts the complex formation between TGF-β type I (also termed ALK5) and type II receptors (TβRII). Misexpression studies revealed that TMED10 attenuated TGF-β-mediated signaling. A 20-amino acid-long region from Thr91 to Glu110 within the extracellular region of TMED10 was found to be crucial for TMED10 interaction with both ALK5 and TβRII. Synthetic peptides corresponding to this region inhibit both TGF-β-induced Smad2 phosphorylation and Smad-dependent transcriptional reporter activity. In a xenograft cancer model, where previously TGF-β was shown to elicit tumor-promoting effects, gain-of-function and loss-of-function studies for TMED10 revealed a decrease and increase in the tumor size, respectively. Thus, we determined herein that TMED10 expression levels are the key determinant for efficiency of TGF-β receptor complex formation and signaling. | 10.1074/jbc.M116.769109 |
pubmed_534_5469 | We present a female patient with severe acute respiratory distress syndrome (ARDS) necessitating intubation and mechanical ventilation on the intensive care unit (ICU). High ventilatory pressures were needed because of hypoxia and severe hypercapnia with respiratory acidosis, resulting in right ventricular dysfunction with impaired haemodynamic stability. A veno-venous extracorporeal CO2 removal (ECCO2R) circuit was initiated, effectively eliminating carbon dioxide while improving oxygenation and enabling a reduction in applied ventilatory pressures. We noted a marked improvement of right ventricular function with restoration of haemodynamic stability. Within one week, the patient was weaned from both ECCO2R and mechanical ventilation. Besides providing adequate gas exchange, extracorporeal assist devices may be helpful in ameliorating right ventricular dysfunction during ARDS. | 10.1177/0267659115621783 |
pubmed_804_8850 | BACKGROUND
Viscoelastic measurements of hemostasis indicate that 20% of seriously injured patients exhibit systemic hyperfibrinolysis, with increased early mortality. These patients have normal clot formation with rapid clot lysis. Targeted proteomics was applied to quantify plasma proteins from hyperfibrinolytic (HF) patients to elucidate potential pathophysiology.
METHODS
Blood samples were collected in the field or at emergency department arrival and thrombelastography (TEG) was used to characterize in vitro clot formation under native and tissue plasminogen activator (tPA)-stimulated conditions. Ten samples were taken from injured patients exhibiting normal lysis time at 30 min (Ly30), "eufibrinolytic" (EF), 10 from HF patients, defined as tPA-stimulated TEG Ly30 >50%, and 10 from healthy controls. Trauma patient samples were analyzed by targeted proteomics and ELISA assays for specific coagulation proteins.
RESULTS
HF patients exhibited increased plasminogen activation. Thirty-three proteins from the HF patients were significantly decreased compared with healthy controls and EF patients; 17 were coagulation proteins with anti-protease consumption (p < 0.005). The other 16 decreased proteins indicate activation of the alternate complement pathway, depletion of carrier proteins, and four glycoproteins. CXC7 was elevated in all injured patients versus healthy controls (p < 0.005), and 35 proteins were unchanged across all groups (p > 0.1 and fold change of concentrations of 0.75-1.3).
CONCLUSION
HF patients had significant decreases in specific proteins and support mechanisms known in trauma-induced hyperfibrinolysis and also unexpected decreases in coagulation factors, factors II, X, and XIII, without changes in clot formation (SP, R times, or angle). Decreased clot stability in HF patients was corroborated with tPA-stimulated TEGs.
LEVEL OF EVIDENCE
Prognostic, level III. | 10.1097/TA.0000000000001878 |
pubmed_817_22562 | Addressing the growing burden of cancer and the shortcomings of chemotherapy in cancer treatment are the current research goals. Research to overcome the limitations of curcumin and to improve its anticancer activity via its heterocycle-fused monocarbonyl analogues (MACs) has immense potential. In this study, 32 asymmetric MACs fused with 1-aryl-1H-pyrazole (7a-10h) were synthesized and characterized to develop new curcumin analogues. Subsequently, via initial screening for cytotoxic activity, nine compounds exhibited potential growth inhibition against MDA-MB-231 (IC50 2.43-7.84 μM) and HepG2 (IC50 4.98-14.65 μM), in which seven compounds showing higher selectivities on two cancer cell lines than the noncancerous LLC-PK1 were selected for cell-free in vitro screening for effects on microtubule assembly activity. Among those, compounds 7d, 7h, and 10c showed effective inhibitions of microtubule assembly at 20.0 μM (40.76-52.03%), indicating that they could act as microtubule-destabilizing agents. From the screening results, three most potential compounds, 7d, 7h, and 10c, were selected for further evaluation of cellular effects on breast cancer MDA-MB-231 cells. The apoptosis-inducing study indicated that these three compounds could cause morphological changes at 1.0 μM and could enhance caspase-3 activity (1.33-1.57 times) at 10.0 μM in MDA-MB-231 cells, confirming their apoptosis-inducing activities. Additionally, in cell cycle analysis, compounds 7d and 7h at 2.5 μM and 10c at 5.0 μM also arrested MDA-MB-231 cells in the G2/M phase. Finally, the results from in silico studies revealed that the predicted absorption, distribution, metabolism, excretion, and the toxicity (ADMET) profile of the most potent MACs might have several advantages in addition to potential disadvantages, and compound 7h could bind into (ΔG -10.08 kcal·mol-1) and access wider space at the colchicine-binding site (CBS) than that of colchicine or nocodazole via molecular docking studies. In conclusion, our study serves as a basis for the design of promising synthetic compounds as anticancer agents in the future. | 10.1021/acsomega.2c02933 |
pubmed_939_10544 | Per- and polyfluoroalkyl substances (PFAS), polybrominated diphenyl ethers (PBDEs), and organophosphate esters (OPEs) are found in building materials and associated with thyroid disease, infertility, and impaired development. This study's objectives were to (1) compare levels of PFAS, PBDEs, and OPEs in dust from spaces with conventional versus "healthier" furniture and carpet, and (2) identify other product sources of flame retardants in situ. We measured 15 PFAS, 8 PBDEs, and 19 OPEs in dust from offices, common areas, and classrooms having undergone either no intervention (conventional rooms in older buildings meeting strict fire codes; n = 12), full "healthier" materials interventions (rooms with "healthier" materials in buildings constructed more recently or gut-renovated; n = 7), or partial interventions (other rooms with at least "healthier" foam furniture but more potential building contamination; n = 28). We also scanned all materials for bromine and phosphorus as surrogates of PBDEs and OPEs respectively, using x-ray fluorescence. In multilevel regression models, rooms with full "healthier" materials interventions had 78% lower dust levels of PFAS than rooms with no intervention (p < 0.01). Rooms with full "healthier" interventions also had 65% lower OPE levels in dust than rooms with no intervention (p < 0.01) and 45% lower PBDEs than rooms with only partial interventions (p < 0.10), adjusted for covariates related to insulation, electronics, and furniture. Bromine loadings from electronics in rooms were associated with PBDE concentrations in dust (p < 0.05), and the presence of exposed insulation was associated with OPE dust concentrations (p < 0.001). Full "healthier" materials renovations successfully reduced chemical classes in dust. Future interventions should address electronics, insulation, and building cross-contamination. | 10.1016/j.envint.2020.106151 |
pubmed_316_9823 | The hypothesis that cAMP or calcium are the second messengers of erythropoietin (Epo) was tested on fractionated, Epo-responsive immature erythroblasts from anemic rabbit bone marrow by examining whether the proliferative effects of the hormone could be mimicked by agents that increase the intracellular concentration of cAMP or Ca2+. None of the compounds tested (including 10(-6)-10(-4) M db-cAMP, forskolin, isoprenaline or 10(-7)-10(-6) M of the calcium ionophore A23187) alone or in combination could either initiate or potentiate the mitogenic action of the hormone. Furthermore, addition of 0.2 U/ml erythropoietin produced no permanent or transient increase in the uptake of 45Ca2+ by erythroblasts at 37 degrees C. However, cells cultured with imidazole or cordycepin (which reduce the level of intracellular cAMP), or with the calcium chelator EGTA, or the drugs verapamil or TMB-8 (which interfere with the utilization of extracellular or intracellular calcium) showed a decreased stimulation of DNA synthesis by Epo. Finally, the tumour promoter phorbol ester TPA could partially mimic the action of Epo when added to cultures containing more immature progenitor cells. We conclude then that an artificial increase in the cytoplasmic concentration of either cAMP or Ca2+ is not sufficient to elicit the proliferation of Epo-responsive cells. | 10.1016/0014-4827(87)90306-5 |
pubmed_188_24305 | BACKGROUND
It was previously difficult to confirm a clinical diagnosis of tuberculosis by a cheap test, but recently ELISA for circulating antibodies has been found to be reliable in certain cases. We have used this test in osteoarticular tuberculosis.
