title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Preparation of hierarchical hollow CaCO3 particles and the application as anticancer drug carrier. | One-pot approach to couple the crystallization of CaCO(3) nanoparticles and the in situ symmetry-breaking assembly of these crystallites into hollow spherical shells was developed under the templating effect of a soluble starch. Further functional study using HP-a as an anticancer drug carrier (DOX) demonstrated its advantages for localizing drug release by the pH value-sensitive structure and enhancing cytotoxicity by increasing cellular uptake, perinuclear accumulation, and nuclear entry. | 18,980,322 |
A method for cleaving an allyl protecting group at the amide nitrogen of peptides by one-pot olefin isomerization-oxidation. | A facile method for N-deallylation at the amide nitrogen of peptides is described. One-pot deallylation of a substrate through ruthenium hydride-catalyzed terminal olefin isomerization and subsequent ozonolysis gave the corresponding deallylated product under mild conditions. | 18,980,332 |
Neutron scattering study of the structural change induced by photopolymerization of AOT/D2O/dodecyl acrylate inverse microemulsions. | Small-angle and ultrasmall-angle neutron scattering (SANS/USANS) measurements were used to determine the structural changes induced by photopolymerization of AOT/D2O/(dodecyl acrylate) inverse microemulsion systems. Scattering profiles were collected for the initial microemulsions and the films resulting from photopolymerization of the oil phase. The SANS data for the microemulsions were modeled as spherical, core-shell droplets. Upon polymerization, the clear mircoemulsions formed opaque films. From the SANS/USANS data of the films, it was apparent that this morphology was not preserved upon polymerization; however, it was clearly observed that the formulation of the microemulsion had a large impact on the structure within the films. The Guinier region in the USANS data (2.5 x 10(-5) A(-1) < or = Q < or = 5.3 x 10(-3) A(-1)) from the films indicates that very large structures are formed. Simultaneously, a well-defined peak (0.15 A(-1) < or = Q < or = 0.25 A(-1)) in the SANS data indicates that there are also much smaller structures formed. It is proposed that the low-Q scattering arises from aggregation of the nanometer-size water droplets in the microemulsion to form droplets large enough to scatter visible light, while the peak in the high-Q region results from bilayered structures formed by the surfactant. | 18,980,349 |
PAMAM dendrimer interactions with supported lipid bilayers: a kinetic and mechanistic investigation. | The interaction kinetics of polyamidoamine (PAMAM) dendrimers with supported lipid bilayers of 1,2-sn-glycero-dimyristoylphosphocholine prepared by the vesicle deposition has been probed by optical waveguide lightmode spectroscopy and atomic force microscopy (AFM). In particular, the influence of PAMAM dendrimer generation (G2, G4, and G6) and concentration (1 to 100 nM) on the levels of adsorption and lipid bilayer removal have been determined as a function of time; hence interaction kinetics and mechanisms have been further elucidated. Dendrimer interaction kinetics with the lipid bilayer are concentration dependent in a complex manner, with net bilayer removal at 1 and 100 nM and net adsorption at 10 nM; these effects are irrespective of dendrimer generation. The pseudo first order rate constant for bilayer removal (at 1 and 100 nM) follows the order G6 > G4 > G2. In contrast, the pseudo first order rate constant for adsorption at 10 nM follows the order G2 > G4 > G6. AFM has confirmed expansion of lipid bilayer defects, hole formation, and adsorption to the bilayer or bilayer defects, and their concentration and generation dependence. These findings have implications when designing dendrimers for specific biopharmaceutical activities, e.g., as drugs, drug delivery vehicles, transfection agents, or antimicrobials. | 18,980,350 |
Structure of molybdenum and tungsten sulfide M(x)S(y)+ clusters: experiment and DFT calculations. | A combination of experiment and density functional theory was used to investigate the energetics of CO adsorption onto several small M(x)S(y)(+) (M = Mo, W; x/y = 2/6, 3/7, 5/7, 6/8) clusters as a probe of their atomic and electronic structure. Experimentally, tandem mass spectrometry was used to measure the relative yields of M(x)S(y)(+)(CO)(n) cluster adducts formed by collisions between a beam of mass-selected M(x)S(y)(+) cluster ions and CO molecules in a high-pressure collision cell (hexapole ion guide). The most probable M(x)S(y)(+)(CO)(n) adducts observed are those with n < or = x, that is, only one CO molecule bound to each metal site. The notable exception is the M(5)S(7)(+) cluster, for which the n = 6 adduct is found to have nearly the same intensity as the n = x = 5 adduct. Density functional calculations were used to search for the lowest energy structures of the bare M(x)S(y)(+) clusters and to obtain their relative stability for sequential CO binding. The calculated trends in CO binding energies were then compared to the experimental adduct distributions for assigning the ground-state structures. In this way, it was possible to distinguish between two nearly isoenergetic ground-state isomers for the M(2)S(6)(+) and M(3)S(7)(+) clusters, as only one isomer gave a calculated CO stabilization energy trend that was consistent with the experimental data. Similar comparisons of predicted and observed CO adsorption trends also provide evidence for assigning the ground-state structures of the M(5)S(7)(+) and M(6)S(8)(+) clusters. The latter contain metallic cores with most of the sulfur atoms bonded along the edges or in the faces of the metal core structure. The n = 6 and 7 adducts of M(5)S(7)(+) are predicted to be more stable than the n = x = 5 adduct, but only the n = 6 adduct is observed experimentally. The DFT calculations show that the n = 7 adduct undergoes internal bond breaking whereas the n = 6 framework is stable, albeit highly distorted. For the M(6)S(8)(+) cluster, the calculations predict that the two lowest energy isomers can bind more than six CO molecules without fragmentation; however, the apparent binding energy drops significantly for adducts with n > 6. In general, the ability of these small M(x)S(y)(+) clusters to bind more CO molecules than the number of metal atoms is a balance between the gain in CO adsorption energy versus the strain introduced into the cluster structure caused by CO crowding, the consequences of which can be fragmentation of the M(x)S(y)(+)(CO)(n) cluster adduct (n > x). | 18,980,366 |
Synthesis of chiral organocatalysts derived from aziridines: application in asymmetric aldol reaction. | We report the synthesis of a new series of highly efficient chiral organocatalysts derived via the regio- and stereoselective ring opening of chiral aziridines with azide anions. The catalysts have proved to be very efficient for a direct asymmetric aldol reaction, both with cyclic as well as acyclic ketones in brine with 2 mol % of catalyst loading, and afforded the products in excellent yields (up to 99%) and enantioselectivities (up to >99%). The chiral aldol adduct obtained has further been converted to a chiral azetidine ring via a convenient pathway. | 18,980,379 |
Comparison of water, sediment, and plants for the monitoring of antibiotics: a case study on a river dedicated to fish farming. | Oxolinic acid, flumequine, oxytetracycline, and florfenicol are antibiotics commonly used in farming. Because an important percentage of these antibiotics given to fish and cattle ends up, directly or indirectly, in the freshwater environment, suitable tools for the monitoring of these antibiotics are needed. A French river was chosen because of the location of four fish farms and a sewage plant on its main course. First, a passive monitoring program involving water, sediment, and autochthonous bryophytes was performed at 25 sampling sites tested once every three months for one year. Second, an active monitoring method was performed using moss bags for a one-month exposure period, both upstream and downstream of each potential source of antibiotics. Sediment and bryophyte samples, but not water samples, were found to be useful for monitoring environmental contamination by oxolinic acid, flumequine, oxytetracycline, and florfenicol. Sediments and bryophytes also appeared to be complementary media for dating the river's contamination by antibiotics. Data collected by both active and passive monitoring methods confirmed contamination of the river, mainly by flumequine and oxytetracycline, attributable to fish farming but also to terrestrial animal farming and perhaps human pharmaceuticals. | 18,980,393 |
CARIN theory reanalysis reanalyzed: a comment on Maguire, Devereux, Costello, and Cater (2007). | P. Maguire, B. Devereux, F. Costello, and A. Cater discussed the Gagné and Shoben (1997) CARIN theory of conceptual combination and, after presenting a sample drawn from the British National Corpus and comparing the two corpora, concluded that the Gagné and Shoben corpus is too small and unrepresentative. They then discussed the mathematical model presented by Gagné and Shoben and claimed that the model does not incorporate relational competition. In this article, the authors present critical aspects of the mathematical model not considered by Maguire et al. and show that the mathematical instantiation of CARIN presented by Gagn and Shoben is, in fact, very sensitive to the number of strong competing relations. The authors then present some new comparisons between the corpora, showing that they correspond surprisingly well. | 18,980,417 |
Assessment of platelet growth factors in supernatants from rehydrated freeze-dried equine platelets and their effects on fibroblasts in vitro. | To determine whether platelet growth factors are preserved in supernatants obtained from rehydrated trehalose-stabilized, freeze-dried (lyophilized) equine platelets and whether those growth factors stimulate fibroblast proliferation and migration and enhance fibroblast-associated contraction in a collagen gel assay. 6 clinically normal adult horses. Blood samples were obtained from 6 horses, and washed platelets were prepared via differential centrifugation. Washed platelets were freeze-dried in a physiologic buffer with a mixture of trehalose and polyethylene glycol 4000. Rehydrated platelet supernatants and releasates prepared from fresh washed platelets stimulated with thrombin or platelet-activating factor were evaluated for transforming growth factor beta1 and platelet-derived growth factor-BB by use of ELISAs. Effects of rehydrated freeze-dried platelet supernatants on fibroblast proliferation, migration, and collagen gel contraction were compared with effects of 1%, 2.5%, or 10% fetal bovine serum (FBS). Supernatants from freeze-dried platelets contained similar amounts of growth factors as thrombin- and platelet-activating factor-stimulated platelet releasates. The supernatants significantly enhanced fibroblast proliferation and migration in a scratch assay, compared with FBS-free control or low (1%) FBS conditions. Additionally, supernatants from freeze-dried platelets enhanced contraction of fibroblast-seeded collagen gels, compared with the effect of 1% FBS. The preparation technique preserved platelet growth factors, enhanced fibroblast proliferation and migration, and improved fibroblastseeded collagen gel contraction under conditions of low FBS concentration; these platelet supernatant preparations may prove useful as an aid to conventional wound management. | 18,980,435 |
Retrospective evaluation of the effects of diazepam in dogs with anxiety-related behavior problems. | To characterize the effects of diazepam in dogs with behavior problems and to determine whether adverse effects were of sufficient concern to owners to prompt drug discontinuation. Cross-sectional study. 37 dogs and their owners. Dogs for which diazepam had been prescribed by the behavior service of a veterinary teaching hospital from July 2005 through June 2007 were identified. Owners were interviewed via telephone to obtain data on dose and frequency of administration of diazepam, effectiveness, adverse effects, and, when applicable, reasons for discontinuing the drug. Diazepam was described as very (24% [9/37]) or somewhat (43% [16/37]) effective by most owners. At the time of the interview, 18 (49%) owners reported that they were still administering diazepam to their dogs. For the remainder, reasons for discontinuation included adverse effects (58% [11/19]) and lack of efficacy (53% [10/19]). Reported adverse effects included sedation, increased appetite, ataxia, agitation, increased activity, and aggression. Owners administering diazepam to ameliorate fear of thunderstorms (24% [9/37]) were more likely to view diazepam as effective than were owners of dogs that received it for separation anxiety (54% [20/37]). Owners of dogs that received > or = 0.8 mg of diazepam/kg (0.36 mg/lb) were more likely to report increased activity as an adverse effect than were owners of dogs that received < 0.8 mg/kg. Adverse effects of diazepam in dogs were commonly reported and often led to drug discontinuation. Owner education and follow-up is recommended to avoid treatment failure when prescribing diazepam for anxiety-related behavior problems in dogs. | 18,980,494 |
Factors associated with survival of neonatal foals with bacteremia and racing performance of surviving Thoroughbreds: 423 cases (1982-2007). | To identify factors associated with short-term survival in bacteremic neonatal foals, evaluate the racing performance of Thoroughbred survivors, and evaluate changes in causative organisms and their antimicrobial susceptibility. Retrospective case series. 423 bacteremic foals. Medical records of foals that were hospitalized in 1982 through 2007 were reviewed, and those with bacteremia were included in the study. Data retrieved included signalment, physical examination and clinicopathologic findings at admission, localized infections, concurrent illnesses, duration of hospitalization, and outcome (survival to discharge from the hospital vs nonsurvival). The number, identity, and antimicrobial susceptibility of organisms isolated from blood samples were also obtained. Racing records for surviving Thoroughbred foals and maternal siblings were examined. Of 423 bacteremic foals, 254 survived. Odds of survival were negatively associated with age at admission, septic arthritis, band neutrophil count, and serum creatinine concentration and positively associated with year of admission, diarrhea, rectal temperature, neutrophil count, and arterial blood pH. Overall, microbial culture of blood samples yielded 554 isolates; Escherichia coli was consistently isolated most frequently. Percentage of isolates susceptible to enrofloxacin, but no other antimicrobial, decreased over time. Surviving Thoroughbred foals did not differ from siblings with regard to percentage of starters, percentage of winners, or number of starts; however, surviving foals had significantly fewer wins and total earnings. During the study period, microbial resistance to antimicrobials commonly used to treat bacteremic foals did not develop. Surviving bacteremic Thoroughbred foals were as likely to start races as their siblings but earned less money. | 18,980,499 |
Lipopolysaccharide-mediated enhancement of bone metabolism in estrogen-deficient mice. | Osteoporosis may be a risk factor in periodontal disease. However, biologic mechanisms explaining the apparent interaction between these two diseases have not been defined. It is well known that lipopolysaccharide (LPS) increases the resorption of alveolar bone. We hypothesized that LPS and estrogen deficiency have synergistic effects on bone metabolism and may lead to enhanced bone resorption. Eighty 8-week-old female ddY mice were divided into two groups and underwent a sham operation or bilateral ovariectomy. They were maintained for 4 weeks to assess estrogen-deficient bone loss. Osteoblasts and bone marrow cells (BMCs) were collected from ovariectomized (OVX) and sham-operated mice. Osteoclast differentiation in a coculture of osteoblasts and BMCs was investigated by tartrate-resistant acid phosphatase staining. Receptor activator of nuclear factor-kappa B ligand (RANKL) mRNA expression in LPS-treated osteoblasts was investigated using real-time polymerase chain reaction. Interferon-gamma (IFN-gamma) and interleukin (IL)-6 and -10 levels in the culture supernatants were evaluated by enzyme-linked immunosorbent assay. Group means were compared by analysis of variance followed by Tukey's honestly significant difference. There was a significant increase in the number of osteoclasts in LPS-treated cocultures from OVX mice compared to sham controls (P <0.05). RANKL mRNA expression in LPS-treated osteoblasts from OVX mice was greater than in sham mice (P <0.05). In contrast, the production of IFN-gamma in LPS-treated coculture from OVX mice was significantly lower than in sham mice (P <0.05). LPS-bearing Gram-negative organisms are abundant in periodontal disease, and the results supported the hypothesis that bone resorption is increased in estrogen-deficient patients. | 18,980,527 |
