Splenic infarction in a patient with Wegener's granulomatosis.
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Adult↗
Biomedical subjects
A George
Publications and source records attributed to A George.
Effect of multiple antigenic exposures in the gut on oral tolerance and induction of antibacterial systemic immunity.
We have analyzed oral tolerance of microbial antigens in an experimental model in which mice are treated orally with a single small dose of soluble antigen and challenged systemically with the antigen in complete Freund's adjuvant. We found that, while oral administration of sonicated extracts of either Leishmania major, Leishmania donovani, or Staphylococcus aureus was tolerogenic, as was administration of the nominal antigen ovalbumin or conalbumin, oral administration of Escherichia coli or Salmonella typhimurium sonicated extract was not. Since E. coli is an enteric commensal that colonizes the intestine soon after birth, these data suggested that lack of demonstrable oral tolerance may be related to the frequency of oral exposure to an antigen. In support of this, we found that multiple oral doses of ovalbumin or S. aureus or L. donovani antigens did not increase systemic hyporesponsiveness beyond that achieved with a single oral dose. We have also tested the ability of mice fed with sonicates of the tolerogenic S. aureus or the nontolerogenic S. typhimurium to clear a subsequent systemic infection with the homologous bacteria and found that, while clearance of S. aureus was unaffected by prior feeding, clearance of S. typhimurium was actually enhanced. The data suggest that frequent oral antigenic exposure may eventually lead to induction of systemic immunity in tolerant mice.
Administration, Oral↗
Recombinant expression and characterization of dentin matrix protein 1.
Dentin matrix protein 1 (DMP1) is an extracellular matrix noncollagenous protein (NCP) initially isolated from dentin and now found to be present in calcified tissues like calvaria and long bone. The characteristic feature of DMP1 is that it contains a large number of acidic domains and has properties which implicate it as a key participant in regulating matrix mineralization. The level of DMP1 in the tissue is sparse and it is not easily isolated from dentin because it copurifies with other dentin NCPs. The exact function of DMP1 is not known and this is due to the inherent difficulty of obtaining enough protein from the mineralized tissues. In order to understand the physiologic role for DMP1 during the formation of mineralized tissues we have produced milligram quantities of recombinant DMP1 in E. coli. The objective of this work was: (1) to prepare unmodified apoprotein so that it could be used for studying the function of DMP1; and (2) to prepare polyclonal antibody against the recombinant DMP1 antigen. The DMP1 polyclonal antibody did not cross-react with other NCPs present in dentin or with bone acidic glycoprotein-75 (BAG-75) present in the bone matrix, confirming the specificity of this antibody and thus making it a valuable tool to determine the in vivo function of DMP1.
Amino Acid Sequence↗
Rat dentin matrix protein 3 is a compound protein of rat dentin sialoprotein and phosphophoryn.
During cloning of the rat incisor phosphophoryn gene, several clones were identified with a PP antibody. One of the clones (2PP) was shown to encode a PP denoted as dentin matrix protein 2, DMP2. We have now sequenced another clone, which appears to be bifunctional, or at minimum, has two distinct domains. The 5' region encodes for dentin sialoprotein (DSP), while the 3' region encodes a small or "mini" PP. There is no stop codon between these domains. The whole gene has been named Dmp3, in keeping with the current nomenclature adopted in our laboratory. The previously reported Dmp2 gene does not encode a DSP domain but has a 114 amino acid carboxy terminal sequence identical except for a single residue with that of the DMP3. Thus, Dmp2, Dmp3 and their corresponding proteins, probably represent related members of a multigene family. There is no evidence for differential splicing. Since the DSP isolated from dentin does not carry the mini-PP domain, it must be cleaved postranslationally from DMP3.
Amino Acid Sequence↗
Molecular diagnosis of dengue by reverse transcriptase-polymerase chain reaction.
The techniques of reverse transcriptase-polymerase chain reaction (RT-PCR) and subsequent PCR were employed in the analysis of serum samples from a range of patients from the Caribbean Epidemiology Centre (CAREC) member countries. Results were compared with those from viral isolation and immunofluorescence. In the second part of the study, ten serum samples were stored for one week under four sets of conditions: -20 degrees C, 4 degrees C, 25 degrees C, and thawed (20 degrees C) and frozen (-20 degrees C) daily. After one week of each treatment the samples were analysed by RT-PCR and PCR. 90.4% of results from PCR agreed with results from viral isolation (VI) and fluorescent antibody (FA) detection. All PCR positive samples originated from sera collected within five days of the date of onset of fever. Frozen, refrigerated and repeat freeze-thawed samples gave consistent positive results by RT-PCR. After storage at 25 degrees C, however, half the dengue-positive samples were negative by RT-PCR. The results indicate the sensitivity and reliability of this rapid technique and its applicability in the Caribbean. It provides a preliminary assessment of its advantages and limitations under certain conditions of serum collection and storage.