METHODS
We studied 50 patients with the disease (34 confirmed by biopsy and 16 who responded to chemotherapy) and compared them with 50 matched control subjects. ELISA was performed using Antigen 60-a cell wall cytoplasmic antigen of Mycobacterium tuberculosis.
RESULTS
The test was positive in 27 out of 34 biopsy proven cases, 11 out of 16 patients who responded to chemotherapy and in only 1 out of 50 control subjects.
CONCLUSIONS
ELISA using Antigen 60 may be a useful confirmatory test for osteoarticular tuberculosis. | pubmed_188_24305 |
pubmed_108_25352 | Xanthomonas oryzae pv. oryzae is the causal agent of bacterial blight in rice, one of the most devastating diseases of rice worldwide. African X. oryzae pv. oryzae strains belong to a clear genetic group distinct from those of Asia. Three new races of the pathogen were characterized among strains from West Africa. We evaluated 107 Oryza glaberrima accessions for resistance to bacterial blight under greenhouse conditions. Six-week-old seedlings were inoculated with five different African X. oryzae pv. oryzae strains originating from the West African nations of Burkina and Mali and representing different races (A1, A2, and A3). Philippine X. oryzae pv. oryzae strain PXO86 (race 2) was also used. Most (48%) of the accessions of O. glaberrima were highly susceptible to X. oryzae pv. oryzae strains from Burkina, while 20 and 36 were resistant to X. oryzae pv. oryzae strains from Mali and the Philippines, respectively. CAPS markers and dot blot assays were used for detection of resistance genes xa5 and Xa21 from a selected set of O. glaberrima accessions. Our results suggest that the O. glaberrima germplasm contains a narrow genetic base for resistance to X. oryzae pv. oryzae. Sources of resistance identified among O. glaberrima are recommended for rice breeding programs to develop bacterial blight-resistant cultivars for West Africa. | 10.1094/PDIS-08-10-0558 |
pubmed_795_9522 | OBJECTIVE
The pharmacological effect of vitamin E ointment at high dose levels was investigated in rats and mice during the development of contact dermatitis.
MATERIALS AND METHODS
Allergic or irritant contact dermatitis was induced in sensitized or unsensitized animals by topical application of chemical agent(s). Cultured keratinocytes were prepared from dorsal skin of rats.
RESULTS
The vitamin E ointment at 20-40% suppressed allergic and irritant contact dermatitis, exerting a comparable effect to that of 0.5% prednisolone ointment. Microscopic findings revealed that 20% vitamin E ointment reduced the keratinocyte damage, whereas 0.5% prednisolone was ineffective. The protective action of vitamin E on keratinocyte damage was also confirmed in a cell culture experiment. Furthermore, 20% vitamin E ointment blocked down-regulation of skin barrier function induced by contact dermatitis, although 0.5% prednisolone ointment was inactive.
CONCLUSIONS
These results indicate that 20% vitamin E ointment suppresses contact dermatitis by stabilizing keratinocytes, concomitantly with novel, interesting properties. | 10.1007/pl00012416 |
pubmed_762_18083 | The importance of the surrounding landscape to aquatic ecosystems has been well established. Most research linking aquatic ecosystems to landscapes has focused on the one-way effect of land on water. However, to understand fully the complex interactions between aquatic and terrestrial ecosystems, aquatic ecosystems must be seen not only as receptors of human modification of the landscape, but also as potential drivers of these modifications. We hypothesized that the presence of aquatic ecosystems influences the spatial distribution of human land use/cover of the nearby landscape (</=1 km) and that this influence has changed through time from the 1930s to the 1990s. To test this hypothesis, we compared the distribution of residential, agricultural, and forested land use/cover around aquatic ecosystems (lakes, wetlands, and streams) to the overall regional land use/cover proportion in an area in southeast Michigan, USA; we also compared the distribution of land use/cover around county roads/highway and towns (known determinants of many land use/cover patterns) to the regional proportion. We found that lakes, wetlands, and streams were strongly associated with the distribution of land use/cover, that each ecosystem type showed different patterns, and that the magnitude of the association was at least as strong as the association with human features. We also found that the area closest to aquatic ecosystems (<500 m) was more strongly associated with land use/cover distribution than areas further away. Finally, we found that the strength of the association between aquatic ecosystems and land use/cover increased from 1938 to 1995, although the overall patterns were similar through time. Our results show that a more complete understanding is needed of the role of aquatic ecosystems on the distribution of land use/cover. | 10.1007/s00267-002-2833-1 |
pubmed_425_24248 | Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer. | 10.1016/j.celrep.2019.09.071 |
pubmed_379_18857 | Relative bioavailability of erythromycin was determined after multiple-dose administration of erythromycin estolate in comparison to erythromycin ethylsuccinate both given as oral suspensions to twelve healthy volunteers. The daily erythromycin dose of erythromycin ethylsuccinate was 50% higher than the respective dose of erythromycin estolate; the dosage interval tau was 12 h for erythromycin estolate and 8 h for erythromycin ethylsuccinate. This scheme was planned in accordance to advices of the respective manufactures. Results of the study confirm the differences in extent of bioavailability of both erythromycin derivatives known from single-dose investigations. Furthermore, the experimental data show that a twice daily administration of 1000 mg erythromycin as erythromycin estolat resulted in sufficiently high plasma concentration of the active compound. | pubmed_379_18857 |
pubmed_1006_5754 | The presence of vascular permeability factors in the extracellular products (ECP) of 10 strains of Renibacterium salmoninarum with different geographical origin and serological characteristics are reported. All the ECP produced haemorrhagic and/or oedematous zones at the injection site with a diameter ranging from 10-30 mm. However, the ECP samples did not display toxic effect in fish at the same dose as inoculated in rabbit (180-400 micrograms protein/0.1 ml). No differences were observed in the production of this dermatotoxic factor between the two antigenic groups found in this microorganism. Whereas heating (80 and 100 degrees C/15 min) the ECP samples resulted in a complete loss of their proteolytic activity, only a decrease (but not total inactivation) of the dermatotoxic effects was detected. Therefore, although proteases could be implicated in the permeability factor, they are not totally responsible for this activity. | 10.1016/0882-4010(92)90024-i |
pubmed_722_21922 | Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH(2)) displayed a 1000-fold increase in both potency (IC(50) = 62 nM) and binding affinity for C3b (K(D) = 2.3 nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues. | 10.1016/j.molimm.2010.10.004 |
pubmed_358_6763 | Interleukin-12 (IL-12) has been shown to play a central role in the innate and acquired immune responses. Its activities include enhancement of natural killer (NK) and cytotoxic T lymphocyte (CTL) activity and promotion of CD4 Th1 cell development. It has also been shown to provide potent activity as a vaccine adjuvant in generating antibody and T cell responses. We have investigated the efficacy of IL-12 protein in promoting CD8 T cell responses when it is used as an adjuvant for immunization. Studies using, as antigen, cDNA from an autologous antigen (P1A) as well as studies of responses to vaccinia virus-delivered self (gp100) and non-self (beta-galactosidase) antigens show that the dose and schedule of IL-12 administration can significantly affect adjuvant activity, leading to enhancement or suppression of antigen-specific responses. | 10.1089/10799900050044787 |
pubmed_463_15996 | BACKGROUND
Oral melanoma (OM) in dogs is an aggressive malignancy, with clinical behavior resembling cutaneous melanomas in humans. Melanoma in humans is promoted by an inflammatory environment that is contributed to by leptin and inducible nitric oxide synthase (iNOS).
OBJECTIVE
To determine if the patterns of leptin and iNOS expression are similar in OM in dogs and cutaneous melanomas in humans.
ANIMALS
Twenty client-owned dogs.
