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At least 847 records · Page 47Linked to original sources
PubMed2004

Key residues contributing to dominant conformational autoantigenic epitopes on thyroid peroxidase identified by mutagenesis.

Thyroid peroxidase (TPO) is a major autoantigen in thyroid autoimmune disease where pathogenic autoantibodies recognise conformational epitopes restricted to two overlapping immunodominant regions (IDR) termed IDR-A and -B. Based upon our structural model of TPO, we report on the localisation of the IDRs to specific amino acids important for autoantibody binding. Using a panel of recombinant human Fabs (rhFabs) from autoimmune patients, specific for the IDR-A or -B epitopes, in combination with eukaryotic expression of 14 single amino acid mutants of TPO, we identify R225 and K627 as key components of IDR-A and -B, respectively. Moreover, each mutant specifically led to the loss of binding of three different IDR-A- or -B-specific rhFabs, without affecting the binding of autoantibodies to the other determinant. Further supportive evidence for the role of amino acids R225 and K627 was obtained with murine monoclonal antibodies that first defined the IDRs. The identification of amino acids R225 and K627 as key residues for the IDR epitopes on TPO will advance our understanding of the molecular basis of autoreactivity and facilitate the design of novel therapeutic agents.

Amino Acids↗
PubMed2006

A genetic model to investigate drug-target interactions at the ribosomal decoding site.

Recent advances in X-ray crystallography have greatly contributed to the understanding of the structural interactions between aminoglycosides and the ribosomal decoding site. Efforts to genetically probe the functional relevance of proposed drug-nucleotide contacts have in part been hampered by the presence of multiple rRNA operons in most bacteria. A derivative of the Gram-positive Mycobacterium smegmatis was rendered single rRNA operon allelic by means of gene inactivation techniques. In this system, genetic manipulation of the single chromosomal rRNA operon results in cells carrying homogeneous populations of mutant ribosomes. An exhaustive mutagenesis study of the ribosomal A site has been performed to define the importance of individual drug-nucleotide contacts. Mutational alterations in the M. smegmatis decoding site are discussed here, comparing the results with those obtained in other organisms. Implications for the selectivity of antimicrobial agents and for the fitness cost of resistance mutations are addressed.

Anti-Bacterial Agents↗
PubMed2005

Plant development is regulated by a family of auxin receptor F box proteins.

The plant hormone auxin has been implicated in virtually every aspect of plant growth and development. Auxin acts by promoting the degradation of transcriptional regulators called Aux/IAA proteins. Aux/IAA degradation requires TIR1, an F box protein that has been shown to function as an auxin receptor. However, loss of TIR1 has a modest effect on auxin response and plant development. Here we show that three additional F box proteins, called AFB1, 2, and 3, also regulate auxin response. Like TIR1, these proteins interact with the Aux/IAA proteins in an auxin-dependent manner. Plants that are deficient in all four proteins are auxin insensitive and exhibit a severe embryonic phenotype similar to the mp/arf5 and bdl/iaa12 mutants. Correspondingly, all TIR1/AFB proteins interact with BDL, and BDL is stabilized in triple mutant plants. Our results indicate that TIR1 and the AFB proteins collectively mediate auxin responses throughout plant development.

Arabidopsis↗
PubMed2004

The effects of heavy metal contamination on the soil arthropod community of a shooting range.

Soils in clay pigeon shooting ranges can be seriously contaminated by heavy metals. The pellets contained in ammunition are composed of Pb, Sb, Ni, Zn, Mn and Cu. The total concentrations of these metals in soils, and the effects of their increasing levels on the arthropod community were investigated at seven sampling sites in a clay pigeon shooting range and compared with two controls. Research revealed that the spatial distribution of Pb and Sb contamination in the shot-fall area was strongly correlated with the flight path of the pellets. Ordination obtained through Redundance Analysis showed that Collembola, Protura and Diplura were positively correlated with major detected contaminants (Pb, Sb), while Symphyla showed a negative correlation with these pollutants. Determination of the soluble lead fraction in soil, and of its bioaccumulation in the saprophagous Armadillidium sordidum (Isopoda) and the predator Ocypus olens (Coleoptera), showed that a significant portion of metallic Pb from spent pellets is bioavailable in the soil and can be bioaccumulated by edaphic organisms, entering the soil trophic network, but without biomagnification.