Pay for performance programs in Australia: a need for guiding principles. | Pay-for-performance (P4P) programs which reward clinical providers with incentive payments based on one or more measures of quality of care are now common in the United States and the United Kingdom and it is likely they will attract increasing interest in Australia. However, empirical evidence demonstrating effectiveness of such programs is limited and many existing programs have not had rigorous outcome evaluation. To maximise success, future P4P programs should incorporate the lessons and insights obtained from previous experience. Based on a review of published trials, program evaluations and position statements, the following principles that may guide future program design and implementation were synthesised: 1) formulate a rationale and a business case for P4P; 2) use established evidence-based performance measures; 3) use rigorous and verifiable methods of data collection and analysis; 4) define performance targets using absolute and relative thresholds; 5) use rewards that are sufficient, equitable and transparent; 6) address appropriateness of provider responses and avoid perverse incentives; 7) implement communication and feedback strategies; 8) use existing organisational structures to implement P4P programs; 9) attribute credit for performance to participants in ways that foster population-based perspectives; and 10) invest in outcomes and health service research. Recommendations flowing from these principles relevant to Australian settings are provided. | 18,980,570 |
A case study of centralised monitoring of hospital access performance. | Access to care for patients remains a concern for all parties in the provision of hospital services. It is the subject of patient complaints, large investments of funds and vigorous debate in the community, hospitals and the political arena. This is a common problem in developed nations. There has been little achievement in information technology solutions to this significant problem in Australia. This paper presents a case study of the development and implementation of an organisational access display system intended to provide real-time, or near to real-time information and feedback on access for staff on the floor. This is believed to be one of the first times such a development has been reported in the Australian literature, albeit limited to the context of a single organisation. | 18,980,571 |
A decade of data linkage in Western Australia: strategic design, applications and benefits of the WA data linkage system. | The report describes the strategic design, steps to full implementation and outcomes achieved by the Western Australian Data Linkage System (WADLS), instigated in 1995 to link up to 40 years of data from over 30 collections for an historical population of 3.7 million. Staged development has seen its expansion, initially from a linkage key to local health data sets, to encompass links to national and local health and welfare data sets, genealogical links and spatial references for mapping applications. The WADLS has supported over 400 studies with over 250 journal publications and 35 graduate research degrees. Applications have occurred in health services utilisation and outcomes, aetiologic research, disease surveillance and needs analysis, and in methodologic research. Longitudinal studies have become cheaper and more complete; deletion of duplicate records and correction of data artifacts have enhanced the quality of information assets; data linkage has conserved patient privacy; community machinery necessary for organised responses to health and social problems has been exercised; and the commercial return on research infrastructure investment has exceeded 1000%. Most importantly, there have been unbiased contributions to medical knowledge and identifiable advances in population health arising from the research. | 18,980,573 |
Quality frameworks for telephone triage. | The establishment of the Grampians After-Hours Service has led to the development of a quality framework for nurse telephone triage. The service providers believe this framework is the basis for the service's success. While quality frameworks including critical evaluation and peer review are not new to the health industry, the development of organisational systems to improve quality in after-hours services is innovative. The framework developed is comprehensive, evidenced-based and emphasises training, protocols and documentation. It also involves a continuous and non-punitive quality review process that operates at the individual, small group, organisation and whole-system level. The framework will continue to improve and at this time provides a foundation for discussion and further application in the pursuit of quality improvement in rural after-hours health services. | 18,980,575 |
Oxysterol activation of phosphatidylcholine synthesis involves CTP:phosphocholine cytidylyltransferase alpha translocation to the nuclear envelope. | In addition to suppressing cholesterol synthesis and uptake, oxysterols also activate glycerophospholipid and SM (sphingomyelin) synthesis, possibly to buffer cells from excess sterol accumulation. In the present study, we investigated the effects of oxysterols on the CDP-choline pathway for PtdCho (phosphatidylcholine) synthesis using wild-type and sterol-resistant CHO (Chinese-hamster ovary) cells expressing a mutant of SCAP [SREBP (sterol-regulatory-element-binding protein) cleavage-activating protein] (CHO-SCAP D443N). [(3)H]Choline-labelling experiments showed that 25OH (25-hydroxycholesterol), 22OH (22-hydroxycholesterol) and 27OH (27-hydroxycholesterol) increased PtdCho synthesis in CHO cells as a result of CCTalpha (CTP:phosphocholine cytidylyltransferase alpha) translocation and activation at the NE (nuclear envelope). These oxysterols also activate PtdCho synthesis in J774 macrophages. in vitro, CCTalpha activity was stimulated 2- to 2.5-fold by liposomes containing 5 mol% 25OH, 22OH or 27OH. Inclusion of up to 5 mol% cholesterol did not further activate CCTalpha. 25OH activated CCTalpha in CHO-SCAP D443N cells leading to a transient increase in PtdCho synthesis and accumulation of CDP-choline. CCTalpha translocation to the NE and intranuclear tubules in CHO-SCAP D443N cells was complete after 1 h exposure to 25OH compared with only partial translocation by 4-6 h in CHO-Mock cells. These enhanced responses in CHO-D443N cells were sterol-dependent since depletion with cyclodextrin or lovastatin resulted in reduced sensitivity to 25OH. However, the lack of effect of cholesterol on in vitro CCT activity indicates an indirect relationship or involvement of other sterols or oxysterol. We conclude that translocation and activation of CCTalpha at nuclear membranes by side-chain hydroxylated sterols are regulated by the cholesterol status of the cell. | 18,980,580 |
How stable is sense of coherence? Changes following an intervention for unemployed individuals. | The present investigation was concerned with the changeability of sense of coherence. We examined changes in sense of coherence (SOC) over a six-month period in a sample of Finnish unemployed individuals (n = 74) participating in an intervention program designed to boost re-employment. Over the study period, participants' sense of coherence improved significantly and re-employed individuals reported the greatest changes. Different changes in the subcomponents of SOC, comprehensibility, manageability and meaningfulness, were found. Contrary to expectations, participants younger than 30 years of age did not show greater changes in their SOC. Initial personal resources were predictors of both positive and negative changes in SOC. | 18,980,600 |
Long-term in vitro reactivity for human leukocyte antigen antibodies and comparison of detection using serum versus plasma. | Human leukocyte antigen (HLA) antibodies are a possible cause of transfusion-related acute lung injury (TRALI), and fluorescent bead assays are often used for antibody detection. Serum is the manufacturer's recommended sample, but plasma may be easier to obtain for studies of HLA antibody prevalence and TRALI case investigations. Specimens were obtained from 44 multiparous females positive for the presence of HLA antibodies by lymphocytotoxicity testing at least 13 years prior and from 1000 contemporary blood donors. Screening tests were performed using a multiplex bead-based assay. In addition to comparing results obtained with paired plasma and serum samples, the effects of storage at 4 degrees C for 1 week and of multiple freeze-thaw cycles were evaluated. Of 42 evaluable subjects with HLA antibodies documented more than 13 years earlier, only 1 showed loss of detectable antibodies, with 39 (93%) positive in the screening assay for HLA Class I and 24 (57%) positive in the screening assay for HLA Class II antibodies. In 968 evaluable contemporary donors, 291 screened positive for the presence of HLA Class I and 206 for HLA Class II antibodies using a low assay cutoff. Screening test concordance using paired plasma and serum samples was high, particularly for subjects with higher-level antibodies. Refrigeration of samples for 1 week did not significantly affect assay results, while repeated freeze-thaw cycles caused a decrement in signal level. Serum and plasma samples gave concordant results in the majority of cases, particularly for specimens with higher-level antibodies. High-level HLA antibodies were present in most individuals for more than 13 years. | 18,980,615 |
Monitoring of human liver and kidney allograft tolerance: a tissue/histopathology perspective. | Several factors acting together have recently enabled clinicians to seriously consider whether chronic immunosuppression is needed in all solid organ allograft recipients. This has prompted a dozen or so centers throughout the world to prospectively wean immunosuppression from conventionally treated liver allograft recipients. The goal is to lessen the impact of chronic immunosuppression and empirically identify occasional recipients who show operational tolerance, defined as gross phenotype of tolerance in the presence of an immune response and/or immune deficit that has little or no significant clinical impact. Rare operationally tolerant kidney allograft recipients have also been identified, usually by single case reports, but only a couple of prospective weaning trials in conventionally treated kidney allograft recipients have been attempted and reported. Pre- and postweaning allograft biopsy monitoring of recipients adds a critical dimension to these trials, not only for patient safety but also for determining whether events in the allografts can contribute to a mechanistic understanding of allograft acceptance. The following is based on a literature review and personal experience regarding the practical and scientific aspects of biopsy monitoring of potential or actual operationally tolerant human liver and kidney allograft recipients where the goal, intended or attained, was complete withdrawal of immunosuppression. | 18,980,624 |
Independent evolution of functional Pm3 resistance genes in wild tetraploid wheat and domesticated bread wheat. | The Pm3 alleles of cultivated bread wheat confer gene for gene resistance to the powdery mildew fungus. They represent a particular case of plant disease resistance gene evolution, because of their recent origin and possible evolution after the formation of hexaploid wheat. The Pm3 locus is conserved in tetraploid wheat, thereby allowing the comparative evolutionary study of the same resistance locus in a domesticated species and in one of its wild ancestors. We have identified 61 Pm3 allelic sequences from wild and domesticated tetraploid wheat subspecies. The Pm3 sequences corresponded to 24 different haplotypes. They showed low sequence diversity, differing by only a few polymorphic sequence blocks that were further reshuffled between alleles by gene conversion and recombination. Polymorphic sequence blocks are different from the blocks found in functional Pm3 alleles of hexaploid wheat, indicating an independent evolution of the Pm3 loci in the two species. A new functional gene was identified in a wild wheat accession from Syria. This gene, Pm3k, conferred intermediate race-specific resistance to powdery mildew, and consists of a mosaic of gene segments derived from non-functional alleles. This demonstrates that Pm3-based resistance is not very frequent in wild tetraploid wheat, and that the evolution of functional resistance genes occurred independently in wild tetraploid and bread wheat. The Pm3 sequence variability and geographic distribution indicated that diversity was higher in wild emmer wheat from the Levant area, compared with the accessions from Turkey. Further screens for Pm3 functional genes in wild wheat should therefore focus on accessions from the Levant region. | 18,980,638 |
A toolbox and procedural notes for characterizing novel zinc finger nucleases for genome editing in plant cells. | The induction of double-strand breaks (DSBs) in plant genomes can lead to increased homologous recombination or site-specific mutagenesis at the repair site. This phenomenon has the potential for use in gene targeting applications in plant cells upon the induction of site-specific genomic DSBs using zinc finger nucleases (ZFNs). Zinc finger nucleases are artificial restriction enzymes, custom-designed to cleave a specific DNA sequence. The tools and methods for ZFN assembly and validation could potentially boost their application for plant gene targeting. Here we report on the design of biochemical and in planta methods for the analysis of newly designed ZFNs. Cloning begins with de novo assembly of the DNA-binding regions of new ZFNs from overlapping oligonucleotides containing modified helices responsible for DNA-triplet recognition, and the fusion of the DNA-binding domain with a FokI endonuclease domain in a dedicated plant expression cassette. Following the transfer of fully assembled ZFNs into Escherichia coli expression vectors, bacterial lysates were found to be most suitable for in vitro digestion analysis of palindromic target sequences. A set of three in planta activity assays was also developed to confirm the nucleic acid digestion activity of ZFNs in plant cells. The assays are based on the reconstruction of GUS expression following transient or stable delivery of a mutated uidA and ZFN-expressing cassettes into target plants cells. Our tools and assays offer cloning flexibility and simple assembly of tested ZFNs and their corresponding target sites into Agrobacterium tumefaciens binary plasmids, allowing efficient implementation of ZFN-validation assays in planta. | 18,980,651 |
HvLsi1 is a silicon influx transporter in barley. | Most plants accumulate silicon in their bodies, and this is thought to be important for resistance against biotic and abiotic stresses; however, the molecular mechanisms for Si uptake and accumulation are poorly understood. Here, we describe an Si influx transporter, HvLsi1, in barley. This protein is homologous to rice influx transporter OsLsi1 with 81% identity, and belongs to a Nod26-like major intrinsic protein sub-family of aquaporins. Heterologous expression in both Xenopus laevis oocytes and a rice mutant defective in Si uptake showed that HvLsi1 has transport activity for silicic acid. Expression of HvLsi1 was detected specifically in the basal root, and the expression level was not affected by Si supply. There was a weak correlation between Si uptake and the expression level of HvLsi1 in eight cultivars tested. In the seminal roots, HvLsi1 is localized on the plasma membrane on the distal side of epidermal and cortical cells. HvLsi1 is also located in lateral roots on the plasma membrane of hypodermal cells. These cell-type specificity of localization and expression patterns of HvLsi1 are different from those of OsLsi1. These observations indicate that HvLsi1 is a silicon influx transporter that is involved in radial transport of Si through the epidermal and cortical layers of the basal roots of barley. | 18,980,663 |
Learning transcriptional regulatory networks from high throughput gene expression data using continuous three-way mutual information. | Probability based statistical learning methods such as mutual information and Bayesian networks have emerged as a major category of tools for reverse engineering mechanistic relationships from quantitative biological data. In this work we introduce a new statistical learning strategy, MI3 that addresses three common issues in previous methods simultaneously: (1) handling of continuous variables, (2) detection of more complex three-way relationships and (3) better differentiation of causal versus confounding relationships. With these improvements, we provide a more realistic representation of the underlying biological system. We test the MI3 algorithm using both synthetic and experimental data. In the synthetic data experiment, MI3 achieved an absolute sensitivity/precision of 0.77/0.83 and a relative sensitivity/precision both of 0.99. In addition, MI3 significantly outperformed the control methods, including Bayesian networks, classical two-way mutual information and a discrete version of MI3. We then used MI3 and control methods to infer a regulatory network centered at the MYC transcription factor from a published microarray dataset. Models selected by MI3 were numerically and biologically distinct from those selected by control methods. Unlike control methods, MI3 effectively differentiated true causal models from confounding models. MI3 recovered major MYC cofactors, and revealed major mechanisms involved in MYC dependent transcriptional regulation, which are strongly supported by literature. The MI3 network showed that limited sets of regulatory mechanisms are employed repeatedly to control the expression of large number of genes. Overall, our work demonstrates that MI3 outperforms the frequently used control methods, and provides a powerful method for inferring mechanistic relationships underlying biological and other complex systems. The MI3 method is implemented in R in the "mi3" package, available under the GNU GPL from http://sysbio.engin.umich.edu/~luow/downloads.php and from the R package archive CRAN. | 18,980,677 |