METHODS
Retrospective case study. Immunostaining of the OM tumors from each dog was scored for percentage and intensity of leptin and iNOS expression. Mitotic index was used as an indicator of tumor aggression.
RESULTS
Leptin was detected in ≥75% of the tumor cells in specimens from 11 dogs. One tumor expressed leptin in ≤25% of the cells. The intensity of leptin expression was variable with 6, 9, and 5 cases exhibiting low-, moderate-, and high-intensity staining, respectively. OM with the lowest percentage of iNOS positive cells displayed the highest mitotic indices (P = .006, ANOVA).
CONCLUSIONS AND CLINICAL IMPORTANCE
The expression of leptin is a common finding in melanomas in dogs. These data suggest that the possibility of future clinical applications, such as measuring the concentrations of plasma leptin as a screening tool or leptin as a target for therapy. The relevance of iNOS is not as clear in dogs with OM, for which other directed therapeutics might be more appropriate. | 10.1111/jvim.12169 |
pubmed_866_20530 | On Fe(100), CO molecules can get activated efficiently so that CO bond breaking occurs with its transition state in close connection to the adsorbate. The CO bonding thus serves as a prototype model, nicely representing a balance of two simultaneous processes, namely, bond making with the surface and bond breaking within the adsorbate. Such unique configuration highlighting the interplay of two fundamental processes in one adsorption geometry, about which chemists have often fantasized, provides a viable solution to understand the very fundamental aspects of chemistry exemplified in a broad range of disciplines. Using density functional theory calculations, in this paper, we get a glimpse into how the CO bond activation is gestated and initiated in the adsorbate, wherein orbital cooperation in CO activation is evidenced by external CO bond making with the metal and internal CO bond breaking. We find that the symmetry breaking of occupied molecular orbitals in both 5σ and 1π symmetries marks efficient CO bond activation, which is reinforced by 1π → 2π excitations and 2π backdonation that are coupled with the symmetry transition of partially occupied 2π orbitals to a rotational symmetry. Our findings promote our knowledge of CO bond activation beyond the established picture of 5σ donation and 2π backdonation without symmetry breaking and may have insightful implications on orbital control of molecular activation, with further possible impact on elucidating the physical basis of heterogeneous catalysis. | 10.1021/acs.langmuir.9b01270 |
pubmed_762_5633 | An L-amino acid oxidase (LAO), designated as TJ-LAO, was purified to homogeneity from the venom of Trimeresurus jerdonii by Sephadex G-100 and Q Sepharose HP chromatography. The molecular weight of this enzyme was 110 kD as estimated by analytical gel filtration and was 55 kD by SDS-polyacrylamide gel electrophoresis, suggesting that the enzyme is composed of two subunits. The enzyme has an absorption spectrum characteristic of flavoproteins, containing 2 moles of FMN per mole of enzyme. The N-terminal sequence of TJ-LAO shares high homology with other viperid snake venom LAOs. Homology with elapid venom LAO is lower. TJ-LAO inhibited the growth of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus megaterium. The antibacterial effect associated with LAO activity was elminated with the addition of catalase. Platelets in platelet-rich plasma aggregated upon the addition of TJ-LAO. The enzyme-induced aggregation was inhibited by catalase, suggesting formation of H2O2 was essential for TJ-LAO to induce platelet aggregation. These results showed H2O2 formation is important for the biological effects of LAO. | pubmed_762_5633 |
pubmed_432_10977 | During activation of visceral smooth muscle there is an increase in cytosolic-free calcium, but the source (intracellular calcium release or calcium influx), kinetics, and stoichiometry of this increase have not been determined. Here, the fluorescent indicator, quin2-acetoxymethyl ester, was used to measure directly cytosolic-free calcium during contraction of isolated stomach muscle cells induced by the two neuropeptides cholecystokinin-octapeptide and Met-enkephalin as well as acetylcholine. An increase in cytosolic-free calcium was seen that was (i) dependent on the concentration of contractile agonist, (ii) derived from intracellular sources (that is, not significantly affected by removal of ambient calcium or addition of a calcium channel blocker), and (iii) kinetically and stoichiometrically related to net calcium efflux and contraction. In contrast, the increase in cytosolic-free calcium induced by depolarizing concentrations of potassium was caused by influx of calcium through voltage-dependent calcium channels. | 10.1126/science.3704641 |
pubmed_254_22646 | Glucagon regulates glucose and lipid metabolism and promotes weight loss. Thus, therapeutics stimulating glucagon receptor (GCGR) signaling are promising for obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating fibroblast growth factor 21 (FGF21), a potent regulator of energy balance. We reported that mice deficient for liver Fgf21 are partially resistant to GCGR-mediated weight loss, implicating FGF21 as a regulator of glucagon's weight loss effects. FGF21 signaling requires an obligate coreceptor (β-Klotho, KLB), with expression limited to adipose tissue, liver, pancreas, and brain. We hypothesized that the GCGR-FGF21 system mediates weight loss through a central mechanism. Mice deficient for neuronal Klb exhibited a partial reduction in body weight with chronic GCGR agonism (via IUB288) compared with controls, supporting a role for central FGF21 signaling in GCGR-mediated weight loss. Substantiating these results, mice with central KLB inhibition via a pharmacological KLB antagonist, 1153, also displayed partial weight loss. Central KLB, however, is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides. Together, these data suggest GCGR agonism mediates part of its weight loss properties through central KLB and has implications for future treatments of obesity and metabolic syndrome. | pubmed_254_22646 |
pubmed_542_19497 | Carbonic anhydrase (CA) of Chlamydomonas reinhardtii is a glycoprotein of 35 kDa which is localized outside the plasma membrane. The activity of CA was increased when the CO2 concentration during photoautotrophic growth was decreased to air level. After decreasing the CO2 concentration from 4% to 0.04%, several polypeptides including CA were induced continuously or transiently. To investigate the biosynthesis and intracellular processing of CA, the cells of wall-less mutant CW-15, which secretes CA into the culture medium, were pulse-labeled with radioactive arginine, chased, and radioactive proteins were immunoprecipitated with anti-CA serum. A 42-kDa polypeptide with isoelectric point (pI) of 7.1-7.3 was first synthesized. Within 5 min the molecular mass of this polypeptide was decreased to 35 kDa and it was then secreted into the culture medium within 30 min. This indicates that the former is the precursor form and the latter the mature form of CA. The primary translation product from poly(A)-rich RNA in a cell-free reticulocyte lysate system from a rabbit was a 38-kDa polypeptide. This was cotranslationally converted into the 42-kDa precursor in vitro in the presence of dog pancreatic microsomal membranes. As the 42-kDa precursor had a high affinity to concanavalin A, it was assumed to have a high-mannose-type oligosaccharide. The mature enzyme had a pI of 6.1-6.2 and was composed of more than two isoforms, which had a complex-type oligosaccharide with low affinity to concanavalin A. Chemical deglycosylation of the mature enzyme by trifluoromethanesulfonic acid indicated that the molecular mass of the polypeptide moiety was 32 kDa and the difference between this and the primary translation product suggests that cleavage of the polypeptide occurs during its biosynthesis. | 10.1111/j.1432-1033.1986.tb09773.x |
pubmed_357_15950 | ABO incompatibility is the most common cause of immune hemolytic disease of the fetus and newborn (HDFN). The American Academy of Pediatrics lists blood group incompatibility as one of the major risk factors for severe hyperbilirubinemia in newborns. We have estimated the risk of ABO HDFN to determine the need for its routine screening. Blood group data from all blood donors who donated in the last 10 years were collected and analyzed. The population prevalence of ABO blood group genes using the phenotype data of blood donors was estimated. This information was further used to calculate an incidence of ABO HDFN requiring intervention in the population. ABO blood group typing was analyzed in 425,743 blood donors. The ABO phenotypes of A, B, O, and AB were 22.48, 36.73, 31.59, and 9.2 percent, respectively. The gene frequencies were 0.1733, 0.2647, and 0.5620 for A, B, and O, respectively. It was estimated that 13.84 percent of group O women would give birth to a non-group O baby and that approximately 2.77 percent of deliveries would likely have ABO HDFN in the study population. In India, the estimated risk of ABO HDFN is 2.9 percent, with a daily 2196 babies at risk of ABO HDFN requiring intervention. This analysis estimates the overall burden of ABO HDFN in the population, which could aid in the decision-making of policymakers, physicians, and community health practitioners to improve neonatal care.