Dengue↗
Sequence-alignment modelling and molecular docking studies of the epoxygenase component of alkene monooxygenase from Nocardia corallina B-276.
Whole cells of Nocardia corallina B-276 catalyse the stereoselective epoxygenation of alkenes to chiral epoxides. The bacterium expresses an enzyme, alkene monooxygenase, which catalyses the epoxygenation reaction stereoselectively. The enzyme consists of a terminal oxygenase (epoxygenase), an NADH-dependent reductase (reductase) and a regulatory component (coupling protein). The epoxygenase component contains a bridged diiron centre similar to that found in the hydroxylase component of soluble methane monooxygenase. Sequence-alignment modelling, supported by chemical modification and fluorescence probing, identified a hydrophobic oxygen/substrate binding site within the epoxygenase. The diiron centre was coordinated by the two His and two Glu residues from two conserved Glu-Xaa-Xaa-His sequences and by two further Glu residues. Molecular docking of substrates and products into the proposed active-site model of the epoxygenase suggested that Ala91 and Ala185 were responsible for the stereoselectivity exerted by AMO. It is proposed that these residues clamped the intermediate and/or product of the reaction, thereby controlling the configuration of the epoxide produced. In soluble methane monooxygenase these residues are replaced by two Gly residues which do not provide sufficient steric hindrance to prevent rotation of the intermediate in the active site and, therefore, the product of the reaction catalysed by this enzyme is achiral.
Amino Acid Sequence↗
Modulation of T cell cytokine profiles and peptide-MHC complex availability in vivo by delivery to scavenger receptors via antigen maleylation.
We have previously shown that conversion of proteins to scavenger receptor (SR) ligands by maleylation increases their immunogenicity. We now show that maleyl-Ag-immune spleen cells make relatively more IFN-gamma and less IL-4 or IL-10 than native Ag-immune cells. This is also reflected in the IgG1:IgG2a ratios in Abs generated in vivo. SR engagement on macrophages does not alter their surface levels of the adhesive/costimulatory molecules CD11a/CD18, CD11b/CD18, CD24, CD54, or CD40, nor does it enhance their ability to support anti-CD3-driven proliferation of naive T cells in vitro. Costimulatory molecules implicated in differential Th1/Th2 commitment--CD80, CD86, and IL-12--are not inducible by SR ligation. In addition to macrophages and dendritic cells, B cells also show receptor-mediated uptake and enhanced presentation of maleyl-Ags. Using a monoclonal T cell line to detect peptide-MHC complexes expressed on spleen cells in Ag-injected mice, we find that higher levels of these complexes are generated in vivo from maleyl-proteins and they persist longer than those generated from the native protein. Together, these data suggest that in certain situations, the levels of cognate ligand available and/or the time course of their availability may play a major role in determining the cytokine profiles of the responding T cells in addition to the costimulatory signals implicated so far.
Animals↗
Presence of activated antigen-binding B cells during immunization enhances relative levels of IFN-gamma in T cell responses.
To examine the influence of Ag presentation by B cells on immune responses, we have used mice transgenic for an Ig heavy chain from a monoclonal anti-azobenzenearsonate (Ars) Ab to deliver Ag to B cells during immunization. A large proportion of transgene-expressing B cells in these mice binds Ars, while transgenic serum Ig shows poor Ars binding. Transgenic B cells present Ars proteins better than their nonhaptenated counterparts. This is associated with an increase in the proliferative responses of transgenic T cells to Ars protein immunization. Although B cell numbers in the transgenic mice are lower, many B cells in them show an activated phenotype, as identified by altered surface levels of peanut agglutinin reactivity, CD23, CD24, CD44, CD62L, and CD86. Even against nonhaptenated immunogens, transgenic responses show significant enhancement in the relative proportions of the Th1 cytokine IFN-gamma over the Th2 cytokines IL-4 and IL-10. Haptenated immunogens further enhance the predilection of transgenic mice to produce relatively more IFN-gamma. Consistent with this, there is an increase in IgG2a/IgG1 ratios in serum Abs in response to haptenated immunogens in transgenic mice. Adoptive transfer of primed hapten-specific secondary B cells into nontransgenic mice also induces an increase in relative levels of IFN-gamma in response to haptenated immunogens. Thus, presentation of immunogen in vivo by activated Ag-binding B cells contributes to enhanced immunogenicity and a Th1 cytokine bias.
Animals↗
Conduction aphasia in a 3-year-old with a left posterior cortical/subcortical abscess.