mtDNA depletion confers specific gene expression profiles in human cells grown in culture and in xenograft. | Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function. However, the effects mitochondrial DNA (mtDNA) levels have on the nuclear transcriptome have not been defined under physiological conditions. In order to address this issue, we characterized the gene expression profiles of A549 lung cancer cells and their mtDNA-depleted rho0 counterparts grown in culture and as tumor xenografts in immune-deficient mice. Cultured A549 rho0 cells were respiration-deficient and showed enhanced levels of transcripts relevant to metal homeostasis, initiation of the epithelial-mesenchymal transition, and glucuronidation pathways. Several well-established HIF-regulated transcripts showed increased or decreased abundance relative to the parental cell line. Furthermore, growth in culture versus xenograft has a significantly greater influence on expression profiles, including transcripts involved in mitochondrial structure and both aerobic and anaerobic energy metabolism. However, both in vitro and in vivo, mtDNA levels explained the majority of the variance observed in the expression of transcripts in glucuronidation, tRNA synthetase, and immune surveillance related pathways. mtDNA levels in A549 xenografts also affected the expression of genes, such as AMACR and PHYH, involved in peroxisomal lipid metabolic pathways. We have identified mtDNA-dependent gene expression profiles that are shared in cultured cells and in xenografts. These profiles indicate that mtDNA-depleted cells could provide informative model systems for the testing the efficacy of select classes of therapeutics, such as anti-angiogenesis agents. Furthermore, mtDNA-depleted cells grown culture and in xenografts provide a powerful means to investigate possible relationships between mitochondrial activity and gene expression profiles in normal and pathological cells. | 18,980,691 |
Bifidobacterium strains suppress in vitro the pro-inflammatory milieu triggered by the large intestinal microbiota of coeliac patients. | Coeliac disease (CD) is an enteropathy characterized by an aberrant immune response to cereal-gluten proteins. Although gluten peptides and microorganisms activate similar pro-inflammatory pathways, the role the intestinal microbiota may play in this disorder is unknown. The purpose of this study was to assess whether the faecal microbiota of coeliac patients could contribute to the pro-inflammatory milieu characteristic of CD and the possible benefits of bifidobacteria. The effect of faeces of 26 CD patients with active disease (mean age 5.5 years, range 2.1-12.0 years), 18 symptom-free coeliac disease (SFCD) patients (mean age 5.5 years, range 1.0-12.3 years) on a gluten-free diet for 1-2 years; and 20 healthy children (mean age 5.3 years, range 1.8-10.8 years) on induction of cytokine production and surface antigen expression in peripheral blood mononuclear cells (PBMCs) were determined. The possible regulatory roles of Bifidobacterium longum ES1 and B. bifidum ES2 co-incubated with faecal samples were also assessed in vitro. Faeces of both active CD and SFCD patients, representing an imbalanced microbiota, significantly increased TNF-alpha production and CD86 expression in PBMCs, while decreased IL-10 cytokine production and CD4 expression compared with control samples. Active CD-patient samples also induced significantly higher IFN-gamma production compared with controls. However, Bifidobacterium strains suppressed the pro-inflammatory cytokine pattern induced by the large intestinal content of CD patients and increased IL-10 production. Cytokine effects induced by faecal microbiota seemed to be mediated by the NFkappaB pathway. The intestinal microbiota of CD patients could contribute to the Th1 pro-inflammatory milieu characteristic of the disease, while B. longum ES1 and B. bifidum ES2 could reverse these deleterious effects. These findings hold future perspectives of interest in CD therapy. | 18,980,693 |
Genetic noise control via protein oligomerization. | Gene expression in a cell entails random reaction events occurring over disparate time scales. Thus, molecular noise that often results in phenotypic and population-dynamic consequences sets a fundamental limit to biochemical signaling. While there have been numerous studies correlating the architecture of cellular reaction networks with noise tolerance, only a limited effort has been made to understand the dynamic role of protein-protein interactions. We have developed a fully stochastic model for the positive feedback control of a single gene, as well as a pair of genes (toggle switch), integrating quantitative results from previous in vivo and in vitro studies. In particular, we explicitly account for the fast binding-unbinding kinetics among proteins, RNA polymerases, and the promoter/operator sequences of DNA. We find that the overall noise-level is reduced and the frequency content of the noise is dramatically shifted to the physiologically irrelevant high-frequency regime in the presence of protein dimerization. This is independent of the choice of monomer or dimer as transcription factor and persists throughout the multiple model topologies considered. For the toggle switch, we additionally find that the presence of a protein dimer, either homodimer or heterodimer, may significantly reduce its random switching rate. Hence, the dimer promotes the robust function of bistable switches by preventing the uninduced (induced) state from randomly being induced (uninduced). The specific binding between regulatory proteins provides a buffer that may prevent the propagation of fluctuations in genetic activity. The capacity of the buffer is a non-monotonic function of association-dissociation rates. Since the protein oligomerization per se does not require extra protein components to be expressed, it provides a basis for the rapid control of intrinsic or extrinsic noise. The stabilization of regulatory circuits and epigenetic memory in general is of direct implications to organism fitness. Our results also suggest possible avenues for the design of synthetic gene circuits with tunable robustness for a wide range of engineering purposes. | 18,980,697 |
Spontaneous transformation of human granulosa cell tumours into an aggressive phenotype: a metastasis model cell line. | Granulosa cell tumours (GCTs) are frequently seen in menopausal women and are relatively indolent. Although the physiological properties of normal granulosa cells have been studied extensively, little is known about the molecular mechanism of GCT progression. Here, we characterise the unique behavioural properties of a granulosa tumour cell line, KGN cells, for the molecular analysis of GCT progression. Population doubling was carried out to examine the proliferation capacity of KGN cells. Moreover, the invasive capacity of these cells was determined using the in vitro invasion assay. The expression level of tumour markers in KGN cells at different passages was then determined by Western blot analysis. Finally, the growth and metastasis of KGN cells injected subcutaneously (s.c.) into nude mice was observed 3 months after injection. During in vitro culture, the advanced passage KGN cells grew 2-fold faster than the early passage cells, as determined by the population doubling assay. Moreover, we found that the advanced passage cells were 2-fold more invasive than the early passage cells. The expression pattern of tumour markers, such as p53, osteopontin, BAX and BAG-1, supported the notion that with passage, KGN cells became more aggressive. Strikingly, KGN cells at both early and advanced passages metastasized to the bowel when injected s.c. into nude mice. In addition, more tumour nodules were formed when the advanced passage cells were implanted. KGN cells cultured in vitro acquire an aggressive phenotype, which was confirmed by the analysis of cellular activities and the expression of biomarkers. Interestingly, KGN cells injected s.c. are metastatic with nodule formation occurring mostly in the bowel. Thus, this cell line is a good model for analysing GCT progression and the mechanism of metastasis in vivo. | 18,980,698 |
Recent advances in understanding depression in adults with diabetes. | The authors review the science linking depression with diabetes. Some recent heuristic research is identified that highlights progress in the field and is directing future research. Issues in the management of depression in diabetes are outlined, including interactions of depression and insulin resistance. | 18,980,733 |
[Bioenergy production from waste: examples of biomethane and biohydrogen]. | This new century addresses several environmental challenges among which distribution of drinking water, global warming and availability of novel renewable energy sources to substitute for fossil fuels are of utmost importance. The last two concerns are closely related because the major part of carbon dioxide (CO(2)), considered as the main cause of the greenhouse effect, is widely produced from fossil fuel combustion. Renewable energy sources fully balanced in CO(2) are therefore of special interest, especially the issue of biological production from organic wastes. Among the possibilities of bioenergy production from wastes, two approaches are particularly interesting: The first one is relatively old and related to the production of biomethane by anaerobic digestion while the second one, more recent and innovative, relies on biohydrogen production by microbial ecosystems. | 18,980,740 |
[Postgenomic analysis of desiccation tolerance]. | Desiccation tolerance is the capacity to survive complete drying. It is an ancient trait that can be found in prokaryotes, fungi, primitive animals (often at the larval stages), whole plants, pollens and seeds. In the dry state, metabolism is suspended and the duration that anhydrobiotes can survive ranges from years to centuries. Whereas genes induced by drought stress have been successfully enumerated in tissues that are sensitive to cellular desiccation, we have little knowledge as to the adaptive role of these genes in establishing desiccation tolerance at the cellular level. This paper reviews postgenomic approaches in a variety of desiccation tolerant organisms in which the genetic responses have been investigated when they acquire the capacity of tolerating extremes of dehydration or when they are dry. Accumulation of non-reducing sugars, LEA proteins and a coordinated repression of metabolism appear to be the essential and universal attributes that can confer desiccation tolerance. The protective mechanisms of these attributes are described. Furthermore, it is most likely that other mechanisms have evolved since the function of about 30% of the genes involved in desiccation tolerance remains to be elucidated. The question of the overlap between desiccation tolerance and drought tolerance is briefly addressed. | 18,980,743 |
Clinical and biochemical presentations of polycystic ovary syndrome among obese and nonobese women. | To study the differences in clinical and biochemical characteristics between obese and nonobese women with polycystic ovary syndrome (PCOS). Retrospective study. University teaching hospital. Four hundred sixty-four Taiwan Chinese women, among whom 295 were diagnosed with PCOS and 169 were non-PCOS controls. Body mass index, average menstrual interval, modified Ferriman-Gallwey score, acne, total T, and waist-to-hip ratio. Obese women with polycystic ovary morphology (PCOM) had a greater risk of developing of PCOS (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.5-10.4) than nonobese women with PCOM. Obese women with PCOM had a higher incidence oligomenorrhea (OR, 2.6; 95% CI, 1.6-4.1) and biochemical hyperandrogenemia (OR, 2.5; 95% CI, 1.6-4.0) than nonobese women with PCOM. Obese subjects with PCOS had a higher risk of developing oligomenorrhea (OR, 2.2; 95% CI, 1.3-3.7) and biochemical hyperandrogenemia (OR, 2.6; 95% CI, 1.6-4.2) than nonobese women with PCOS. Moreover, obese women with PCOS had significantly higher serum total T levels and more prolonged menstrual intervals than nonobese women with PCOS. Notably, the obese women with PCOS presented less acne than the nonobese subjects (OR, 0.5; 95% CI, 0.3-0.9). Obese women with PCOS had more severe ovulatory dysfunction and higher serum total T levels than nonobese subjects. Moreover, obese women with PCOS had a significantly lower frequency of acne than nonobese subjects. | 18,980,763 |
The influence of disinfection on aquatic biodegradable organic carbon formation. | The aim of this paper was to assess the extent of biodegradable dissolved organic carbon formation upon disinfection of water with chlorine dioxide. Wide diversity of natural waters has been subjected to reactions with various amounts of ClO(2). For comparison examined waters have also been treated with ozone and chlorine. The application of chlorine dioxide and ozone significantly changed the molecular weight distribution of aquatic organic matter. As a result significant amounts of biodegradable carboxylic acids and aldehydes were generated. The formic, acetic, oxalic and ketomalonic acids as well as formaldehyde, acetaldehyde, glyoxal, methylglyoxal were identified. The productivity of aldehydes calculated for all examined waters and disinfectants amounted 12.7-47.7microgmg(-1) DOC in the case of ozonation, 1.3-8.1microgmg(-1) DOC after chlorination and 1.7-9.4microgmg(-1) DOC for ClO(2) treatment. The highest total concentration of carboxylic acids was determined after the ozonation processes. In this case the organic acids' formation potential was in the range 10.8-62.8microgmg(-1) DOC. Relatively high formation potential (5.3-17.9microgmg(-1) DOC) was determined after the oxidation with ClO(2) as well. In the case of chlorination, the productivity of organic acids was low and did not exceed 3.4microgmg(-1) DOC. The relatively high correlation between BDOC formation and carboxylic acids' formation potential was observed. Thus, carboxylic acids' formation potential may be used as a measure of water potential to form BDOC. | 18,980,774 |
RNA polymerases I and III, non-coding RNAs and cancer. | Oncogenically transformed cells overexpress the non-coding RNAs, such as pre-ribosomal RNA (rRNA) and transfer RNA (tRNA), which are produced by RNA polymerases (Pols) I and III. Recent results indicate that levels of pre-rRNA have prognostic value and that a tRNA has oncogenic potential. Transcription by Pols I and III is restrained in healthy cells by the tumour suppressors RB, p53, ARF and PTEN. Such restraints are compromised during cell transformation and the problem is accentuated by oncogene products, such as c-Myc, that stimulate the output of Pol I and Pol III. The resultant increases in rRNA and tRNA expression might promote the generation of cancers. | 18,980,784 |
Examination of femoral-neck structure using finite element model and bone mineral density using dual-energy X-ray absorptiometry. | Research regarding femoral-neck fractures has mainly focused on bone mineral density and limited studies have been performed on relationship between the femoral-neck structure and its fracture. Finite element models were established to estimate stress distributions across the femoral neck with various femoral-neck angle from 115 degrees to 140 degrees. The bone mineral density measurements across the femoral-neck region using dual-energy X-ray absorptiometry were taken from 89 healthy and 10 patients with a femoral-neck fracture. Femoral neck angles were determined on radiographs from a separate group of participants. The results showed that the bone mineral density of the fracture patients was significantly smaller in all examined areas around femoral neck, especially in the ward's triangle. Under a same loading condition, the stress level may easily reach its intensity limit and therefore cause a fracture. The modeling results indicated that the posteromedial side of the femoral neck experienced the highest stress and was inversely related with the femoral-neck angle. As the angle decreased below 125 degrees, the stress around the femoral neck increased significantly and therefore increases risk of fracture at the site. It is recommended that if the femoral-neck angle is below 125 degrees and is accompanied by low bone mineral density, the patient should be considered a high risk candidate for femoral-neck fracture. In addition, if the femoral-neck angle of one hip is significantly smaller than the other side and 125 degrees, the hip should be also considered as high risk. | 18,980,785 |
MRI documented acute myelitis in a patient with Vogt-Koyanagi-Harada syndrome: first report. | MRI findings in transverse myelitis complicating Vogt-Koyanagi-Harada (VKH) syndrome have not been documented before. Here, we present a case with acute myelitis complicating VKH syndrome and show the MRI findings. | 18,980,794 |