ABO incompatibility is the most common cause of immune hemolytic disease of the fetus and newborn (HDFN). The American Academy of Pediatrics lists blood group incompatibility as one of the major risk factors for severe hyperbilirubinemia in newborns. We have estimated the risk of ABO HDFN to determine the need for its routine screening. Blood group data from all blood donors who donated in the last 10 years were collected and analyzed. The population prevalence of ABO blood group genes using the phenotype data of blood donors was estimated. This information was further used to calculate an incidence of ABO HDFN requiring intervention in the population. ABO blood group typing was analyzed in 425,743 blood donors. The ABO phenotypes of A, B, O, and AB were 22.48, 36.73, 31.59, and 9.2 percent, respectively. The gene frequencies were 0.1733, 0.2647, and 0.5620 for A, B, and O, respectively. It was estimated that 13.84 percent of group O women would give birth to a non–group O baby and that approximately 2.77 percent of deliveries would likely have ABO HDFN in the study population. In India, the estimated risk of ABO HDFN is 2.9 percent, with a daily 2196 babies at risk of ABO HDFN requiring intervention. This analysis estimates the overall burden of ABO HDFN in the population, which could aid in the decision-making of policymakers, physicians, and community health practitioners to improve neonatal care. | 10.21307/immunohematology-2021-009 |
pubmed_58_10030 | The zebrafish (Danio rerio) has become a valuable model organism for behavioral studies examining learning and memory. Its diurnal circadian rhythm and characterized sleep-like state make it comparable to mammals, features that have contributed to establishing this small vertebrate as a translational model for sleep research. Despite sleep being an evolutionarily conserved behavior, its mechanisms and functions are still debated. Sleep deprivation is commonly associated with decreased attention, reduced responsiveness to external stimuli, altered locomotor activity and impaired performance on cognitive tasks. In the current study, we examined the effects of partial and total sleep deprivation on zebrafish learning performance in an active avoidance conditioning paradigm. In addition, we examined the effects of two drugs known to alter sleep (alcohol and melatonin) on learning performance in sleep deprived animals. Our results suggest that although partial sleep deprivation did not alter learning performance, total sleep deprivation was found to significantly impair behavioral responses to the electric shock as well as avoidance learning. However, when sleep deprived fish were treated with alcohol the night before the learning task, learning performance was similar to the control group. In contrast, melatonin treatment did not alter learning performance in sleep deprived animals. We conclude that the zebrafish is a sensitive tool for investigating the effects of sleep deprivation on cognitive performance and may be a useful model for dissecting the mechanisms underlying learning and memory. | 10.1016/j.beproc.2018.04.004 |
pubmed_467_18600 | O-Linked β-N-acetylglucosamine (O-GlcNAc) is a monosaccharide that plays an essential role in cellular signaling throughout the nucleocytoplasmic proteome of eukaryotic cells. Strategies for selectively increasing O-GlcNAc levels on a target protein in cells would accelerate studies of this essential modification. Here, we report a generalizable strategy for introducing O-GlcNAc into selected target proteins in cells using a nanobody as a proximity-directing agent fused to O-GlcNAc transferase (OGT). Fusion of a nanobody that recognizes GFP (nGFP) or a nanobody that recognizes the four-amino acid sequence EPEA (nEPEA) to OGT yielded nanobody-OGT constructs that selectively delivered O-GlcNAc to a series of tagged target proteins (e.g., JunB, cJun, and Nup62). Truncation of the tetratricopeptide repeat domain as in OGT(4) increased selectivity for the target protein through the nanobody by reducing global elevation of O-GlcNAc levels in the cell. Quantitative chemical proteomics confirmed the increase in O-GlcNAc to the target protein by nanobody-OGT(4). Glycoproteomics revealed that nanobody-OGT(4) or full-length OGT produced a similar glycosite profile on the target protein JunB and Nup62. Finally, we demonstrate the ability to selectively target endogenous α-synuclein for O-GlcNAcylation in HEK293T cells. These first proximity-directed OGT constructs provide a flexible strategy for targeting additional proteins and a template for further engineering of OGT and the O-GlcNAc proteome in the future. The use of a nanobody to redirect OGT substrate selection for glycosylation of desired proteins in cells may further constitute a generalizable strategy for controlling a broader array of post-translational modifications in cells. | 10.1021/acschembio.0c00074 |
pubmed_935_964 | The ability of dexamethasone (DEX) to reduce the severity of the late stage of radiation-induced heart disease (RIHD) was assessed in 25 New Zealand white rabbits. Ten rabbits served as unirradiated controls (CONT). In Group A, seven rabbits received intravenous DEX prior to irradiation and every 24 hours for three consecutive days. DEX was not administered to the eight rabbits in Group B. At 100 days postirradiation, the severity of the late state was determined by microscopic examination (MICRO) for myocardial fibrosis and determination of myocardial hydroxyproline content (MHP). Myocardial fibrosis was evident in Groups A (40%) and B (80%) while none was present in CONT by MICRO. One rabbit in Group B with no fibrosis by MICRO had abnormally increased MHP. MHP was significantly increased in Groups A and B, as compared to CONT (p less than 0.01). In addition to less fibrosis by MICRO, Group A demonstrated a significant reduction of MHP when compared to Group B (p less than 0.05). Determination of MHP may be superior to MICRO in the detection of the late stage of RIHD. Also, early DEX administration appears to reduce myocardial collagen content (fibrosis) in this experimental model. | 10.1148/radiology.134.2.7352245 |
pubmed_100_1150 | OBJECTIVE
To observe the clinical characteristics, treatment options and outcome of diabetic patients with non-ST elevation acute coronary syndromes (NSTEACS).
METHODS
Consecutive patients admitted with NSTEACS from 38 centers in north China were enrolled. Medical histories, clinical characteristics, treatments and outcomes were evaluated and follow-up was made at 6, 12, and 24 months after their initial hospital admission. Cumulative event rates were compared between diabetic and non-diabetic patients.
RESULTS
There were 420 diabetic patients out of 2294 NSTEACS patients (18.3%). Diabetic patients were older [(64.9 ± 6.7) years vs. (62.3 ± 8.6) years, P < 0.01], more often women (48.1% vs. 35.3%, P < 0.05) and were associated with higher baseline comorbidities such as previous hypertension, myocardial infarction, congestive heart failure and stroke than non-diabetic patients. The incidence of antiplatelet therapy (92.1% vs. 95.0%, P < 0.05), coronary angiography (30.0% vs. 36.3%, P < 0.05) and revascularization (12.1% vs.18.8%, P < 0.05) was lower in patients with diabetes than non-diabetic patients. In hospital and 2-year mortality as well as the incidence of congestive heart failure and composite outcomes of myocardial infarction, stroke, congestive heart failure and death were substantially higher in diabetic patients compared with non-diabetic patients. Multivariate Cox regression analysis revealed that age ≥ 70 years, diabetes, previous myocardial infarction, previous congestive heart failure, systolic blood pressure less than 90 mm Hg (1 mm Hg = 0.133 kPa) and heart rate more than 100 bpm at admission were risk factors for 2-year death.
CONCLUSION
In NSTEACS, diabetes is associated with higher rate of in-hospital and 2-year death, congestive heart failure and composite outcomes of myocardial infarction, stroke, congestive heart failure and death. Diabetes mellitus is a major independent predictor of 2-year mortality post NSTEACS. Status of antiplatelet therapy, coronary angiography and revascularization should be improved for diabetic patients with NSTEACS during hospitalization. | pubmed_100_1150 |
pubmed_81_22257 | UNLABELLED
Obesity is associated with increased inflammation. C-reactive protein (CRP) is a proinflammatory molecule, and alpha1-antitrypsin is an inflammation-sensitive plasma protein. Proinflammatory process may be influenced by postprandial hyperglycemia.
OBJECTIVE
The aim of the present study was to evaluate the role of high-glucose load on postprandial circulating levels of PCR and alpha1-antitrypsin in obese women with normal glucose tolerance.