Animals↗
PubMed2005

Gene silencing with STAT6 specific siRNAs blocks eotaxin release in IL-4/TNFalpha stimulated human epithelial cells.

Small interfering RNAs have evolved as effective tools for the study of gene functions. Here, we demonstrate the use of different siRNAs for the specific knock down of the STAT6 transcription regulator and the complete silencing of the downstream signaling pathway. The knock down of STAT6 resulted in a complete loss of STAT6 specific DNA binding activity and blocked the release of eotaxin-3 in human epithelial cells (BEAS-2B) stimulated with IL-4 and TNFalpha with no signs of unspecific gene silencing. Other signaling pathways like the EGF stimulated release of IL-8 were still active in BEAS-2B cells treated with STAT6 specific siRNAs, demonstrating the specificity of these molecules.

Chemokine CCL11↗
PubMed2005

Biased use of VH5 IgE-positive B cells in the nasal mucosa in allergic rhinitis.

BACKGROUND: IgE antibody-producing B cells are enriched in the nasal mucosa in patients with allergic rhinitis because of local class switching to IgE. The expressed IgE VH genes also undergo somatic hypermutation in situ to generate clonal families. The antigenic driving force behind these events is unknown. OBJECTIVE: To examine the possible involvement of a superantigen in allergic rhinitis, we compared the variable (VH) gene use and patterns of somatic mutation in the expressed IgE heavy-chain genes in nasal biopsy specimens and blood from allergic patients and the IgA VH use in the same biopsy specimens and also those from nonallergic controls. METHODS: We extracted mRNA from the nasal biopsy specimens of 13 patients and 4 nonallergic control subjects and PBMCs from 7 allergic patients. IgE and IgA VH regions were RT-PCR amplified, and the DNA sequences were compared with those of control subjects. We constructed a molecular model of VH5 to locate amino acids of interest. RESULTS: We observed a significantly increased frequency of IgE and IgA VH5 transcripts in the nasal mucosa of the allergic patients compared with the normal PBMC repertoire. Within IgE and IgA VH5 sequences in the nasal mucosa, the distribution of replacement amino acids was skewed toward the immunoglobulin framework regions. Three of 4 nonintrinsic hotspots of mutation identified in the VH5 sequences were in framework region 1. The hotspots and a conserved VH5-specific framework residue form a tight cluster on the surface of VH5. CONCLUSION: Our results provide evidence for the activity of a superantigen in the nasal mucosa in patients with allergic rhinitis.

Adolescent↗
PubMed2004

Shear-induced structure in polymer-clay nanocomposite solutions.

The equilibrium structure and shear response of model polymer-clay nanocomposite gels are measured using X-ray scattering, light scattering, optical microscopy, and rheometry. The suspensions form physical gels via the "bridging" of neighboring colloidal clay platelets by the polymer, with reversible adsorption of polymer segments onto the clay surface providing a short-range attractive force. As the flow disrupts this transient network, coupling between composition and stress leads to the formation of a macroscopic domain pattern, while the clay platelets orient with their surface normal parallel to the direction of vorticity. We discuss the shear-induced structure, steady-shear rheology, and oscillatory-shear response of these dynamic networks, and we offer a physical explanation for the mesoscale shear response. In contrast to flow-induced "banding" transitions, no stress plateau is observed in the region where macroscopic phase separation occurs. The observed platelet orientation is different from that reported for polymer-melt clay nanocomposites, which we attribute to effects associated with macroscopic phase separation under shear flow.

Journal Article↗
PubMed2005

Breakup of carbon nanotube flocs in microfluidic traps.