Analytical methodologies for the determination of sertraline. | Sertraline is a widely used antidepressant belonging to the selective serotonin reuptake inhibitor class; its efficacy has been demonstrated not only in the treatment of major depression, obsessive compulsive and panic disorders, but also for eating, premenstrual dysphoric and post-traumatic stress disorders. Several methods have been published for the determination of sertraline in pharmaceuticals, biological materials and environmental samples. The purpose of the current review is to provide a systematic survey of the latest analytical techniques for the determination of sertraline covering the period from 1987 until 2008. | 18,980,823 |
Chorioallantoic membrane assays have been based on diffusion control--problems arising with a diversity of mass transfers in egg white. | The chorioallantoic membrane (CAM) assays have been intensively used to determine angiogenesis and anti-angiogenesis of medicines. In view of bioactivity, this technique should be performed with kinetic control regime in chicken embryos. Whether the dosages ever used had satisfied this requirement, we explored by mathematical analysis. A diffusion-in-egg model was established to describe several medicinal diffusions in egg white that involved the instantaneous transient kinetic behavior, the diffusion of medicines in capping volume (the volume from the air sac to the interface of egg yolk). By reviewing the diffusion of various compounds including the cited and the experimentals in this work, we conclude that all the CAM assays ever cited were performed under diffusion control regime rather than kinetic control, which may bring forth deviations caused by a diversity of constitutes in egg white through various medicine-protein interactions. | 18,980,833 |
Polymerizing immobilization of acrylamide-modified nucleic acids and its application. | The immobilization of nucleic acids on solid supports has been widely used in the detection of DNA and other biomolecules in sensor technology. Because three dimensional (3-D) hydrogel matrixes offer significant advantages for capturing probes over more conventional two dimensional (2-D) rigid substrates and the ability to provide a solution-mimicking environment, they are becoming increasingly attractive as desired supports for bio-analysis. Acrylamide-modified nucleic acids and acrylamide monomers being polymerized directly to immobilize nucleic acids is only one-step chemical process which is not interfered by exterior surroundings, and the 3-D polyacrylamide gel fabricated by this method is not required to be activated by some labile chemical treatments. Moreover, the attachment is extremely stable to withstand the cycling process involved in the polymerase chain reaction (PCR). In this paper, the development of polymerizing immobilization of acrylamide-modified nucleic acids is reviewed, and its applications in DNA sequence high-throughput analysis including mutation analysis and the whole genome sequencing are summarized. | 18,980,839 |
Sternoclavicular septic arthritis in a previously healthy patient: a case report and review of the literature. | Sternoclavicular septic arthritis is an unusual event in healthy patients. Cases have been reported in diabetes mellitus patients, intravenous drug abusers and patients affected by rheumatoid arthritis. We report a case of this unique infection that occurred in a patient who was not at risk of septic arthritis. Through this case and a review of the literature, we discuss the difficulty of diagnosing this disorder, and the consequences of delayed treatment in terms of life-threatening outcomes and therapeutic options. | 18,980,853 |
Dissociating nociceptive modulation by the duration of pain anticipation from unpredictability in the timing of pain. | Waiting longer to receive pain increases its perceived unpleasantness by inducing 'dread'. However, it is not clear how unpredictability in the timing of the impending pain stimulus interacts with dread and whether the two factors show differential effects on the neural generators of the pain-evoked response. We manipulated the duration of anticipation of laser-induced pain independently of unpredictability of stimulus delivery timing, to observe the relative effect on P2 amplitudes of the laser-evoked potential (LEP) response and its estimated sources. Subjects (n=12) reported increased pain ratings after longer pain anticipation, irrespective of unpredictability in the timing of stimulus delivery. By contrast, unpredictability in stimulus timing increased the amplitude of the P2 irrespective of anticipation duration. The modulation of P2 amplitude by unpredictability was localized to midcingulate cortex (MCC) and ipsilateral secondary somatosensory (S2) areas. Greater anticipation duration increased activity in a hippocampal-insula-prefrontal network but not in MCC areas. Distinct neural networks contribute to the P2 and are differentially affected by pain anticipation duration and unpredictability in stimulus timing. ERP research into dread should be careful to appreciate the neural generators of pain-evoked responses and their potential modulation by unpredictability. | 18,980,863 |
Major pitfalls in the measurement of artemisinin derivatives in plasma in clinical studies. | A bioanalytical method for the analysis of artesunate (ARS) and its metabolite dihydroartemisinin (DHA) in human plasma using protein precipitation and liquid chromatography coupled to positive tandem mass spectroscopy was developed. The method was validated according to published US FDA-guidelines and showed excellent performance. However, when it was applied to clinical pharmacokinetic studies in malaria, variable degradation of the artemisinins introduced an unacceptable large source of error, rendering the assay useless. Haemolytic products related to sample collection and malaria infection degraded the compounds. Addition of organic solvents during sample processing and even low volume addition of the internal standard in an organic solvent caused degradation. A solid phase extraction method avoiding organic solvents eliminated problems arising from haemolysis induced degradation. Plasma esterases mediated only approximately 20% of ex vivo hydrolysis of ARS into DHA. There are multiple sources of major preventable error in measuring ARS and DHA in plasma samples from clinical trials. These various pitfalls have undoubtedly contributed to the large inter-subject variation in plasma concentration profiles and derived pharmacokinetic parameters for these important antimalarial drugs. | 18,980,865 |
Willingness among college students to help a smoker quit. | Between February and March 2003, the authors examined college students' willingness to help a smoker quit and assessed demographic and psychosocial characteristics associated with willingness to help. Survey respondents were 701 college students (474 women, 227 men) aged 18 to 24 years who indicated there was someone close to them whom they thought should quit smoking. Respondents completed measures of willingness to help. The authors used multivariate logistic regression analysis to examine respondent characteristics associated with willingness to help. About half (54%; n = 381) reported that they "definitely would" be interested in helping this smoker quit. Characteristics significantly associated with willingness to help were lower levels of perceived stress, being a non-tobacco user, concern for a boyfriend, girlfriend, or spouse who smoked, and more severe levels of distress caused by this person's smoking. A high percentage of college students are willing to help a smoker. Future studies are needed to engage college students who are nonsmokers in tobacco control efforts, including the Healthy Campus 2010 initiatives to reduce smoking among college students. | 18,980,882 |
The use of nutritional labels by college students in a food-court setting. | Between January and September 2006, the authors examined when, why, if, and how nutrition labels impact food purchase decisions of college students. Participants were 16 college-aged students at a large northeastern university. As part of a larger study undertaken at a large northeastern university on the effect of nutrition labels in restaurant settings on food purchases, the authors held a focus group to look more deeply at when and why nutrition labeling impacted college student food purchases. Although results of the large study are still being discerned, the focus group results reveal that college women and men were interested in the provision of nutrition labels in the food court-like setting found at the university, and that those exposed to labels over the course of the study noticed these labels and often referred to them when making purchase decisions. Additional findings reveal that price and convenience also play a role in food purchases and that, of those items listed on each label, calories and fat were most important to the study population. Although more research is needed, this qualitative study finds that students want nutrition labels and would use them to make food purchasing decisions. | 18,980,885 |
Readiness to change among a group of heavy-drinking college students: correlates of readiness and a comparison of measures. | Although several multi-item scales assess readiness to change alcohol consumption, some researchers have proposed that a small number of single-item rulers may assess readiness nearly as well. In fall 2006 and spring 2007, the authors assessed 279 participants who reported at least 1 heavy drinking episode in the 2 weeks prior to the survey. The authors compared answers from the Readiness to Change Questionnaire with rulers measuring importance and confidence regarding change. Importance correlated strongly with readiness to change, whereas confidence correlated negatively and less strongly with readiness. The validity of the importance ruler as a proxy for readiness was supported by its correlations with several measures of patterns of alcohol use, as well as its precursors and consequences. Given the strong correlation between the importance ruler and the Readiness to Change score, this method may have practical utility as a brief assessment tool. Adding confidence as a second dimension slightly improved the ability to predict readiness. | 18,980,889 |
Risk of unwanted sex for college women: evidence for a red zone. | University and college health and counseling centers frequently warn female students about the red zone-a period early in a student's first year at college during which she may be at higher risk for unwanted sexual experiences (UWS). The authors designed this study to assess temporal risk for UWS in 1st- and 2nd-year college women. In March 2006, the authors randomly selected 50 first-year and 52 second-year students (representing one-sixth of each class year) to complete a modified Sexual Experiences Survey. First-year women were at higher risk for UWS than were second-year women--particularly, early in the fall semester. The authors observed a significant linear effect during participants' combined first years in school, with more reports of UWS occurring early in the year. This study provides support for a red zone and highlights the need for investigating local norms for UWS. | 18,980,890 |
The role of haptic exploration of ground surface information in perception of overhead reachability. | The authors performed an experiment in which participants (N = 24) made judgments about maximum jump and reachability on ground surfaces with different elastic properties: sand and a trampoline. Participants performed judgments in two conditions: (a) while standing and after having recently jumped on the surface in question and (b) while standing on a third control surface, eliminating haptic exploration of the surface in question. There was a high correlation between perceived maximum reachable height and actual maximum reachable height in all conditions. Judging performance on the basis of visual and haptic exploration of ground surface information was slightly overestimated, whereas performance on the basis of visual information alone was underestimated and variable for the different surfaces. The authors discuss possible causes for the observed errors. They emphasize that there is a considerable nonvisual aspect to the nature of the information specifying affordances for overhead reach and jumping and that perceptual performance is degraded when spontaneous exploratory movement is restricted. | 18,980,903 |
The experience of imagery as a post-treatment intervention in patients with breast cancer: program, process, and patient recommendations. | To better understand the common themes of women participating in an imagery program designed to improve quality of life (QOL). Qualitative. Classroom setting at Alaska Regional Hospital in Anchorage. 10 women with a confirmed diagnosis of breast cancer who had completed conventional care participated in a six-class, eight-week-long imagery program titled Envision the Rhythms of Life (ERL). Focus group audio recordings and notes were interpreted with the Krueger focus group method and confirmed by an outside evaluator. Breast cancer survivors' descriptions of imagery practice and experience as they created passive, active, and targeted imagery. Participants reported the importance of engaging passive and active imagery, letting targeted imagery take on a life of its own, performing homework, understanding the science, practicing, hearing imagery stories, engaging all the senses, trusting imagery, and group interaction. Imagery practice improved mood state. When delivered by expert imagery trainers in collaboration with oncology nurses, ERL can improve breast cancer survivors' QOL. The present study is one of few reports that evaluated survivors' imagery experiences from a clinical trial and produced significant QOL improvements. The present study provides oncology nurses understanding of the psychological risks faced by breast cancer survivors after completion of primary care and explains the critical need for post-treatment programs for survivors dealing with post-traumatic stress disorder, depression, anxiety, or high levels of stress. | 18,980,915 |
Effects of a supervised exercise intervention on recovery from treatment regimens in breast cancer survivors. | To investigate the effects of supervised exercise training on cardiopulmonary function and fatigue in cancer survivors undergoing various clinical treatments. Pretest and post-test quasiexperimental. Outpatient oncology rehabilitation center. 96 breast cancer survivors undergoing various clinical treatments. Subjects were divided into four groups based on the specific type of clinical treatment: surgery alone (n = 22); surgery and chemotherapy (n = 30); surgery and radiation (n = 17); and surgery, chemotherapy, and radiation (n = 27). Following a comprehensive screening and medical examination, cardiovascular endurance, pulmonary function, and fatigue were assessed, leading to the development of an individualized exercise prescription and a six-month exercise intervention. Repeated-measures analysis of variance and covariance were used to compare the effectiveness of the intervention and differences among treatment groups. Systolic and diastolic blood pressure, resting heart rate, forced vital capacity, forced expiratory volume, predicted oxygen consumption, time on treadmill, and fatigue. Cardiopulmonary function (predicted maximal oxygen consumption and time on treadmill) significantly increased in all groups after exercise training. In addition, resting heart rate and forced vital capacity significantly improved in those receiving surgery, chemotherapy, and radiation. Psychologically, the exercise intervention resulted in significant reductions in behavioral, affective, sensory, cognitive and mood, and total fatigue scale scores in all three groups who received treatment with surgery. The breast cancer survivors in the surgery-alone group showed significant reductions in behavioral, affective, and total fatigue scale scores but not in sensory and cognitive and mood fatigue scale scores. The results suggest that moderate intensity, individualized, prescriptive exercise maintains or improves cardiopulmonary function with concomitant reductions in fatigue regardless of treatment type. Moreover, cancer survivors receiving combination chemotherapy and radiotherapy following surgery appear to benefit to a greater extent as a result of an individualized exercise intervention. Clinicians need to be aware of adjuvant therapies such as moderate exercise that attenuate negative side effects of cancer treatments. Symptom management recommendations should be given to cancer survivors concerning the effectiveness of exercise throughout the cancer continuum and the importance of participating in a cancer rehabilitation exercise program. | 18,980,921 |