DESIGN
A total of 15 obese women (age=34.4+/-4.3 years, BMI=35.5+/-5.3 kg/m2) and 15 lean controls women (age=33.9+/-2.9 years, BMI=21.8+/-1.9 kg/m2) were recruited for this study. After and overnight fast subjects underwent a 2 h-75 g oral glucose tolerance test. Preprandial and postprandial CRP and alpha1-antitrypsin were measured. Anthropometry and blood biochemical parameters were measured in both groups.
RESULTS
The obese women had fasting serum PCR levels higher (P=or<0.001) than those of control women. There weren't differences in fasting serum alpha1-antitrypsin levels in obese group in comparison to lean control group (P=0.26). Serum PCR and alpha1-antitrypsin did not change postprandially (P=or>0.05 difference to fasting levels). Serum CRP levels was positively related to body mass index (BMI) in obese group. Serum alpha1-antitrypsin was not related to BMI in both groups.
CONCLUSION
A high glucose load is not associated with serum PCR and alpha1-antitrypsin levels increase. Serum alpha1-antitripsin levels are not increased in obese women. Serum PCR levels are increased in obese women, and are positively related to BMI. | pubmed_81_22257 |
pubmed_721_15996 | A combination of scanning and transmission electron microscopy was used to investigate the morphology and ultrastructure of normal human articular cartilage sampled from adult amputation specimens. This study confirms our previous observations on canine articular cartilage, which showed middle and deep layer chondrocytes surrounded by a pericellular matrix and enclosed within a pericellular capsule composed of filamentous and fine fibrillar materials. Pores in the "felt-like" organization of the capsular weave progressively decreased in size from the inner to the outer border of the capsule. Matrix vesicles were found embedded within the capsular weave and distributed throughout the territorial matrix. It is suggested that the chondrocyte, its pericellular matrix, and capsule together constitute the "chondron," a primary functional and metabolic unit of cartilage that acts hydrodynamically to protect the integrity of the chondrocyte and its pericellular microenvironment during compressive loading. | 10.1002/jor.1100050406 |
pubmed_372_16278 | BACKGROUND
Neutrophil-lymphocyte ratio (NLR) is a novel marker of inflammation. Emerging studies have evaluated the relationship of NLR with cardiovascular diseases and malignant conditions. However, rare studies regarded the association between NLR and long-term health status. This study aimed to evaluate the association of NLR with all-cause mortality and cause-specific mortality among adults in the United States.
METHODS
We obtained eight cycles data of National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2014, and enrolled 32328 participants after certain screening. By weighted chi-square test and linear regression analysis, we analyzed the correlation between NLR and baseline characteristics of the participants. Kaplan-Meier curves and Cox regression models were used to assess the survival relevance of NLR. We conducted stratified analysis, interaction analysis, and sensitivity analysis to robustness of our results.
RESULTS
Participants with high NLR levels had a higher risk of death. After adjustment for baseline characteristics, the hazard ratio comparing the higher vs lower NLR levels was 1.43 (95% CI, 1.18-1.73) for all-cause mortality, 1.27 (95% CI, 0.84-1.92) for cancer mortality, and 1.44 (95% CI, 0.96-2.16) for cardiovascular disease mortality. Stratified analysis found that the observed associations between NLR levels and mortality did not differ significantly.
CONCLUSION
In this nationally representative cohort of US adults, higher NLR was significantly associated with an increased risk of all-cause mortality. | 10.2147/IJGM.S339378 |
pubmed_939_22993 | BACKGROUND
The posterior aspect of the leg is an ideal donor site for flap surgery. In this study, the anatomy was investigated of the lateral sural cutaneous nerve (LSCN) and its accompanying artery, superficial lateral sural artery (SLSA), and a lateral sural neurocutaneous flap was designed.
METHODS
Five fresh adult cadaver legs perfused with red latex were dissected to observe the course and relationship between LSCN and SLSA. The outer diameter of SLSA at its origin was measured. Then a lateral sural neurocutaneous flap was designed and used to repair soft tissue defects in six patients.
RESULTS
The anatomic results showed that the SLSA gave rise to branches that followed the LSCN and ramified into terminals at the ramification of the nerve. It originated directly from the popliteal artery 4.2 ± 0.2 mm above the fibular head, where its outer diameter was 0.96 ± 0.23 mm. Several perforators penetrated from the crural fascia and anastomosed to the SLSA, creating a fine anastomotic network. The clinical results showed that the size of the flap ranged from 12 × 6 cm to 25 × 8 cm. All six flaps survived completely without complications. Follow-up ranged from 6 to 18 months with 11 months on average. The overall contour and sensory recovery of the flap were satisfied.
CONCLUSION
A free innervated flap may be elevated safely based on the LSCN and its accompanying vessels. It provides an alternative in reconstruction of soft tissue defects where sensory recovery is important. | 10.1080/2000656X.2020.1838294 |
pubmed_939_22514 | In malaria-naïve children and adults, Plasmodium falciparum -infected red blood cells ( Pf -iRBCs) trigger fever and other symptoms of systemic inflammation. However, in endemic areas where individuals experience repeated Pf infections over many years, the risk of Pf -iRBC-triggered inflammatory symptoms decreases with cumulative Pf exposure. The molecular mechanisms underlying these clinical observations remain unclear. Age-stratified analyses of monocytes collected from uninfected, asymptomatic Malian individuals before the malaria season revealed an inverse relationship between age and Pf -iRBC-inducible inflammatory cytokine (IL-1β, IL-6 and TNF) production, whereas Malian infants and malaria-naïve U.S. adults produced similarly high levels of inflammatory cytokines. Accordingly, monocytes of Malian adults produced more IL-10 and expressed higher levels of the regulatory molecules CD163, CD206, Arginase-1 and TGM2. These observations were recapitulated in an in vitro system of monocyte to macrophage differentiation wherein macrophages re-exposed to Pf -iRBCs exhibited attenuated inflammatory cytokine responses and a corresponding decrease in the epigenetic marker of active gene transcription, H3K4me3, at inflammatory cytokine gene loci. Together these data indicate that Pf induces epigenetic reprogramming of monocytes/macrophages toward a regulatory phenotype that attenuates inflammatory responses during subsequent Pf exposure. These findings also suggest that past malaria exposure could mitigate monocyte-associated immunopathology induced by other pathogens such as SARS-CoV-2.
AUTHOR SUMMARY
The malaria parasite is mosquito-transmitted and causes fever and other inflammatory symptoms while circulating in the bloodstream. However, in regions of high malaria transmission the parasite is less likely to cause fever as children age and enter adulthood, even though adults commonly have malaria parasites in their blood. Monocytes are cells of the innate immune system that secrete molecules that cause fever and inflammation when encountering microorganisms like malaria. Although inflammation is critical to initiating normal immune responses, too much inflammation can harm infected individuals. In Mali, we conducted a study of a malaria-exposed population from infants to adults and found that participants' monocytes produced less inflammation as age increases, whereas monocytes of Malian infants and U.S. adults, who had never been exposed to malaria, both produced high levels of inflammatory molecules. Accordingly, monocytes exposed to malaria in the laboratory became less inflammatory when re-exposed to malaria again later, and these monocytes 'turned down' their inflammatory genes. This study helps us understand how people become immune to inflammatory symptoms of malaria and may also help explain why people in malaria-endemic areas appear to be less susceptible to the harmful effects of inflammation caused by other pathogens such as SARS-CoV-2. | 10.1101/2020.10.21.346197 |
pubmed_411_2638 | BACKGROUND
Hip effusion-synovitis may be relevant to osteoarthritis (OA) but is of uncertain etiology. The aim of this study was to describe the cross-sectional and longitudinal associations of hip effusion-synovitis with clinical and structural risk factors of OA in older adults.
METHODS
One hundred ninety-six subjects from the Tasmanian Older Adult Cohort (TASOAC) study with a right hip STIR (Short T1 Inversion Recovery) Magnetic Resonance Imaging (MRI) on two occasions were included. Hip effusion-synovitis CSA (cm2) was assessed quantitatively. Hip pain was determined by WOMAC (Western Ontario and McMaster Universities Osteoarthritis) while hip bone marrow lesions (BMLs), cartilage defects (femoral and/or acetabular) and high cartilage signal were assessed on MRI. Joint space narrowing (0-3) and osteophytes (0-3) were measured on x-ray using Altman's atlas.