The critical stress to break flocs of multiwalled-carbon nanotubes suspended in low-molecular-weight polymer fluid is measured in planar elongational flow. Through image analysis of aggregates and their fragments, the extension rate of the flow and the size and aspect ratio of the aggregates are measured in real time. While trapping an aggregate at the stagnation point of the device, the flow rate is increased continually and breaking events are recorded, establishing a correlation between aggregate size and the critical elongation stress for fragmentation sigma. This relationship resembles that for the breakup of flocs comprising spherical particles, yet it indicates that the strength of these fibrous flocs depends much more strongly on the local particle concentration. Fracture avalanches (or cascades) are also observed.

Journal Article↗
PubMed2005

Validity and responsiveness of the patient evaluation measure as an outcome measure for carpal tunnel syndrome.

The aim of this study was to assess the validity of the Patient Evaluation Measure questionnaire (PEM) as an outcome measure in carpal tunnel syndrome. The PEM was compared to the DASH questionnaire and to objective measurements of hand function. We also compared its responsiveness to changes following carpal tunnel release with that of the DASH score. Twenty-four patients completed the PEM and DASH questionnaires before and 3 months after open carpal tunnel release. Grip strength, static two-point discrimination and the nine-hole peg test were measured. There was a significant correlation between individual items of the PEM and the objective measures. There was also strong correlation between PEM and DASH scores. The PEM showed a greater responsiveness to change (effect size 0.97) than the DASH score (effect size 0.49). The PEM correlates well with objective measures of hand function and the DASH score when used in carpal tunnel syndrome. It is more responsive to change than the DASH score. It is very simple to complete and score and is an appropriate and practical outcome measure in carpal tunnel syndrome.

Adult↗
PubMed2005

The effect of age and gender upon symptoms and surgical outcomes in carpal tunnel syndrome.

There is conflicting evidence regarding the effectiveness of carpal tunnel release in older patients. This is a prospective study which evaluates the impact of age and gender upon symptoms, self-reported disability and surgical outcome in a series of 97 patients with carpal tunnel syndrome. Symptom severity, hand function and patient satisfaction were assessed using the Boston Carpal Tunnel Questionnaire and the Patient Evaluation Measure. A statistical correlation of age and gender with symptoms, hand function and surgical outcome was performed with questionnaires administered before open carpal tunnel decompression and 6 months after surgery. Women reported greater pre-operative symptoms and disability than men, but there was no gender-related difference in surgical outcome or patient satisfaction. There was no difference in surgical outcome between patients 60 and 70 years of age and younger patients. The majority of patients over the age of 70 reported an improvement in symptoms and function, but they were less satisfied with their treatment than younger patients. Some patients had problems with persistent numbness and loss of dexterity following surgery. The outcome of carpal tunnel release in terms of improvement in the symptom and functional scores is sufficient to justify surgery in the elderly, but surgical outcomes are less predictable than in younger patients and we recommend that this is explained to them when obtaining consent for surgery.

Adult↗
PubMed2005

A review of hand surgery provision in England.

This study reviews hand surgical activity and the resources available for provision of hand surgery in England in 2001. Operation rates for three common procedures, viz. carpal tunnel release, Dupuytren's surgery and ganglion surgery, were considered. The local population and the number of hand surgeons in each NHS Hospital Trust were compared. We identified 275 consultant surgeons with an interest in hand surgery working in the NHS in England. Approximately two-thirds were orthopaedic surgeons, almost one-third were plastic surgeons and a small number were accident and emergency surgeons. Half of all hand surgeons worked in large units, with three or more hand surgeons, but almost 20% of hand surgery was delivered in hospitals in which there was no surgeon with a declared interest in hand surgery. Surgery rates for Dupuytren's contracture varied from 0.04 to 0.36 cases per 1,000 population per annum and for carpal tunnel syndrome varied from 0.25 to 1.31 cases per 1,000 per annum. We found a correlation between rates of surgery and the number of hand surgeons, locally. A recent audit (Burke, Dias, Heras-Pelou, Bradley, & Wildin, 2004. Providing care for hand disorders, a reappraisal of need. Journal of Hand Surgery, 29B: 575-579.) has suggested that one hand surgeon is required to meet the needs of a population of 125,000, with a national requirement for 393 hand surgeons. We conclude that there are insufficient hand surgeons in England and believe that the wide local variations in hand surgery rates are indicative of a significant unmet demand for hand surgery in the English population.