Differential palmitoylation of the endosomal SNAREs syntaxin 7 and syntaxin 8. | Palmitoylation is a posttranslational modification that regulates protein trafficking and stability. In this study we investigated whether the endosomal soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) proteins syntaxin 7 and syntaxin 8 are modified with palmitate. Using metabolic labeling and site-directed mutagenesis, we show that human syntaxins 7 and 8 are modified with palmitate through a thioester linkage. Palmitoylation is dependent upon cysteine 239 of human syntaxin 7 and cysteine 214 of syntaxin 8, residues that are located on the cytoplasmic face of the transmembrane domain (TMD). Palmitoylation of syntaxin 8 is minimally affected by the Golgi-disturbing agent brefeldin A (BFA), whereas BFA dramatically inhibits palmitoylation of syntaxin7. The differential effect of BFA suggests that palmitoylation of syntaxins 7 and 8 occurs in distinct subcellular compartments. Palmitoylation does not affect the rate of protein turnover of syntaxins 7 and 8 nor does it influence the steady-state localization of syntaxin 8 in late endosomes. Syntaxin 7 actively cycles between endosomes and the plasma membrane. Palmitoylation-defective syntaxin 7 is selectively retained on the plasma membrane, suggesting that palmitoylation is important for intercompartmental transport of syntaxin 7. | 18,980,942 |
Corresponding increase in long-chain acyl-CoA and acylcarnitine after exercise in muscle from VLCAD mice. | Long-chain acylcarnitines accumulate in long-chain fatty acid oxidation defects, especially during periods of increased energy demand from fat. To test whether this increase in long-chain acylcarnitines in very long-chain acyl-CoA dehydrogenase (VLCAD(-/-)) knock-out mice correlates with acyl-CoA content, we subjected wild-type (WT) and VLCAD(-/-) mice to forced treadmill running and analyzed muscle long-chain acyl-CoA and acylcarnitine with tandem mass spectrometry (MS/MS) in the same tissues. After exercise, long-chain acyl-CoA displayed a significant increase in muscle from VLCAD(-/-) mice [C16:0-CoA, C18:2-CoA and C18:1-CoA in sedentary VLCAD(-/-): 5.95 +/- 0.33, 4.48 +/- 0.51, and 7.70 +/- 0.30 nmol x g(-1) wet weight, respectively; in exercised VLCAD(-/-): 8.71 +/- 0.42, 9.03 +/- 0.93, and 14.82 +/- 1.20 nmol x g(-1) wet weight, respectively (P < 0.05)]. Increase in acyl-CoA in VLCAD-deficient muscle was paralleled by a significant increase in the corresponding chain length acylcarnitine. Exercise resulted in significant lowering of the free carnitine pool in VLCAD(-/-) muscle. This is the first study demonstrating that acylcarnitines and acyl-CoA directly correlate and concomitantly increase after exercise in VLCAD-deficient muscle. | 18,980,943 |
Deep venous thrombosis caused by congenital malformation of the inferior vena cava and heterozygous factor V leiden presenting as venous claudication. | A case of an 18-year-old man with deep venous thrombosis of the lower limbs caused by hypoplasia of the inferior vena cava in combination with heterozygous factor V Leiden is presented. Both anomalies were found when the patient complained of venous claudication in both thighs. Inferior vena cava malformation is a rare condition and may predispose to the development of deep venous thrombosis. This patient was at an even higher risk for deep venous thrombosis as the inferior vena cava malformation was combined with a hypercoagulable state. | 18,980,946 |
BRCA1 5083del19 mutant allele selectively up-regulates periostin expression in vitro and in vivo. | The aim of this study was to explore the gene expression pattern produced by the cancer-associated BRCA1 5083del19 founder mutation by using a microarray analysis. Such a mutation, identified in a subset of familial breast cancer patients, involves a deletion at the 3' end of the BRCA1 messenger leading, in the mature protein, to the ablation of the BRCT tandem domain. We generated HeLa cells stably expressing both exogenous wild-type (HeLa/(wt)BRCA1), used as a control, and 5083del19 BRCA1 (HeLa/(5083del19)BRCA1) alleles; gene chips were then used to investigate any changes in the transcription profile induced by the 5083del19 BRCA1 mutant compared with controls. Among the genes showing perturbation of their expression, periostin was found to be up-regulated in HeLa/(5083del19)BRCA1 cells to an extent of 72-fold versus HeLa/(pcDNA3.1/empty) and 76-fold versus HeLa/(wt)BRCA1 cells. This finding was validated both in vitro in breast cancer cell lines harboring mutations of BRCA1 and in vivo by immunohistochemistry of breast cancer specimens bearing the 5083del19 BRCA1 mutation as well as by Western blot analysis of sera obtained from patients and healthy carriers of the same mutation. Our results suggest that periostin overexpression, whose product is released from cells in the extracellular fluids, might be a potential marker for early cancer detection in a specific subset of hereditary breast carcinomas triggered by cancer-associated BRCA1 mutations that affect the BRCT tandem domain. | 18,980,973 |
Sulforaphane enhances the therapeutic potential of TRAIL in prostate cancer orthotopic model through regulation of apoptosis, metastasis, and angiogenesis. | The purpose of this study was to examine the molecular mechanisms by which sulforaphane enhances the therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in prostate cancer. Cell viability and apoptosis assays were done by XTT and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, respectively. Tumor-bearing mice were treated with vehicle, sulforaphane, TRAIL, and sulforaphane plus TRAIL. Markers of apoptosis, angiogenesis, and metastasis were measured by immunohistochemistry. Sulforaphane enhanced the therapeutic potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Sulforaphane-induced apoptosis in PC-3 cells correlated with the generation of intracellular reactive oxygen species (ROS), collapse of mitochondrial membrane potential, activation of caspase-3 and caspase-9, and up-regulation of DR4 and DR5. Sulforaphane induced the expression of Bax, Bak, Bim, and Noxa and inhibited the expression of Bcl-2, Bcl-X(L), and Mcl-1. The quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against sulforaphane-induced ROS generation, mitochondrial membrane potential disruption, caspase-3 activation, and apoptosis. Sulforaphane inhibited growth of orthotopically implanted PC-3 tumors by inducing apoptosis and inhibiting proliferation and also enhanced the antitumor activity of TRAIL. Sulforaphane up-regulated the expressions of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax and Bak and inhibited the activation of nuclear factor-kappaB P13K/AKT and MEK/ERK pathways in tumor tissues. The combination of sulforaphane and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis and activating FOXO3a transcription factor than single agent alone. The ability of sulforaphane to inhibit tumor growth, metastasis, and angiogenesis and to enhance the therapeutic potential of TRAIL suggests that sulforaphane alone or in combination with TRAIL can be used for the management of prostate cancer. | 18,980,980 |
Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas. | Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade 4 malignant glioma, salvage therapies following recurrence offer essentially palliative benefit. We did a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with recurrent grade 3 malignant glioma. Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan every 14 days, a second cohort (n=24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle. For both cohorts, the dose of irinotecan was 340 mg/m(2) for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m(2) for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance imaging. The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95% confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient, and one patient who developed thrombotic thrombocytopenic purpura. Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant glioma. | 18,981,004 |
Population pharmacokinetics and pharmacogenetics of imatinib in children and adults. | The aim of this study was to explore the effect of several demographic, biological, and pharmacogenetic covariates on the disposition of imatinib and its main metabolite (CGP74588) in both adults and children. Thirty-three children with solid malignancies included in a phase II exploratory study and 34 adults with gastrointestinal stromal tumors received 340 mg/m(2) and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by a population pharmacokinetic method (NONMEM) to evaluate the effect of age, body weight, age, sex, albuminemia, plasma alpha1-acid glycoprotein (AGP), and eight polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5, and AGP (pharmacogenetic data available for 46 of 67 patients). Analysis of the whole data set in 67 patients showed that apparent clearance (CL/F) of imatinib was positively correlated with body weight and albuminemia and negatively with AGP. By considering these three covariates, the interindividual variability on CL/F decreased from 47% to 19%. The apparent clearance of CGP74588 was similarly dependent on both body weight and AGP and significantly lower (30% reduction) at steady-state. By adding genotype status to the final covariate imatinib model, a 22% reduction in CL/F was observed in heterozygous compared with wild-type patients corresponding to ABCG2 c.421C>A (P<0.05). By considering morphologic and biological covariates, a unique covariate model could be used to accurately describe imatinib pharmacokinetics in patients ages 2 to 84 years. Morphologic and biological characteristics have a stronger influence than pharmacogenetics on imatinib pharmacokinetics. | 18,981,009 |
A meta-analysis of impact exercise on postmenopausal bone loss: the case for mixed loading exercise programmes. | To assess the effects of differing impact exercise protocols on postmenopausal bone loss at the hip and spine. Systematic review and meta-analysis. Electronic bibliographic databases, key journals and reference lists of reviews and articles. Two independent reviewers assessed controlled trials evaluating effects of impact exercise on lumbar spine, femoral neck and total hip bone mineral density (BMD) in postmenopausal women for inclusion. Heterogeneity amongst trials and publication bias were assessed. Trial quality assessment was also performed. Impact protocols that included jogging mixed with walking and stair climbing, and protocols that incorporated impact exercise with high-magnitude loading (resistance exercises), were effective at lumbar spine (weighted mean difference (random effects) 0.025 g/cm(2) 95% CI (0.004 to 0.046) and 0.016 g/cm(2) 95% CI (0.005 to 0.027); p = 0.02 and p = 0.005 respectively), although heterogeneity was evident (I(2) = 88% and I(2) = 73%, where I(2) measures the extent of inconsistency among the trials). Effects on femoral neck BMD following these types of protocols were significant (weighted mean difference (fixed effect) 0.022 g/cm(2) 95% CI (0.014 to 0.030); p<0.001 and 0.005 g/cm(2) 95% CI (0.001 to 0.010); p = 0.03 respectively). High-impact only and odd-impact only protocols were ineffective in increasing BMD at any site. Mixed loading exercise programmes combining jogging with other low-impact loading activity and programmes mixing impact activity with high-magnitude exercise as resistance training appear effective in reducing postmenopausal bone loss at the hip and spine. Other forms of impact exercise appear less effective at preserving BMD in this population. However, diverse methodological and reporting discrepancies are evident in current published trials. | 18,981,037 |
Experimental antibody therapy of liver metastases reveals functional redundancy between Fc gammaRI and Fc gammaRIV. | Many patients with colorectal cancer will develop liver metastases, even after successful surgical removal of the primary tumor at a time at which no visible metastases are present. We previously demonstrated that surgery--although mandatory--paradoxically enhances the risk of developing liver metastases. Because Ab therapy has been acknowledged as a successful strategy to treat malignancies, we studied the potential of postoperative adjuvant Ab therapy to prevent outgrowth of liver metastases. Treatment with murine anti-gp75 (TA99) mAb completely prevented outgrowth of B16F10 liver metastases in over 90% of mice. Therapeutic efficacy was maintained in either C1q- or complement receptor 3-deficient mice but was completely abrogated in FcR gamma-chain knockout mice. This indicates that the classical complement pathway was not essential, but interaction with activatory Fc gammaR was necessary for successful therapy. TA99-treatment was still effective in Fc gammaRI(-/-), Fc gammaRIII(-/-), Fc gammaRI/III(-/-), and Fc gammaRI/II/III(-/-) mice, suggesting an important role for Fc gammaRIV. However, wild-type mice that were treated with TA99 Abs and an Fc gammaRIV blocking Ab (mAb 9E9) were protected against development of liver metastases as well. Only when both Fc gammaRI and Fc gammaRIV functions were simultaneously inhibited, TA99-mediated curative Ab treatment was abrogated, indicating functional redundancy between both IgG receptors in the liver. Furthermore, depletion of liver macrophages (Kupffer cells) reduced the efficacy of Ab therapy, supporting that Kupffer cells are involved as effector cells. Importantly, since Ab treatment almost completely prevented development of liver metastases, postoperative adjuvant Ab therapy may help to improve patient prognosis. | 18,981,101 |
Human CD4+ CD25+ Foxp3+ regulatory T cells do not constitutively express IL-35. | EBV-induced gene 3 (EBI3) can associate with p28 to form the heterodimeric cytokine IL-27, or with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, recently named IL-35. In mice, IL-35 has been shown to be constitutively expressed by CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) and suggested to contribute to their suppressive activity. In this study, we investigated whether human Treg cells express IL-35. Double-staining analysis of human thymuses showed that neither Foxp3(+) nor CD25(+) cells coexpressed EBI3. Similarly, Foxp3(+) cells present in human lymph nodes, tonsils, spleens, and intestines did not express EBI3. Consistent with these in situ observations, Treg cells purified from blood or tonsils were negative for EBI3 by immunoblotting. Other human T cell subsets, including effector T cells, naive and memory CD4(+) T cells, CD8(+) and gammadelta T cells also did not constitutively express EBI3, which contrasts with IL-35 expression observed in murine CD8(+) and gammadelta T cells. Furthermore, although CD3/CD28 stimulation consistently induced low levels of EBI3 in various CD4(+) T cell subsets, no EBI3 could be detected in CD3/CD28-stimulated Treg cells. RT-PCR analysis showed that, whereas p35 transcripts were detected in both Teff and Treg cells, EBI3 transcripts were detected only in activated Teff cells, but not in resting or activated Treg cells. Thus, in contrast to their murine counterpart, human Treg cells do not express detectable amounts of IL-35. | 18,981,109 |
A novel role for neutrophils as critical activators of NK cells. | Neutrophils are essential players in innate immune responses to bacterial infection. Despite the striking resistance of Legionella pneumophila (Lpn) to bactericidal neutrophil function, neutrophil granulocytes are important effectors in the resolution of legionellosis. Indeed, mice depleted of neutrophils were unable to clear Lpn due to a lack of the critical cytokine IFN-gamma, which is produced by NK cells. We demonstrate that this can be ascribed to a previously unappreciated role of neutrophils as major NK cell activators. In response to Lpn infection, neutrophils activate caspase-1 and produce mature IL-18, which is indispensable for the activation of NK cells. Furthermore, we show that the IL-12p70 response in Lpn-infected neutropenic mice is also severely reduced and that the Lpn-induced IFN-gamma production by NK cells is strictly dependent on IL-12. However, since dendritic cells, and not neutrophils, are the source of Lpn-induced IL-12, its paucity is a consequence of the absence of IFN-gamma produced by NK cells rather than the absence of neutrophils per se. Therefore, neutrophil-derived IL-18, in combination with dendritic cell-produced IL-12, triggers IFN-gamma synthesis in NK cells in Lpn-infected mice. We propose a novel central role for neutrophils as essential IL-18 producers and hence NK cell "helpers" in bacterial infection. | 18,981,133 |
TNF-alpha is a positive regulatory factor for human Vgamma2 Vdelta2 T cells. | Vgamma2 Vdelta2 T cells in human peripheral blood recognize phosphoantigen and play important roles in host defense and immunoregulation. The TCR is required for Vgamma2 Vdelta2 T cell responses to phosphoantigen, but less is known about soluble or cell-associated costimulatory molecules. In this study, we show that human Vgamma2 Vdelta2 T cell responses to phosphoantigen, including activation, proliferation, cytokine production, and tumor cell cytotoxicity, require TNF-alpha binding to its receptor, with a preference for TNFR2. Because stimulated Vgamma2 Vdelta2 cells also produce TNF-alpha, this may be a positive control mechanism to sustain the response. Impaired proliferation in the presence of TNF-alpha or TNFR blocking agents was partially rescued by a TLR2 agonist, Pam(3)Cys. Our studies demonstrate that TNF-alpha plays a critical role in regulating human Vgamma2 Vdelta2 T cell immune responses. | 18,981,134 |
Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease. | Microglial activation is an important pathological component in brains of patients with Alzheimer's disease (AD), and fibrillar amyloid-beta (Abeta) peptides play an important role in microglial activation in AD. However, mechanisms by which Abeta peptides induce the activation of microglia are poorly understood. The present study underlines the importance of TLR2 in mediating Abeta peptide-induced activation of microglia. Fibrillar Abeta1-42 peptides induced the expression of inducible NO synthase, proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), and integrin markers (CD11b, CD11c, and CD68) in mouse primary microglia and BV-2 microglial cells. However, either antisense knockdown of TLR2 or functional blocking Abs against TLR2 suppressed Abeta1-42-induced expression of proinflammatory molecules and integrin markers in microglia. Abeta1-42 peptides were also unable to induce the expression of proinflammatory molecules and increase the expression of CD11b in microglia isolated from TLR2(-/-) mice. Finally, the inability of Abeta1-42 peptides to induce the expression of inducible NO synthase and to stimulate the expression of CD11b in vivo in the cortex of TLR2(-/-) mice highlights the importance of TLR2 in Abeta-induced microglial activation. In addition, ligation of TLR2 alone was also sufficient to induce microglial activation. Consistent to the importance of MyD88 in mediating the function of various TLRs, antisense knockdown of MyD88 also inhibited Abeta1-42 peptide-induced expression of proinflammatory molecules. Taken together, these studies delineate a novel role of TLR2 signaling pathway in mediating fibrillar Abeta peptide-induced activation of microglia. | 18,981,147 |
The structure of binder of Arl2 (BART) reveals a novel G protein binding domain: implications for function. | The ADP-ribosylation factor-like (Arl) family of small G proteins are involved in the regulation of diverse cellular processes. Arl2 does not appear to be membrane localized and has been implicated as a regulator of microtubule dynamics. The downstream effector for Arl2, Binder of Arl 2 (BART) has no known function but, together with Arl2, can enter mitochondria and bind the adenine nucleotide transporter. We have solved the solution structure of BART and show that it forms a novel fold composed of six alpha-helices that form three interlocking "L" shapes. Analysis of the backbone dynamics reveals that the protein is highly anisotropic and that the loops between the central helices are dynamic. The regions involved in the binding of Arl2 were mapped onto the surface of BART and are found to localize to these loop regions. BART has faces of differing charge and structural elements, which may explain how it can interact with other proteins. | 18,981,177 |
Structural and functional analysis of a glycoside hydrolase family 97 enzyme from Bacteroides thetaiotaomicron. | SusB, an 84-kDa alpha-glucoside hydrolase involved in the starch utilization system (sus) of Bacteroides thetaiotaomicron, belongs to glycoside hydrolase (GH) family 97. We have determined the enzymatic characteristics and the crystal structures in free and acarbose-bound form at 1.6A resolution. SusB hydrolyzes the alpha-glucosidic linkage, with inversion of anomeric configuration liberating the beta-anomer of glucose as the reaction product. The substrate specificity of SusB, hydrolyzing not only alpha-1,4-glucosidic linkages but also alpha-1,6-, alpha-1,3-, and alpha-1,2-glucosidic linkages, is clearly different from other well known glucoamylases belonging to GH15. The structure of SusB was solved by the single-wavelength anomalous diffraction method with sulfur atoms as anomalous scatterers using an in-house x-ray source. SusB includes three domains as follows: the N-terminal, catalytic, and C-terminal domains. The structure of the SusB-acarbose complex shows a constellation of carboxyl groups at the catalytic center; Glu532 is positioned to provide protonic assistance to leaving group departure, with Glu439 and Glu508 both positioned to provide base-catalyzed assistance for inverting nucleophilic attack by water. A structural comparison with other glycoside hydrolases revealed significant similarity between the catalytic domain of SusB and those of alpha-retaining glycoside hydrolases belonging to GH27, -36, and -31 despite the differences in catalytic mechanism. SusB and the other retaining enzymes appear to have diverged from a common ancestor and individually acquired the functional carboxyl groups during the process of evolution. Furthermore, sequence comparison of the active site based on the structure of SusB indicated that GH97 included both retaining and inverting enzymes. | 18,981,178 |
Regions of melanocortin 2 (MC2) receptor accessory protein necessary for dual topology and MC2 receptor trafficking and signaling. | MRAP, melanocortin 2 (MC2) receptor accessory protein, is required for trafficking by the MC2 (ACTH) receptor. MRAP is a single transmembrane protein that forms highly unusual antiparallel homodimers. We used molecular complementation to ask where MRAP achieves dual topology. Fragments of yellow fluorescent protein (YFP) were fused to the NH2 or COOH terminus of MRAP such that YFP fluorescence could occur only in antiparallel homodimers; fluorescence was present in the endoplasmic reticulum. MRAP retained dual topology after deletion of most of the amino terminus. In contrast, deletion of residues 31-37, just NH2-terminal to the transmembrane domain, forced MRAP into a single Nexo/Ccyt orientation and blocked its ability to promote MC2 receptor trafficking and homodimerize. When the transmembrane domain of MRAP was replaced with the corresponding region from RAMP3, dual topology was retained but MRAP was inactive. Insertion of MRAP residues 29-37 conferred dual topology to RAMP3, normally in an Nexo/Ccyt orientation. When expressed with MRAPDelta1-30, MRAPDelta10-20, or MRAPDelta21-30, MC2 receptor was localized on the plasma membrane but unable to respond to ACTH. Residues 18-21 of MRAP were critical; MC2 receptor expressed with MRAP(18-21A) localized to the plasma membrane but did not bind 125I-ACTH or increase cAMP in response to ACTH. A newly identified MRAP homolog, MRAP2, lacks amino acids 18LDYI21 of MRAP and, like MRAP(18-21A), allows MC2 receptor trafficking but not signaling. MRAP2 with an LDYI insertion functions like MRAP. These results demonstrate that MRAP not only facilitates MC2 receptor trafficking but also allows properly localized receptor to bind ACTH and consequently signal. | 18,981,183 |
Constraint-induced therapy versus dose-matched control intervention to improve motor ability, basic/extended daily functions, and quality of life in stroke. | Trials of constraint-induced movement therapy (CIT) to improve upper extremity function after stroke have usually not included an actively treated control group. This study compared a modified CIT intervention with a dose-matched control intervention that included restraint of the less affected hand and assessed for differences in motor and functional performance and health-related quality of life. This 2-group randomized controlled trial, using pretreatment and posttreatment measures, enrolled 32 patients within 6 to 40 months after onset of a first stroke (mean age, 55.7 years). They received either CIT (restraint of the less affected limb combined with intensive training of the affected limb for 2 hours daily 5 days per week for 3 weeks and restraint of the less affected hand for 5 hours outside of the rehabilitation training) or a conventional intervention with hand restraint for the same duration. Outcome measures were the Fugl-Meyer Assessment, Functional Independence Measure, Motor Activity Log, Nottingham Extended Activities of Daily Living Scale, and Stroke Impact Scale. Compared with the control group, the CIT group exhibited significantly better performance in motor function, level of functional independence, mobility of extended activities during daily life, and health-related quality of life after treatment. The robust effects of this form of CIT were demonstrated in various aspects of outcome, including motor function, basic and extended functional ability, and quality of life. | 18,981,188 |
Endobronchial polyp derived from a myxosarcoma in the lung of a dog. | An endobronchial polyp was visible radiographically and bronchoscopically in an 11-year-old, mixed-breed dog with a persistent cough. The polyp was removed by traction. Initial histological examination suggested it was a myxomatous fibroma. The cough resolved but recurred with polyp regrowth. Two additional lung masses became visible radiographically. The polyp was removed twice more at 6-month intervals. Euthanasia was performed 15 months after first presentation when coughing recurred soon after the final bronchoscopy. Histological examination revealed that the mass was a myxomatous sarcoma. The lung contained two other unrelated tumors: a bronchioloalveolar carcinoma and a carcinoma of unknown origin. | 18,981,198 |
Sarcospan reduces dystrophic pathology: stabilization of the utrophin-glycoprotein complex. | Mutations in the dystrophin gene cause Duchenne muscular dystrophy and result in the loss of dystrophin and the entire dystrophin-glycoprotein complex (DGC) from the sarcolemma. We show that sarcospan (SSPN), a unique tetraspanin-like component of the DGC, ameliorates muscular dystrophy in dystrophin-deficient mdx mice. SSPN stabilizes the sarcolemma by increasing levels of the utrophin-glycoprotein complex (UGC) at the extrasynaptic membrane to compensate for the loss of dystrophin. Utrophin is normally restricted to the neuromuscular junction, where it replaces dystrophin to form a functionally analogous complex. SSPN directly interacts with the UGC and functions to stabilize utrophin protein without increasing utrophin transcription. These findings reveal the importance of protein stability in the prevention of muscular dystrophy and may impact the future design of therapeutics for muscular dystrophies. | 18,981,229 |
P bodies promote stress granule assembly in Saccharomyces cerevisiae. | Recent results indicate that nontranslating mRNAs in eukaryotic cells exist in distinct biochemical states that accumulate in P bodies and stress granules, although the nature of interactions between these particles is unknown. We demonstrate in Saccharomyces cerevisiae that RNA granules with similar protein composition and assembly mechanisms as mammalian stress granules form during glucose deprivation. Stress granule assembly is dependent on P-body formation, whereas P-body assembly is independent of stress granule formation. This suggests that stress granules primarily form from mRNPs in preexisting P bodies, which is also supported by the kinetics of P-body and stress granule formation both in yeast and mammalian cells. These observations argue that P bodies are important sites for decisions of mRNA fate and that stress granules, at least in yeast, primarily represent pools of mRNAs stalled in the process of reentry into translation from P bodies. | 18,981,231 |
A hemidominant Naip5 allele in mouse strain MOLF/Ei-derived macrophages restricts Legionella pneumophila intracellular growth. | Mouse-derived macrophages have the unique ability to restrict or permit Legionella pneumophila intracellular growth. The common inbred mouse strain C57BL/6J (B6) restricts L. pneumophila growth, whereas macrophages derived from A/J mice allow >10(3)-fold bacterial growth within three days. This phenotypic difference was mapped to the mouse Naip5 allele. The B6 restrictive Naip5 allele is dominant, and six amino acid changes in its product were predicted to control permissiveness. By using the wild-derived mouse strain MOLF/Ei, we found that MOLF/Ei-derived macrophages also restrict L. pneumophila growth, yet the Naip5 protein is identical to the A/J Naip5 at the six-amino-acid signature. The MOLF/Ei restrictive trait, unlike that of B6-derived macrophages, was not dominant over the A/J trait. In spite of this phenotypic difference, the L. pneumophila growth restriction in MOLF/Ei macrophages was mapped to the Naip5 region as well, indicating that the originally predicted change in the A/J Naip5 allele may not be critical for restriction. In the product of the A/J Naip5 permissive allele, there are four unique amino acid changes that map to a NACHT-like domain. Similar misregulating mutations have been identified in the NACHT domains of Nod-like receptor (NLR) proteins. Therefore, one of these mutations may be critical for restriction of L. pneumophila intracellular growth, and this parallels results found with human NLR variants with defects in the innate immune response. | 18,981,241 |
The C-type lectin SIGNR1 binds Schistosoma mansoni antigens in vitro, but SIGNR1-deficient mice have normal responses during schistosome infection. | The de novo immune response to infectious organisms arises from the innate recognition of pathogen-associated molecular patterns (PAMPs) by the host's pattern recognition receptors (PRRs). As the generation of type 2 cytokine responses by the human trematode parasite Schistosoma mansoni is glycan mediated, there is a particular potential role for a C-type lectin receptor (CLR) to mediate the innate recognition of schistosome PAMPs. One such CLR, dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN; CD209), has been shown to recognize glycans expressed by S. mansoni eggs. We show that SIGNR1 (SIGN-related 1; CD209b), a murine homologue of DC-SIGN that is expressed on macrophages, also binds both schistosome-soluble egg antigens and worm antigens in vitro. The generation of schistosome egg-induced pulmonary egg granulomas was not altered in SIGNR1-deficient mice. Following S. mansoni infection, the SIGNR1-deficient mice had an unaltered phenotype with an intact immunological response and no difference in pathology. In this study we demonstrate that although SIGNR1 recognizes S. mansoni antigens in vitro, this CLR is redundant during infection. This study highlights the finding that although there was binding of SIGNR1 to immunogenic factors produced in the S. mansoni life cycle, this recognition does not translate to a functional in vivo role for the PRR during infection. | 18,981,244 |
Diverse cytomegalovirus UL27 mutations adapt to loss of viral UL97 kinase activity under maribavir. | In vitro resistance to maribavir (MBV), a cytomegalovirus UL97 kinase inhibitor currently in clinical trials, is known to result from viral UL97 mutations that confer moderate to high-level resistance and UL27 mutations that confer low-level resistance. To add to the four reported UL27 mutations, cytomegalovirus isolates or strains were propagated under MBV. Four clinical isolates evolved UL27 mutations, which were first detected after 8 to 30 passages under drug selection. In three separate experiments, laboratory strain T2294, which contained an exonuclease mutation, developed UL27 mutations at 10 to 12 passages under MBV. Most of these isolates and strains also developed a UL97 mutation, commonly T409M, before or after the appearance of the UL27 mutation. The passage of two laboratory strains genetically defective in UL97, in the absence of MBV, likewise resulted in UL27 mutations. The nine UL27 mutations observed included multiple instances of point, stop, and frameshift mutations, which were individually transferred to a reference CMV strain and which were shown to confer two- to threefold increases in MBV inhibitory concentrations. In contrast, seven common UL27 amino acid changes found in baseline clinical isolates conferred no MBV resistance. The mutants with UL27 mutations had slightly attenuated growth. The frequent mutation of UL27 suggests that its normal expression is mildly disadvantageous to the virus in the absence of UL97 kinase activity, whether the latter results from MBV inhibition or a genetic defect. Although the function of UL27 is unknown, it does not appear to be a direct antiviral target for MBV. | 18,981,262 |
Depressive symptoms and serum lipid fractions in middle-aged men: physiologic and health behavior links. | To investigate alternative hypothetical models that could clarify the relationship between depressive symptoms and serum cholesterol fractions, i.e., high-density lipoprotein (HDL) and low-density lipoprotein (LDL). It was hypothesized that the impact of the depressive symptoms on cholesterol fractions is mediated through health behavior and body mass index, and at the same time there would be a direct link from depression to cholesterol. The study sample consisted of 893 middle-age men who participated in a trial aimed at preventing the metabolic syndrome, Type 2 diabetes and cardiovascular diseases. Serum cholesterol was measured by the enzymatic method. Participants completed self-report questionnaires assessing health behavior and depressive symptoms. Depressive symptoms consistently correlated statistically significantly with adverse lifestyle factors and, as hypothesized, positively with HDL. Path analyses supported the parallel existence of two main pathways: from depression through adverse health behavior to unfavorable cholesterol fraction balance, and a direct physiological link indicative of beneficial effect of depression on cholesterol levels. It is concluded that, among a sample of men, depressive symptoms are linked to cholesterol fractions through two different pathways. An adverse relationship of depression with serum lipids HDL-LDL balance is partly mediated through harmful health behaviors. At the same time, the results indicate a direct, physiological link between depressive symptoms and cholesterol that has a beneficial influence on the HDL-LDL balance. | 18,981,271 |