RESULTS
Of 196 subjects, 32% (n = 63) had no or a small hip effusion-synovitis while 68% (n = 133) subjects had a moderate or large hip effusion-synovitis. Both groups were similar but those with moderate or large hip effusion-synovitis were older, had higher BMI and more hip pain. Cross-sectionally, hip effusion-synovitis at multiple sites was associated with presence of hip pain [Prevalence ratio (PR):1.42 95%CI:1.05,1.93], but not with severity of hip pain. Furthermore, hip effusion-synovitis size associated with femoral defect (βeta:0.32 95%CI:0.08,0.56). Longitudinally, and incident hip cartilage defect (PR: 2.23 95%CI:1.00, 4.97) were associated with an increase in hip effusion-synovitis CSA. Furthermore, independent of presence of effusion-synovitis, hip BMLs predicted incident (PR: 1.62 95%CI: 1.13, 2.34) and worsening of hip cartilage defects (PR: 1.50 95%CI: 1.20, 1.86). While hip cartilage defect predicted incident (PR: 1.11 95%CI: 1.03, 1.20) and worsening hip BMLs (PR: 1.16 95%CI: 1.04, 1.30).
CONCLUSIONS
Hip effusion-synovitis at multiple sites (presumably reflecting extent) may be associated with hip pain. Hip BMLs and hip cartilage defects are co-dependent and predict worsening hip effusion-synovitis, indicating causal pathways between defects, BMLs and effusion-synovitis. | 10.1186/s12891-020-03532-7 |
pubmed_80_3609 | BACKGROUND
The associations between sleep characteristics and adiposity in children under three years are not fully understood yet.
OBJECTIVE
The objective of the study is to examine the cross-sectional and prospective associations between sleep characteristics and adiposity in toddlers over a 12-month period.
METHODS
Participants were 202 toddlers from the GET-UP!
STUDY
Sleep duration, sleep timing, and sleep variability were assessed using 24-hour accelerometry for seven consecutive days. Height and weight were measured, and BMI z scores were calculated. Linear mixed models were performed to examine the cross-sectional and prospective associations between sleep characteristics and adiposity, with adjustments for clustering effects and demographic factors.
RESULTS
Total sleep duration was negatively associated with higher adiposity cross-sectionally (B = -0.12; 95% CI: -0.23, -0.01; .033) but not prospectively (B = 0.01; 95% CI: -0.13, 0.10; .843). Nap duration was prospectively associated with higher levels of adiposity (B = 0.41; 95% CI: 0.14, 0.68; .003). Sleep variability and sleep timing were not associated with concurrent or subsequent adiposity.
CONCLUSION
Although sleep duration is an important factor associated with obesity in toddlerhood, the potential effects of different types of sleep duration may vary. While longer total sleep duration may protect children from increasing adiposity, longer nap duration seems to be risk factor. As evidence in this age group is scarce, more research is needed to confirm this finding. | 10.1111/ijpo.12557 |
pubmed_286_21269 | INTRODUCTION
Information about oxidative stress in preterms with Respiratory Distress Syndrome (RDS) is defective, so various researches in this area are required, which may open new roads in understanding the pathogenesis of the disease, hence provide additional helpful therapeutic approaches.
AIM
To assess and compare the plasma level of protein carbonyls as a marker for oxidant status and the antioxidant enzymes; Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) and the related trace minerals in the form of Copper (Cu), Zinc (Zn) and Selenium (Se) as markers for antioxidant status, in preterms with and without RDS.
MATERIALS AND METHODS
A hospital-based case-control study was conducted on fifty-seven preterm neonates (37 preterms with RDS and 20 preterms without RDS) admitted to neonatal intensive care unit of Qena University Hospitals after approval of the University Hospital Ethical Committee. Plasma protein carbonyls assay was done using commercially available ELISA assay kit. Plasma Cu, Zn, Se, erythrocyte SOD and GPx activities assays were done using commercially available colorimetric assay kits.
RESULTS
Significant higher plasma levels of protein carbonyls and oxidant/antioxidants ratio (protein carbonyls/{SOD+GPx}) with significant lower plasma levels of Zn, Cu, Se, erythrocyte SOD and GPx activities were found in the preterms with RDS when compared with the preterms without RDS (p<0.001 for all measured markers for both groups). In terms of birth weights and gestational ages, they were negatively correlated with both plasma protein carbonyls and oxidant/antioxidants ratio and positively correlated with plasma copper, zinc, selenium, erythrocyte SOD and GPx activities in a statistically significant manner. Non-significant correlations were found between the measured oxidative stress markers and the severity of RDS.
CONCLUSION
Oxidative stress may have a contributory role in the development of RDS among preterms. Lower birth weight and prematurity may increase the susceptibity to oxidative stress among such patients. | 10.7860/JCDR/2017/29085.10310 |
pubmed_323_19534 | Small RNA (19-23 nucleotides) molecules play an important role in gene regulation, embryonic differentiation, hematopoiesis, and a variety of cancers. Here, we present an ultrasensitive, extremely specific, label-free, and rapid electronic detection of microRNAs (miRNAs) using a carbon nanotubes field-effect transistor functionalized with the Carnation Italian ringspot virus p19 protein biosensor. miRNA-122a was chosen as the target, which was first hybridized to a probe molecule. The probe-miRNA duplex was then quantified by measuring the change in resistance of biosensor resulting from its binding to p19, which selects 21-23 bp RNA duplexes in a size-dependent but sequence-independent manner. The biosensor displayed a wide dynamic range up to 10(-14) M and was able to detect as low as 1 aM miRNA in the presence of a million-fold excess of total RNA, paving the way for simple, point-of-care, low-cost early detection of miRNA as a biomarker in diagnosis of many diseases, including cancer. | 10.1021/ac4018346 |
pubmed_448_10072 | Complex biological functions within organisms are frequently orchestrated by systemic communication between tissues. In the model organism Caenorhabditis elegans, the pharyngeal and body wall neuromuscular junctions are two discrete structures that control feeding and locomotion, respectively. Separate, the well-defined neuromuscular circuits control these distinct tissues. Nonetheless, the emergent behaviors, feeding and locomotion, are coordinated to guarantee the efficiency of food intake. Here, we show that pharmacological hyperactivation of cholinergic transmission at the body wall muscle reduces the rate of pumping behavior. This was evidenced by a systematic screening of the effect of the cholinesterase inhibitor aldicarb on the rate of pharyngeal pumping on food in mutant worms. The screening revealed that the key determinants of the inhibitory effect of aldicarb on pharyngeal pumping are located at the body wall neuromuscular junction. In fact, the selective stimulation of the body wall muscle receptors with the agonist levamisole inhibited pumping in a lev-1-dependent fashion. Interestingly, this response was independent of unc-38, an alpha subunit of the nicotinic receptor classically expressed with lev-1 at the body wall muscle. This implies an uncharacterized lev-1-containing receptor underpins this effect. Overall, our results reveal that body wall cholinergic transmission not only controls locomotion but simultaneously inhibits feeding behavior. | 10.1016/j.jbc.2021.101466 |
pubmed_385_22106 | This paper uses John Rawls' theory of justice to defend the patent system against charges that it has an unfair effect on access to medications,from the perspective of national and international justice. The paper argues that the patent system is fair in a national context because it respects intellectual property rights and it benefits the least advantaged members of society by providing incentives for inventors, investors, and entrepreneurs. The paper also argues that the patent system is fair in an international context, provided that developed nations take steps to help disease-stricken countries secure internal justice. Fairness in a national or international context also requires that the patent system should include emergency exceptions to deal with short-term inequities. | 10.1023/B:HCAN.0000041185.52817.8c |
pubmed_786_21862 | A cell can be thought of as a well-coached sports team. To win, it needs superstar players with specialized tasks, but it also needs team players who can be relied on to maintain constant performance. Growth factor receptors or transcriptional activators might be considered to be the cell's superstars, whereas ribosomes could be considered team players that faithfully carry out directions from mRNA. The team also needs a head coach for overall direction and assistant coaches to direct the basic skills. The assistant coaches should ensure that basic cellular functions proceed correctly and that the cell responds to specific stimuli. Since almost every phosphorylatable protein is modified by several protein kinases, protein kinases like casein kinases I and II might be the assistant coaches of cellular regulation. | 10.1016/0962-8924(92)90022-f |