Carpal Tunnel Syndrome↗
PubMed2004

Mutagenesis of 16S rRNA C1409-G1491 base-pair differentiates between 6'OH and 6'NH3+ aminoglycosides.

Using a single rRNA allelic Gram-positive model system, we systematically mutagenized 16S rRNA positions 1409 and 1491 to probe the functional relevance of structural interactions between aminoglycoside antibiotics and the A-site rRNA that were suggested by X-ray crystallography. At the structural level, the interaction of the 2-deoxystreptamine aminoglycosides with the rRNA base-pair C1409-G1491 has been suggested to involve the following features: (i) ring I of the disubstituted 2-deoxystreptamines stacks upon G1491 and H-bonds to the Watson-Crick edge of A1408; (ii) ring III of the 4,5-disubstituted aminoglycosides shows hydrogen bonding to G1491. However, we found that mutants with altered 16S rRNA bases 1409 and 1491 discriminated poorly between 4,5-disubstituted and 4,6-disubstituted 2-deoxystreptamines, but differentially affected aminoglycosides with a hydroxyl group versus an ammonium group at position 6' of ring I, e.g. G1491U conferred high-level drug resistance to paromomycin and geneticin, but not to neomycin, tobramycin or gentamicin.

Aminoglycosides↗
PubMed2006

The Finch factor.

Explore the source record for details and available documents.

Angina, Unstable↗
PubMed2006

Safety in the sleep laboratory.

The importance of workplace safety cannot be understated. The safety of employees affects morale, attendance, and workman's compensation. Federal organizations and agencies have provided guidelines to help ensure the health and safety of the technician and the patients who visit the sleep center. This article discusses commonly encountered hazards and ways to address them.

Accidents, Occupational↗
PubMed2006

Auxin and cell polarity: the emergence of AXR4.

Polar localization of the Arabidopsis auxin influx facilitator protein AUX1 in certain cell types is essential for normal root gravitropism and lateral root formation. Sunethra Dharmasiri and colleagues recently reported that this polar localization requires the activity of the AXR4 gene. The sequence of the AXR4 gene suggests that novel mechanisms could be important for targeting certain proteins to specific cellular locations.

Arabidopsis↗
PubMed2002

Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome.

BACKGROUND: Fifty-one patients with major depression were classified for 5-HTT promoter region polymorphism and platelet 5-HTT kinetics before treatment with fluoxetine, and then examined for treatment outcome. METHODS: Dose was stratified from 1.25 mg to 40 mg per day to allow for the possibility that one genotype could express a lower-dose fluoxetine response. A repeated-measures analysis of variance of 24-item Hamilton depression change through baseline, 1-week placebo lead-in, and 6, 12, and 18 weeks treatment was done to test a genotype effect on outcome. RESULTS: Genotype had a significant effect on outcome (F = 4.7, p <.02), with the initial affinity constant (K(m)) (F = 11.9, p =.001), and dose (F = 6.0, p <.02) being significant covariates on outcome as well. The gene effect, however, was complex in that the 5-HTT promoter region insertion showed two effects: both a placebo response effect (F = 4, p <.025), and a drug dose response effect (r =.40, p <.01). The long allele group was more responsive to placebo, as well as more responsive to drug dose than was the short allele group. CONCLUSIONS: This is the first study to examine the antidepressant dose-response relationship to 5-HTT kinetics and genetics. The findings indicate that both the initial affinity and genotype of 5-HTT may contribute in unique ways to the variation in the outcome of depression treatment trials.

Adolescent↗