Home health care and patterns of subsequent VA and medicare health care utilization for veterans. | The Veterans Affairs or VA health care system is in the process of significantly expanding home health care (HHC) nationwide. We describe VA HHC use in 2003 for all VA HHC users from 2002; we examine whether VA utilization across a broad spectrum of services differed for a sample of VA HHC users and their propensity-score-matched controls. We also consider crossover between the VA and Medicare. This is a retrospective study using propensity score and stratified analysis to control for selection bias on observable characteristics. We examined the full cohort of 2002 VA HHC users (n = 24,169) and a 2:1 sample of age- and race-based nonusers (n = 53,356). Utilization measures included VA and Medicare outpatient, inpatient, nursing home, and hospice use, as well as VA home-based primary care, respite care, and adult day health care. VA HHC users had a higher absolute probability of outpatient use by around 3%, of inpatient use by 12%, and nursing home use by 6% than their propensity-score-matched controls. Veterans who used HHC services had a higher rate of VA service use in the subsequent year than controls did, even after we adjusted for differences in observed health status, eligibility advantages, and supplemental insurance status. High utilization for VA home health users spilled over into high Medicare utilization. | 18,981,283 |
Variation in the use of federal and state civil money penalties for nursing homes. | The study examined factors associated with state variations in the use of federal and state civil money penalties (CMPs) for nursing homes. We collected federal and state CMP data from state survey and certification agencies for 2004. We also used federal CMP data from the federal enforcement action database for 2000-2004. Logistic regressions examined factors related to whether states issued CMPs, and ordinary least squares regressions examined the number and amount of federal CMPs (2000-2004) and the total federal and state CMPs (2004). In 2004, 3,159 federal and state CMPs were collected, for a total of $21.6 million, but CMPs were given for only 2% of deficiencies issued. The number of federal CMPs collected was positively related to average facility occupancy rates, the percentage of facilities with deficiencies for harm or jeopardy, and state survey and certification budgets but was negatively related to the number of facility complaints per nursing home bed. Total federal and state CMPs were positively related to state senators' liberal voting records, having a democratic governor, and the percentage of Medicaid nursing home residents and were negatively related to the population aged 65 and older, complaints per nursing home bed, percentage of hospital-based facilities, and home- and community-based expenditures. The Centers for Medicare & Medicaid Services should address the state variations in CMPs by providing states and federal regional offices with guidelines on the use of federal CMPs. It should also improve accuracy and completeness by including federal and state CMPs in its enforcement database. | 18,981,284 |
Harvest health: translation of the chronic disease self-management program for older African Americans in a senior setting. | We describe the translation of K. R. Lorig and colleagues' Chronic Disease Self-Management Program (CDSMP) for delivery in a senior center and evaluate pre-post benefits for African American participants. Modifications to the CDSMP included a name change; an additional introductory session; and course augmentations involving culturally relevant foods, stress reduction techniques, and communicating with racially/ethnically diverse physicians. We recruited participants from senior center members, area churches, and word of mouth. We conducted baseline and 4-month post-interviews. A total of 569 African American elders attended an introductory session, with 519 (91%) enrolling in the 6-session program. Of the 519, 444 (86%) completed >/=4 sessions and 414 (79%) completed pre-post interviews. We found small but statistically significant improvements for exercise (p =.001), use of cognitive management strategies (p =.001), energy/fatigue (p =.001), self-efficacy (p =.001), health distress (p =.001), and illness intrusiveness in different life domains (probabilities from.001-.021). We found no changes for health utilization. Outcomes did not differ by gender, number of sessions attended, number and type of chronic conditions, facilitator, leader, or recruitment site. The CDSMP can be translated for delivery by trained senior center personnel to African American elders. Participant benefits compare favorably to original trial outcomes. The translated program is replicable and may help to address health disparities. | 18,981,286 |
N-(2-hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), a novel, potent, and selective acid pump antagonist for the treatment of gastroesophageal reflux disease. | Inhibition of H(+),K(+)-ATPase is accepted as the most effective way of controlling gastric acid secretion. However, current acid suppressant therapy for gastroesophageal reflux disease, using histamine H(2) receptor antagonists and proton pump inhibitors, does not fully meet the needs of all patients because of their mechanism of action. This study sought to characterize the in vitro and in vivo pharmacology of a novel acid pump antagonist, N-(2-Hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), and to compare it with other acid suppressants. Porcine, canine, and human recombinant gastric H(+),K(+)-ATPase activities were measured by ion-leaky and ion-tight assay. The affinities for a range of receptors, ion channels, and enzymes were determined to analyze selectivity profile. Acid secretion in Ghosh-Schild rats and Heidenhain pouch dogs were measured by titrating perfusate and gastric juice samples. PF-03716556 demonstrated 3-fold greater inhibitory activity than 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine (revaprazan), the only acid pump antagonist that has been available on the market, in ion-tight assay. The compound did not display any species differences, exhibiting highly selective profile including the canine kidney Na(+),K(+)-ATPase. Kinetics experiments revealed that PF-03716556 has a competitive and reversible mode of action. More rapid onset of action than 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-sulfinyl}-benzimidazole (omeprazole) and 3-fold greater potency than revaprazan were observed in Ghosh-Schild rats and Heidenhain pouch dogs. PF-03716556, a novel acid pump antagonist, could improve upon or even replace current pharmacological treatment for gastroesophageal reflux disease. | 18,981,288 |
Opportunities and strategies for breast cancer prevention through risk reduction. | Due to the high incidence of breast cancer among US females, risk-reduction strategies are essential. Before considering approaches to breast cancer risk reduction, it is important for clinicians to complete individualized qualitative and quantitative assessments of risk for their patients in order to inform physicians' clinical decision making and management and to engage patients collaboratively in a thorough discussion of risks and benefits. This review will summarize information on potential pharmacologic, nutritional, surgical, and behavioral approaches to reducing breast cancer risk. While there is no clear evidence that specific dietary components can effectively reduce breast cancer risk, weight gain and obesity in adulthood are risk factors for the development of postmenopausal breast cancer. Alcohol consumption, even at moderate levels, increases breast cancer risk, although some of the detrimental effects may be reduced by sufficient folate intake. Women at increased risk of breast cancer can opt to reduce their breast cancer risk through the use of tamoxifen or raloxifene; other chemopreventive agents remain under investigation. Surgical approaches to risk reductions are restricted to those patients with a substantially increased risk of developing breast cancer. Patients should be encouraged to maintain a healthy lifestyle for their overall well-being and to remain up to date with recommendations for screening and surveillance. | 18,981,297 |
Exercise-induced pulmonary arterial hypertension. | The clinical relevance of exercise-induced pulmonary arterial hypertension (PAH) is uncertain, and its existence has never been well studied by direct measurements of central hemodynamics. Using invasive cardiopulmonary exercise testing, we hypothesized that exercise-induced PAH represents a symptomatic stage of PAH, physiologically intermediate between resting pulmonary arterial hypertension and normal. A total of 406 consecutive clinically indicated cardiopulmonary exercise tests with radial and pulmonary arterial catheters and radionuclide ventriculographic scanning were analyzed. The invasive hemodynamic phenotype of exercise-induced PAH (n=78) was compared with resting PAH (n=15) and normals (n=16). Log-log plots of mean pulmonary artery pressure versus oxygen uptake (V(.)o(2)) were obtained, and a "join-point" for a least residual sum of squares for 2 straight-line segments (slopes m1, m2) was determined; m2<m1="plateau," and m2>m1="takeoff" pattern. At maximum exercise, V(.)o(2) (55.8+/-20.3% versus 66.5+/-16.3% versus 91.7+/-13.7% predicted) was lowest in resting PAH, intermediate in exercise-induced PAH, and highest in normals, whereas mean pulmonary artery pressure (48.4+/-11.1 versus 36.6+/-5.7 versus 27.4+3.7 mm Hg) and pulmonary vascular resistance (294+/-158 versus 161+/-60 versus 62+/-20 dyne x s x cm(-5), respectively; P<0.05) followed an opposite pattern. An exercise-induced PAH plateau (n=32) was associated with lower o(2)max (60.6+/-15.1% versus 72.0+/-16.1% predicted) and maximum cardiac output (78.2+/-17.1% versus 87.8+/-18.3% predicted) and a higher resting pulmonary vascular resistance (247+/-101 versus 199+/-56 dyne x s x cm(-5); P<0.05) than takeoff (n=40). The plateau pattern was most common in resting PAH, and the takeoff pattern was present in nearly all normals. Exercise-induced PAH is an early, mild, and clinically relevant phase of the PAH spectrum. | 18,981,305 |
Neurologic manifestations of localized scleroderma: a case report and literature review. | We describe a young woman with localized scleroderma, seizures, numerous persistently enhancing white matter lesions on brain MRI, and oligoclonal bands in the CSF. The case is remarkable in the widespread bilateral distribution of the lesions and their enhancement during more than a year of follow-up despite immunosuppression. Literature search yielded 54 case descriptions of localized scleroderma associated with neurologic symptoms and neuroimaging findings. All patients had craniofacial scleroderma: linear scleroderma en coup de sabre (LScs), progressive facial hemiatrophy (PFH, or Parry-Romberg syndrome) or both. LScs and PFH should be viewed as variants of craniofacial localized scleroderma as they often manifest in the same patient, share the same neurologic manifestations and imaging features, and evidence pathologic inflammation in skin and CNS. | 18,981,376 |
Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol. | Tolerance, described as the loss of drug effectiveness over time, is an important component of addiction. The degree of acute behavioral tolerance to alcohol exhibited by a naïve subject can predict the likelihood of alcohol abuse. Thus, the determinants of acute tolerance are important to understand. Calcium- and voltage-gated (BK) potassium channels, consisting of pore forming alpha and modulatory beta subunits, are targets of ethanol (EtOH) action. Here, we examine the role, at the molecular, cellular, and behavioral levels, of the BK beta4 subunit in acute tolerance. Single channel recordings in HEK-293 cells show that, in the absence of beta4, EtOH potentiation of activity exhibits acute tolerance, which is blocked by coexpressing the beta4 subunit. BK channels in acutely isolated medium spiny neurons from WT mice (in which the beta4 subunit is well-represented) exhibit little tolerance. In contrast, neuronal BK channels from beta4 knockout (KO) mice do display acute tolerance. Brain slice recordings showed tolerance to EtOH's effects on spike patterning in KO but not in WT mice. In addition, beta4 KO mice develop rapid tolerance to EtOH's locomotor effects, whereas WT mice do not. Finally, in a restricted access ethanol self-administration assay, beta4 KO mice drink more than their WT counterparts. Taken together, these data indicate that the beta4 subunit controls ethanol tolerance at the molecular, cellular, and behavioral levels, and could determine individual differences in alcohol abuse and alcoholism, as well as represent a therapeutic target for alcoholism. | 18,981,408 |
Ceramide starves cells to death by downregulating nutrient transporter proteins. | Ceramide induces cell death in response to many stimuli. Its mechanism of action, however, is not completely understood. Ceramide induces autophagy in mammalian cells maintained in rich media and nutrient permease downregulation in yeast. These observations suggested to us that ceramide might kill mammalian cells by limiting cellular access to extracellular nutrients. Consistent with this proposal, physiologically relevant concentrations of ceramide produced a profound and specific downregulation of nutrient transporter proteins in mammalian cells. Blocking ceramide-induced nutrient transporter loss or supplementation with the cell-permeable nutrient, methyl pyruvate, reversed ceramide-dependent toxicity. Conversely, cells became more sensitive to ceramide when nutrient stress was increased by acutely limiting extracellular nutrients, inhibiting autophagy, or deleting AMP-activated protein kinase (AMPK). Observations that ceramide can trigger either apoptosis or caspase-independent cell death may be explained by this model. We found that methyl pyruvate (MP) also protected cells from ceramide-induced, nonapoptotic death consistent with the idea that severe bioenergetic stress was responsible. Taken together, these studies suggest that the cellular metabolic state is an important arbiter of the cellular response to ceramide. In fact, increasing nutrient demand by incubating cells in high levels of growth factor sensitized cells to ceramide. On the other hand, gradually adapting cells to tolerate low levels of extracellular nutrients completely blocked ceramide-induced death. In sum, these results support a model where ceramide kills cells by inducing intracellular nutrient limitation subsequent to nutrient transporter downregulation. | 18,981,422 |
Parathyroid hormone signaling through low-density lipoprotein-related protein 6. | Intermittent administration of PTH stimulates bone formation, but the precise mechanisms responsible for PTH responses in osteoblasts are only incompletely understood. Here we show that binding of PTH to its receptor PTH1R induced association of LRP6, a coreceptor of Wnt, with PTH1R. The formation of the ternary complex containing PTH, PTH1R, and LRP6 promoted rapid phosphorylation of LRP6, which resulted in the recruitment of axin to LRP6, and stabilization of beta-catenin. Activation of PKA is essential for PTH-induced beta-catenin stabilization, but not for Wnt signaling. In vivo studies confirmed that PTH treatment led to phosphorylation of LRP6 and an increase in amount of beta-catenin in osteoblasts with a concurrent increase in bone formation in rat. Thus, LRP6 coreceptor is a key element of the PTH signaling that regulates osteoblast activity. | 18,981,475 |
Coordinated but physically separable interaction with H3K27-demethylase and H3K4-methyltransferase activities are required for T-box protein-mediated activation of developmental gene expression. | During cellular differentiation, both permissive and repressive epigenetic modifications must be negotiated to create cell-type-specific gene expression patterns. The T-box transcription factor family is important in numerous developmental systems ranging from embryogenesis to the differentiation of adult tissues. By analyzing point mutations in conserved sequences in the T-box DNA-binding domain, we found that two overlapping, but physically separable regions are required for the physical and functional interaction with H3K27-demethylase and H3K4-methyltransferase activities. Importantly, the ability to associate with these histone-modifying complexes is a conserved function for the T-box family. These novel mechanisms for T-box-mediated epigenetic regulation are essential, because point mutations that disrupt these interactions are found in a diverse array of human developmental genetic diseases. | 18,981,476 |
Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity. | Genome endoreduplication during mammalian development is a rare event for which the mechanism is unknown. It first appears when fibroblast growth factor 4 (FGF4) deprivation induces differentiation of trophoblast stem (TS) cells into the nonproliferating trophoblast giant (TG) cells required for embryo implantation. Here we show that RO3306 inhibition of cyclin-dependent protein kinase 1 (CDK1), the enzyme required to enter mitosis, induced differentiation of TS cells into TG cells. In contrast, RO3306 induced abortive endoreduplication and apoptosis in embryonic stem cells, revealing that inactivation of CDK1 triggers endoreduplication only in cells programmed to differentiate into polyploid cells. Similarly, FGF4 deprivation resulted in CDK1 inhibition by overexpressing two CDK-specific inhibitors, p57/KIP2 and p21/CIP1. TS cell mutants revealed that p57 was required to trigger endoreduplication by inhibiting CDK1, while p21 suppressed expression of the checkpoint protein kinase CHK1, thereby preventing induction of apoptosis. Furthermore, Cdk2(-/-) TS cells revealed that CDK2 is required for endoreduplication when CDK1 is inhibited. Expression of p57 in TG cells was restricted to G-phase nuclei to allow CDK activation of S phase. Thus, endoreduplication in TS cells is triggered by p57 inhibition of CDK1 with concomitant suppression of the DNA damage response by p21. | 18,981,479 |