pubmed_938_14590 | We report our ongoing work to characterize the molecular nature of neurofibrillary tangles (NFT). An epitope map of tau protein using monoclonal antibodies that crossreact with NFT reveals the presence of epitopes that span the entire tau molecule from the amino terminus to the carboxy terminus. Several antibodies that recognize tau protein including Alz50 do not recognize primary amino acid sequence but are directed either against a post-translational modification or a complex higher order structure. The importance of tau protein in the development of the pathology is underscored by the extent of the tau-reactive neuritic lesions. These dystrophic neurites or "curly fibers" extend well beyond the classical distributions of the senile plaques and NFT. Furthermore, the neuropil lesion is considerably more extensive than either the senile plaques or neurofibrillary tangles. One of the features of the dystrophy in Alzheimer's disease is widespread neuronal sprouting characteristic of dystrophic neurites and tangle-bearing cells. | 10.3109/07853898909149195 |
pubmed_1084_16411 | Each year, more than 4 million patients receive a blood transfusion in the United States to control symptoms associated with anemia, coagulopathy, thrombocytopenia, or some combination thereof. In each of these cases, the physician and the patient must weigh the potential benefits of the transfusion along with the associated risks. To assess accurately the risk:benefit ratio and to discuss this with the patient, the physician must be familiar with the range of adverse transfusion outcomes and the current estimates of their frequency. Most important, during the past decade the risk profile of transfusion has changed significantly. Transfusion-transmitted disease, although still a rare outcome of transfusion, is no longer an overriding concern in transfusion safety considerations; however, risks such as hemolysis, transfusion-related lung injury, and anaphylaxis continue to represent significant concerns and are relatively more common than the transmission of infectious diseases after transfusion. Against this background, the development of a national hemovigilance system, designed to evaluate more accurately transfusion adverse outcomes in the United States, will require greater precision and reliability in the assessment of adverse transfusion outcomes by clinicians if the proposed benefits of this system are to be realized. | 10.1097/SMJ.0b013e31823213b6 |
pubmed_403_16411 | The SARS-CoV-2 virus and its homolog SARS-CoV penetrate human cells by binding of viral spike protein and human angiotensin converting enzyme II (ACE2). SARS-CoV causes high fever in almost all patients, while SARS-CoV-2 does not. Moreover, analysis of the clinical data revealed that the higher body temperature is a protective factor in COVID-19 patients, making us to hypothesize a temperature-dependent binding affinity of SARS-CoV-2 to human ACE2 receptor. In this study, our molecular dynamics simulation and protein surface plasmon resonance cohesively proved the SARS-CoV-2-ACE2 binding was less affinitive and stable under 40 °C (~18 nM) than the optimum temperature 37 °C (6.2 nM), while SARS-CoV-ACE2 binding was not (6.4 nM vs. 8.5 nM), which evidenced the temperature-dependent affinity and explained that higher temperature is related to better clinical outcome. The decreased infection at higher temperature was also validated by pseudovirus entry assay using Vero and Caco-2 cells. We also demonstrated the structural basis of the distinct temperature-dependence of the two coronaviruses. Furthermore, the meta-analysis revealed a milder inflammatory response happened in the early stage of COVID-19, which explained the low fever tendency of COVID-19 and indicated the co-evolution of the viral protein structure and the inflammatory response. The temperature dependence of the binding affinity also indicated that higher body temperature at early stages might be beneficial to the COVID-19 patients. | 10.1016/j.csbj.2020.12.005 |
pubmed_594_22208 | The human plasma protein mannan-binding lectin (MBL) is an essential part of the innate immune defense system. Low levels of MBL are associated with recurrent infections and other clinically significant signs of a compromised immune defense. Previous studies have addressed the possibility of reconstitution therapy by the use of recombinant or plasma-derived protein. Natural MBL is a multimeric protein, which consists of up to 18 identical polypeptide chains. Synthesis by in vitro methods of MBL with the proper multimeric structure is difficult. We here report that mice obtain MBL levels comparable to those found in normal human plasma when injected with an MBL expression construct as naked plasmid DNA contained in a large volume of physiologic salt solution. The expression was confined to the liver and high MBL expression levels were obtained with less than 5% of the liver cells transfected. The multimeric structure of the MBL found in plasma of injected mice was similar to that of natural MBL. Thus, liver expression following injection of naked DNA is an alternative to reconstitution therapy with a protein having a complex quaternary structure. | 10.1006/mthe.2001.0335 |
pubmed_588_18973 | We have compiled two comprehensive gene expression profiles from mature leaf and immature seed tissue of rice (Oryza sativa ssp. japonica cultivar Nipponbare) using Serial Analysis of Gene Expression (SAGE) technology. Analysis revealed a total of 50 519 SAGE tags, corresponding to 15 131 unique transcripts. Of these, the large majority (approximately 70%) occur only once in both libraries. Unexpectedly, the most abundant transcript (approximately 3% of the total) in the leaf library was derived from a type 3 metallothionein gene. The overall frequency profiles of the abundant tag species from both tissues differ greatly and reveal seed tissue as exhibiting a non-typical pattern of gene expression characterized by an over abundance of a small number of transcripts coding for storage proteins. A high proportion ( approximately 80%) of the abundant tags (> or = 9) matched entries in our reference rice EST database, with many fewer matches for low abundant tags. Singleton transcripts that are common to both tissues were collated to generate a summary of low abundant transcripts that are expressed constitutively in rice tissues. Finally and most surprisingly, a significant number of tags were found to code for antisense transcripts, a finding that suggests a novel mechanism of gene regulation, and may have implications for the use of antisense constructs in transgenic technology. | 10.1046/j.1467-7652.2003.00026.x |
pubmed_270_13700 | This study compared the in-vitro properties and in-vivo effects of Escherichia coli filaments, spheroplasts and normal cells in a murine thigh infection model. E. coli was exposed to ceftazidime, meropenem or saline to obtain filaments, spheroplasts or normal bacilli, which were then injected into neutropenic mice. After 24 h, morphology, CFUs, local and circulating endotoxin levels, cytokine levels and mortality were recorded, and correlations between bacterial and host parameters of infection were investigated. Filaments and spheroplasts contained more endotoxin/CFU than controls. Histological studies showed that morphologically altered bacteria changed into rod-shaped cells in the absence of antibiotics. Bacterial spread to the liver was significantly higher in mice challenged with rod-shaped cells, compared with antibiotic-exposed bacteria (p 0.007). Muscle endotoxin levels correlated significantly with circulating interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha, and both pro-inflammatory cytokines were correlated significantly (p 0.011). Despite a tendency toward higher local and systemic concentrations of endotoxin in the filament group, inflammatory responses and survival did not differ between groups. It was concluded that morphologically altered bacteria contain more endotoxin and can regain a rod shape after withdrawal of antibiotics, while non-antibiotic-exposed bacteria show greater spread to the liver. There was a clear intra-individual relationship between local endotoxin, systemic endotoxin, TNF-alpha and IL-6 production, but these parameters did not differ among groups. | 10.1111/j.1469-0691.2006.01503.x |
pubmed_964_14835 | BACKGROUND AND OBJECTIVES
To assess trends in the acquisition of new sexually transmitted diseases (STDs) among patients who test positive for human immunodeficiency virus (HIV) at STD clinics.
STUDY DESIGN
Cohorts of HIV-positive and HIV-negative persons were compared using computerized records from Miami STD clinics for 1988-1992. Persons were assigned to cohorts according to their first positive or first negative HIV test results. New STDs were defined if persons had new diagnoses of gonorrhea, primary or secondary syphilis, chancroid, or lymphogranuloma venereum; were undergoing treatment as contacts for syphilis or gonorrhea; or were undergoing epidemiologic treatment for syphilis or gonorrhea.
RESULTS
Of the 103,549 persons who visited the clinics, 53,467 were tested for HIV, and 5,615 had results that were positive. The percentages returning with new STDs were similar for the HIV-positive and HIV-negative cohorts, and both decreased over time. For the 1988 cohorts, 26% of those testing positive and 30% of those testing negative for HIV returned with at least one STD within 5 years. Returns with STD within 1 year decreased from 16% in 1988 to 3% in 1992.
CONCLUSIONS
Returns decreased dramatically among HIV-positive cohorts; however, there were similar decreases of new STDs among HIV-negative cohorts, so the decrease may have been caused by the decreasing prevalence of bacterial STD in the community rather than by behavioral changes among HIV-positive persons. | 10.1097/00007435-199605000-00012 |
pubmed_352_14285 | Performance indicators have been introduced by the DHSS for scrutinizing the activity of regional and district health authorities. Because these are based on routine information, there are a number of problems in understanding what these indicators mean and there is a need to look at alternative ways of measuring performance. | pubmed_352_14285 |
pubmed_307_12096 | Azithromycin at clinically relevant doses does not inhibit planktonic growth of the opportunistic pathogen Pseudomonas aeruginosa but causes markedly reduced formation of biofilms and quorum-sensing-regulated extracellular virulence factors. In the Gac/Rsm signal transduction pathway, which acts upstream of the quorum-sensing machinery in P. aeruginosa, the GacA-dependent untranslated small RNAs RsmY and RsmZ are key regulatory elements. As azithromycin treatment and mutational inactivation of gacA have strikingly similar phenotypic consequences, the effect of azithromycin on rsmY and rsmZ expression was investigated. In planktonically growing cells, the antibiotic strongly inhibited the expression of both small RNA genes but did not affect the expression of the housekeeping gene proC. The azithromycin treatment resulted in reduced expression of gacA and rsmA, which are known positive regulators of rsmY and rsmZ, and of the PA0588-PA0584 gene cluster, which was discovered as a novel positive regulatory element involved in rsmY and rsmZ expression. Deletion of this cluster resulted in diminished ability of P. aeruginosa to produce pyocyanin and to swarm. The results of this study indicate that azithromycin inhibits rsmY and rsmZ transcription indirectly by lowering the expression of positive regulators of these small RNA genes. | 10.1128/AAC.01801-10 |
pubmed_917_3491 | Obstructive sleep apnea syndrome (OSAS) is a complex disorder characterized by a sleep-related collapse of the upper airway. The most likely candidate for the common pathway linking various abnormalities casually associated with OSAS (such as adenotonsillar hypertrophy, obesity, retro- or micrognathia, acromegaly, or more subtle structural anomalies) is an abnormally small upper airway lumen. Symptoms of OSAS that appear during sleep include snoring, abnormal motor activity, disturbed nocturnal sleep, a sensation of choking, heartburn, nocturia, nocturnal enuresis, and heavy sweating. Daytime waking symptoms are dominated by often profound sleepiness, which may secondarily be associated with automatic behavior, retrograde amnesia, hypnagogic hallucinations, personality changes, sexual difficulties, and headaches. Careful evaluation, both sleeping and waking, are essential to select appropriate treatment. Treatments include nasal continuous positive airway pressure, tracheostomy, weight loss, uvulopalatopharyngoplasty, mandibular advancement, and so forth. | pubmed_917_3491 |
pubmed_353_17497 | The introduction of a novel entomopathogenis nematode Steinernema carpocapsae strain "agriotos" (Rhabditida: Steinernematidae) into the soil of an orchard resulted in the reduction (up to 50 %) of total amount of phytophagous insects. No negative effect on the groups of beneficial arthropods, caused by the nematode, has been found. Recommended optimal application rate is 500 thousand invasive nematode larvae per 1 m2 of the soil. Increase or decrease of the application rate resulted in the rise of the abundance of phytophagous insects. This fact proved the existence of regulating factors determining optimal ratios of the amounts of parasites at micro- and macro-levels. Activation of native populations of entomopathogenic nematodes in soil surface layer has been observed after the introduction of the novel parasite species. | pubmed_353_17497 |
pubmed_929_13013 | North Indian Ocean witnesses varied dynamical response due to independent climate modes such as Indian Ocean Dipole (IOD)/El Niño Southern Oscillations (ENSO) and their co-occurrences. These modes have a significant impact on ocean productivity, which in turn shows feedback for the strengthening of these patterns. Keeping this in view, the present work attempts to analyze the biological activity during the combined influence of positive IOD with El Niño during 2006-2007 event. To divulge the biological variability along with the dynamical response, the study includes intra-annual variability surface chlorophyll anomaly with D20 anomaly using satellite observations. Here, the individual role of IOD and ENSO on both surface chlorophyll and D20 is segregated through partial regression analysis for a period of 25 years (1993-2017). By the regression method, it can be seen varied chlorophyll response for the 2006-2007 event with the IOD forcing leads to the major spatial and temporal variability with positive anomalies in Eastern Equatorial Indian Ocean (EEIO) (generally oligotrophic), Northwestern Bay of Bengal (NWBoB), and Northwestern Arabian Sea (NAS2) where production begins in fall intermonsoon and peaks up during November. On the other hand, negative anomalies are observed around the southern tip of India (SBoB) and the Northern Arabian Sea (NAS1). While ENSO depicts the high surface chlorophyll variability in the Western Indian Ocean (WIO1, WIO2) with negative anomalies of surface chlorophyll. This study observed an asymmetric response of chlorophyll variability over the North Indian Ocean during the 1997-1998 and 2006-2007 events with a major influence of IOD mode compared with the El Niño. Therefore, understanding the chlorophyll anomalies during different climate modes will help us to better understand the interannual variability and improve the predictability of chlorophyll productivity regions. | 10.1007/s10661-019-7754-z |
pubmed_520_15021 | We have previously reported that preconception exposure to iAs may contribute to the development of diabetes in mouse offspring by altering gene expressions in paternal sperm. However, the individual contributions of iAs and its methylated metabolites, monomethylated arsenic (MAs) and dimethylated arsenic (DMAs), to changes in the sperm transcriptome could not be determined because all three As species are present in sperm after in vivo iAs exposure. The goal of the present study was to assess As species-specific effects using an ex vivo model. We exposed freshly isolated mouse sperm to either 0.1 or 1 μM arsenite (iAsIII) or the methylated trivalent arsenicals, MAsIII and DMAsIII, and used RNA-sequencing to identify differentially expressed genes, enriched pathways, and associated protein networks. For all arsenicals tested, the exposures to 0.1 μM concentrations had greater effects on gene expression than 1 μM exposures. Transcription factor AP-1 and B cell receptor complexes were the most significantly enriched pathways in sperm exposed to 0.1 μM iAsIII. The Mre11 complex and Antigen processing were top pathways targeted by exposure to 0.1 μM MAsIII and DMAsIII, respectively. While there was no overlap between gene transcripts altered by ex vivo exposures in the present study and those altered by in vivo exposure in our prior work, several pathways were shared, including PI3K-Akt signaling, Focal adhesion, and Extracellular matrix receptor interaction pathways. Notably, the protein networks associated with these pathways included those with known roles in diabetes. This study is the first to assess the As species-specific effects on sperm transcriptome, linking these effects to the diabetogenic effects of iAs exposure. | 10.1016/j.taap.2022.116266 |
pubmed_126_4802 | The ability of a soy-derived antiapoptotic fraction to inhibit methotrexate-induced gastrointestinal toxicity was examined. Male Sprague-Dawley rats treated with methotrexate were fed diets containing casein as a sole protein source or diets supplemented with a protein-phospholipid fraction isolated from soy flour. This soy fraction has also been shown to inhibit serum deprivation-induced programmed cell death (apoptosis) in the mouse embryonic C3H10T1/2 cell. Rats that received high doses of the soy-derived antiapoptotic fraction-supplemented diets experienced significantly less weight loss and diarrhea and better maintained their pretreatment appetite. | 10.1080/01635589709514627 |
pubmed_658_6819 | Infection with hepatitis B and/or hepatitis C virus is strongly associated with hepatocellular carcinoma (HCC). HCC likely develops through a sequence of chronic inflammation to fibrosis to cirrhosis and, eventually, dysplasia. Medical therapies aimed at the prevention of HCC are predicated on the interruption of this sequence by means of antiviral therapy. In this review, the authors summarize the available experience with prophylactic medical therapies and a number of questions that remain unanswered. Overall, although it appears that interferon-alpha therapy is beneficial in the prevention of HCC in patients with viral hepatitis, more experience is required before definitive recommendations can be made. | 10.1016/s1051-0443(07)61786-2 |
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