Intraspecific evolution of the intercellular signaling network underlying a robust developmental system. | Many biological systems produce an invariant output when faced with stochastic or environmental variation. This robustness of system output to variation affecting the underlying process may allow for "cryptic" genetic evolution within the system without change in output. We studied variation of cell fate patterning of Caenorhabditis elegans vulva precursors, a developmental system that relies on a simple intercellular signaling network and yields an invariant output of cell fates and lineages among C. elegans wild isolates. We first investigated the system's genetic variation in C. elegans by means of genetic tools and cell ablation to break down its buffering mechanisms. We uncovered distinct architectures of quantitative variation along the Ras signaling cascade, including compensatory variation, and differences in cell sensitivity to induction along the anteroposterior axis. In the unperturbed system, we further found variation between isolates in spatio-temporal dynamics of Ras pathway activity, which can explain the phenotypic differences revealed upon perturbation. Finally, the variation mostly affects the signaling pathways in a tissue-specific manner. We thus demonstrate and characterize microevolution of a developmental signaling network. In addition, our results suggest that the vulva genetic screens would have yielded a different mutation spectrum, especially for Wnt pathway mutations, had they been performed in another C. elegans genetic background. | 18,981,482 |
Trypanosoma cruzi transmission cycle among wild and domestic mammals in three areas of orally transmitted Chagas disease outbreaks. | We report Trypanosoma cruzi infection in wild and domestic mammals from three orally acquired Chagas disease outbreak areas in Brazil. Cachoeiro do Arari (Pará) displayed a panzootic scenery (positive mammals in all ecologic strata), and human cases were probably the consequence of their exposure within the sylvatic T. cruzi transmission cycle. In Navegantes (Santa Catarina), Didelphis spp. was the main reservoir host, given that 93% were infected. In Redenção (Ceará), Monodelphis domestica and Thrichomys laurentius were also important for parasite maintenance. TCI was present in the three studied areas. Additionally, Z3 was detected in an armadillo from Pará and TCII in a triatomine from Navegantes. Domestic animals showed a high seroprevalence and should be considered sentinels in surveillance programs. The importance of a reduction in wild mammalian fauna diversity and selection of suitable T. cruzi reservoir hosts are discussed as risk factors for the re-emergence of Chagas disease. | 18,981,516 |
Does rooibos tea (Aspalathus linearis) support regeneration of rat liver after intoxication by carbon tetrachloride? | This study evaluates the effect of rooibos tea (RT, Aspalathus linearis) on biochemical and histological parameters during rat liver regeneration after intoxication by carbon tetrachloride (CCl4). From the 10th week, when the administration of CCl4 was terminated, the liver tissue began to regenerate. Seven days later in the regeneration phase, the animals treated by RT during whole period of the experiment, and those which drunk RT only during the regeneration period, exhibited a trend for decrease in the activity of alanine aminotransferase and significant decrease in the activity of aspartate aminotransferase and in total bilirubin content when compared with the water-drinking group. At the same time, the concentration of plasma albumin was elevated and that of tissue malondialdehyde decreased in the both groups drinking RT. After 42 days of regeneration, all biochemical parameters in all three groups reached the level of control healthy animals. In both groups treated with RT, the extent of fibrotic tissue was lower than in the group which received water. We conclude that RT can be recommended not only for the prevention but also as a co-adjuvant for the therapy of liver diseases. | 18,981,533 |
Reducing post-surgical adhesions utilizing a drug-enhanced device: sodium carboxymethylcellulose aqueous gel/poly(p-dioxanone) and Tranilast. | Post-surgical adhesion formation has numerous deleterious side effects in a wide variety of surgical settings. Physical barriers used together with laparoscopy were developed to reduce tissue trauma seen with open procedures. However, despite surgeons' meticulous techniques and the use of such barriers, adhesion formation remains a serious clinical problem, creating complications that cost the health care system over $1 billion annually. Our laboratories have combined a previously marketed drug, Tranilast, with a sodium carboxymethylcellulose (NaCMC) gel in a sustained release formulation using poly(p-dioxanone) (PDO) to provide a locally delivered medicated device that significantly reduces adhesions. This paper describes the preparation of the gel and the sustained release formulation, its key physical properties, and its sustained release kinetics. Pre-clinical data on inhibition of adhesion formation by the sustained release poly(p-dioxanone)/sodium carboxymethylcellulose/Tranilast drug enhanced device are also presented. | 18,981,543 |
Ameliorative effect of Captopril and Valsartan on an animal model of diabetic cardiomyopathy. | The objective of this study was to clarify the relationship between angiotensin II and the pathogenesis of diabetic cardiomyopathy by observing the effects of related drugs on diabetic cardiomyopathy in rats. Captopril and Valsartan, an automatic biochemical analyzer, and radioimmunoassay technology were used to an experimental rat model of diabetic cardiomyopathy to dynamically measure the levels of creatine kinase-MB, lactate dehydrogenase-1 in the serum, and angiotensin I and II in the plasma, and to observe changes in the myocardial ultrastructure. The content of angiotensin I and II was increased and the renin-angiotensin system was in a hyperfunctional state in experimental rats with myocardial damage. Angiotensin-converting enzyme inhibitors and angiotensin II receptor 1 antagonists improved the myocardial structure and cardiac function. It is concluded that hyperfunction of the renin-angiotensin system is involved in the pathogenesis of diabetic cardiomyopathy, with an increase in angiotensin being a key factor. Preventing the increase in angiotensin II or the action of angiotensin II on its receptor can prevent the occurrence and development of diabetic cardiomyopathy. | 18,981,571 |
Nicorandil, a potassium channel opener and nitric oxide donor, improves the frequent urination without changing the blood pressure in rats with partial bladder outlet obstruction. | It was studied to determine if nicorandil can improve frequent urination in rats with partial bladder outlet obstruction (BOO) without changing the blood pressure. Voiding behavior was observed 6 to 8 d after obstruction in female rats with BOO that loaded 30 ml/kg of water. A drug was administered orally. Changes in systemic blood pressure and heart rate were studied in conscious BOO rats using the tail cuff method. The voiding frequency was increased and the average voided volume was decreased in BOO rats compared with normal rats. Nicorandil (1 mg/kg), cromakalim (0.1 mg/kg) and isosorbide dinitrate (ISDN; 1000 mg/kg) decreased voiding frequency significantly in BOO rats. Nicorandil also increased the average voided volume significantly. Although cromakalim and ISDN at doses effective at decreasing voiding frequency caused blood pressure to drop, nicorandil at an effective dose did not affect blood pressure and heart rate. Nicorandil improved frequent urination without changing the blood pressure. These results suggested that a hybrid of a K(ATP) channel opener and nitric oxide donor, nicorandil was bladder-selective compared with vasculature in BOO rats. | 18,981,577 |
Active infective endocarditis: management and risk analysis of hospital death from 24 years' experience. | This study was performed to identify risk factors for hospital death in patients with acute and active infective endocarditis (AAIE) after surgical intervention. From 1980 to 2004, 94 patients underwent surgery for AAIE (age range, 3-77 years; 76% males). Congestive heart failure (CHF) was present in 44 patients, as well as vegetations in 64, septicemia in 16, abscesses in 17, and emboli in 22; 16 patients had prosthetic valve endocarditis. Streptococci were the most common bacteria (34 patients), followed by staphylococci (17 patients). Mechanical valves were selected for 73 patients and bioprosthetic valves for 16. Mitral valve plasty was performed in 4 patients. Aortic root or aorto-mitral discontinuity was repaired in 17 patients, including Manouguian's double valve replacement in 6 and aortic root replacement in 4. Overall hospital mortality was 15% (14 patients). Univariate analysis identified CHF (p=0.016), abscess (p=0.014), and prosthetic valve endocarditis (p=0.043) as risk factors. However, multivariate analysis only identified CHF (p=0.019) as an independent risk factor. In AAIE, early surgical intervention is advisable before the occurrence of complications such as root abscess and CHF, particularly before the onset of CHF. | 18,981,596 |
Structures of new monoterpenes from Thai herbal medicine Curcuma comosa. | Three new monoterpenes, comosoxide A (1), comosoxide B (2), and comososide (3), were isolated from the methanolic extract of the rhizomes of Curcuma comosa cultivated in Thailand. Their structures were elucidated on the basis of chemical and physicochemical evidence. | 18,981,614 |
Incidence and clinical significances of human T-cell lymphotropic virus type I-associated myelopathy with T2 hyperintensity on spinal magnetic resonance images. | To clarify the incidence and clinical significance of HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) showing T2 hyperintensity in the spinal cord on magnetic resonance images (MRI). We reviewed the spinal cord MRI of 38 HAM/TSP patients and analyzed them in relation to clinical and laboratory findings. Analyzed data were: age at onset, disease duration, disability status, responsiveness to interferon therapy, brain abnormalities on MRI, serum anti-HTLV-I titers, and cerebrospinal fluid (CSF) findings. MRI findings of the spinal cord were classified into 3 types, "normal" (n=22, 57.9%), "atrophy" (n=13, 34.2%) and "T2-hyperintensity" (n=3, 7.9%). Patients in the normal and atrophy types showed slowly progressive paraparesis. Significant differences were not found between the normal and atrophy types in any clinical or laboratory data, including disease duration, disability status and responsiveness to interferon-alpha therapy. Meanwhile, all patients showing T2-hyperintensity had severe paraparesis of a rapid progressive nature, with CSF IgG elevation. HAM/TSP with T2-hyperintensity on spinal MRI shows a rapid progressive clinical course with severe motor impairment. The incidence of this malignant form of HAM/TSP is estimated to be around 7.9%. | 18,981,631 |
Establishment of an efficient enzyme-linked immunosorbent assay for the detection of Eperythrozoon sius antibody in swine. | The Eperythrozoon suis (E. suis) antigen was purified using a Sephadex G-200 chromatograph, and thereby, a high-affinity, specific E. suis antigen was collected and confirmed with Western blotting. Using this antigen, an enzyme-linked immunosorbent assay (ELISA) system to detect the antibody against E. suis in swine was established. There was no cross-reaction with swine sera, which were affected with Mycoplasmal pneumonia, swine fever, swine colibacillosis, or toxoplasmosis. A comparison of this ELISA system with an indirect hemagglutination (IHA) test using 78 swine samples revealed that the ELISA system significantly improved the sensitivity, specificity, and stability for the serodiagnosis of swine E. suis. | 18,981,677 |
[Bio-database literacy and its application with cis-regulatory modules to find novel drug target proteins]. | We have expected Bioinformatics as tools to extract new knowledge from whole genome sequences of various organisms. In the post-genome era, to find some knowledge of the gene regulation including locations of cis-regulatory elements, modules and those combinations became one of the big challenges on Bioinformatics field. Because, it is difficult and inefficient to determine all possible combinations of cis-regulatory elements by bio-chemical approach. However, computational ways might allow us to find out all cis-elements within a time frame. In this review, we introduce the current status of public available databases on Internet comparing our original database for the cis-modules. We also explain our new mathematical measurement to characterize sequence patterns for cis-elements of each transcription factors and its application to predict the gene expression regulation network. | 18,981,686 |
Dietary flaxseed prevents radiation-induced oxidative lung damage, inflammation and fibrosis in a mouse model of thoracic radiation injury. | Flaxseed (FS) has high contents of omega-3 fatty acids and lignans with antioxidant properties. Its use in preventing thoracic X-ray radiation therapy (XRT)-induced pneumonopathy has never been evaluated. We evaluated FS supplementation given to mice given before and post-XRT. FS-derived lignans, known for their direct antioxidant properties, were evaluated in abrogating ROS generation in cultured endothelial cells following gamma radiation exposure. Mice were fed 10% FS or isocaloric control diet for three weeks and given 13.5 Gy thoracic XRT. Lungs were evaluated at 24 hours for markers of radiation-induced injury, three weeks for acute lung damage (lipid peroxidation, lung edema and inflammation), and at four months for late lung damage (inflammation and fibrosis). FS-Lignans blunted ROS generation in vitro, resulting from radiation in a dose-dependent manner. FS-fed mice had reduced expression of lung injury biomarkers (Bax, p21 and TGF-beta1) at 24 hours following XRT and reduced oxidative lung damage as measured by malondialdehyde (MDA) levels at 3 weeks following XRT. In addition, FS-fed mice had decreased lung fibrosis as determined by hydroxyproline content and decreased inflammatory cell influx into lungs at 4 months post XRT. Importantly, when Lewis lung carcinoma cells were injected systemically in mice, FS dietary supplementation did not appear to protect lung tumors from responding to thoracic XRT. Dietary FS is protective against pulmonary fibrosis, inflammation and oxidative lung damage in a murine model. Moreover, in this model, tumor radioprotection was not observed. FS lignans exhibited potent radiation-induced ROS scavenging action. Taken together, these data suggest that dietary flaxseed may be clinically useful as an agent to increase the therapeutic index of thoracic XRT by increasing the radiation tolerance of lung tissues. | 18,981,722 |
Current concepts of neurohormonal activation in heart failure: mediators and mechanisms. | Neurohormonal activation is a commonly cited array of phenomena in the body's physiologic response to heart failure. Although various neurohormones and pharmacologic agents that moderate their pathophysiologic effects have been reviewed in the nursing literature, both the mechanisms of neurohormonal system activation and cellular and organ system effects have been described only in brief. Accordingly, this article reviews mechanisms of neurohormonal activation and describes cellular and cardiovascular effects of the (1) sympathetic nervous system, (2) renin-angiotensin-aldosterone system, (3) kallikrein-kininogen-kinin system, (4) vasopressinergic system, (5) natriuretic peptide systems, and (6) endothelin in the context of heart failure. This article implicitly details the physiologic basis for numerous current and potential future pharmacologic agents used in the management of heart failure. It is intended that this article be used as a reference for advanced clinical nursing practice, research, and education. | 18,981,739 |
Chronic wound infection and antimicrobial use. | To provide the wound care practitioner with a review of the assessment and management of chronic wound infection. This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. After reading this article and taking this test, the reader should be able to: 1. Discuss the etiology of chronic wounds. 2. Describe the agents used for the treatment of chronic wound infections. | 18,981,758 |
Event reporting: the value of a nonpunitive approach. | This article will discuss why patient safety has been so hard to achieve due to long standing beliefs that when errors occur individuals must be blamed or punished. It will offer suggestions as to how a culture of learning can be advanced by fostering a different approach to medical errors and how reporting systems and an analytic process that always identifies root causes of problems can help physicians reduce harm to patients and ultimately malpractice risk. | 18,981,789 |
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