A 3-year-old, right-handed girl developed a conduction-type aphasia following a second generalized seizure in the setting of a developing abscess involving left subcortical and cortical angular gyrus and arcuate fasciculus, and the posterior corpus callosum. The language disorder was fluent, characterized by age appropriate mean length of utterance and syntax, but with markedly reduced spontaneity of output, rapid rate of speech and mild dysarthria. Comprehension was relatively, but not completely spared. Naming, repetition, and reading (letters) were initially markedly impaired. Improvements in naming and repetition were associated with both literal and semantic paraphasias. Writing skills in the form of drawing were spared, but a mild apraxia to verbal command and imitation was initially present. Despite her young age, this child's fluent conduction aphasia and lesion localization were adult-like. Multimodal memory difficulties appeared to underlie what is best described as conduction aphasia.
Abscess↗
Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1.
Recent evidence points to a role of cytokines like tumor necrosis factor-alpha (TNF) in the generation of hyperalgesia not only in inflammatory, but also in neuropathic pain. We used the model of chronic constrictive injury (CCI) of one sciatic nerve in the mouse to investigate which of the two known TNF receptors is involved in the process that leads to hyperalgesia after nerve injury. Neutralizing antibodies to TNF, to the TNF receptor 1 (TNFR1), and to the TNF receptor 2 (TNFR2) were administered by epineurial injection once daily to mice with CCI. Testing of the animals' hind paws with thermal and innocuous mechanical stimuli revealed a reduction in thermal hyperalgesia and mechanical allodynia in mice treated with neutralizing antibodies to TNF and to TNFR1. Neutralizing antibodies to TNFR2 had no effect. We conclude that TNFR1, but not TNFR2, is mediating thermal hyperalgesia and mechanical allodynia after nerve injury.
Animals↗
The phosphophoryn gene family: identical domain structures at the carboxyl end.
Phosphophoryns (PPs), a family of aspartic acid and phosphoserine rich dentin proteins, are considered to be archetypal regulators of extracellular matrix biomineralization. Their very unusual composition, extensive phosphorylation, and tissue-specific heterogeneity have made their characterization a difficult task. We have recently cloned several rat incisor PP genes from our odontoblast cDNA library. The first clone, designated as DMP2, was 2.4 kb long, with an open reading frame of approximately 700 bp and an untranslated region of approximately 1.7 kb. Northern blot analysis of odontoblast mRNA showed a single message between 5 and 6 kb. When a 5' RACE technique was used to obtain the full length clone, a second approximately 2 kb DNA fragment (DMP3) was also found. Cloning and sequencing of DMP3 showed that the 3' end was highly homologous to the 3' end of DMP2, but the 5' end of this clone had 100% homology to dentin sialoprotein (DSP). DMP3 is not a typical Asp-rich phosphophoryn, but DMP2 contains a domain N-terminal to the common region which has the hallmark Asp- and Ser-rich composition of the phosphophoryns. Both DMP2 and DMP3 are closely localized on mouse chromosome 5q21, corresponding to human chromosome 4q21. The expression of these two genes is regulated differently. Thus, there may be a family of phosphophoryn-related genes coding for a common C-terminal peptide sequence domain, but involving different N-terminal domains with different functions.
Amino Acid Sequence↗
Properties of the (DSS)n triplet repeat domain of rat dentin phosphophoryn.
Phosphophoryns (PPs) are unique aspartic acid and phosphoserine-rich proteins present in all species of dentin. Rat incisor odontoblast cDNA libraries contain messages encoding several acidic phosphorylated, serine-rich proteins. At least two of these share a common C-terminal domain coding region sequence. The polypeptide sequences in the N-terminal direction immediately adjacent to the conserved C-terminal domains of these two proteins (DMP2, DMP3) are distinctly different. In this domain, the DMP2 has extensive sequences of (DSS)n repeats with n as large as 24. DMP3 has fewer and shorter triplet sequences, n = 3, 4. The major rat incisor PPs (90-95 kDa) probably have the (DSS)n>>3. We propose that the name phosphophoryn be reserved for the extracellular matrix proteins with these extended repeats. DMPI, although strongly acidic, does not fit this category. If the S residues are phosphorylated and n > 3, conformational energy minimization computations show the (DSS)n sequence to assume a unique extended structure with parallel arrays of carboxylate and phosphate groups which may function as Ca2+ ion interaction edges. The phosphorylation of recombinant DMP2 C-terminal domain by various kinases has been examined. The repeat domains are not direct substrates for the CK2-like kinases but the kinases act in concert, so that the phosphorylation is hierarchical, apparently controlled by the presence of specific interruptions between the triplet domains.
Amino Acid Sequence↗
Comparison of aerobic exercise, clomipramine, and placebo in the treatment of panic disorder.
OBJECTIVE: The purpose of this study was to compare the therapeutic effect of exercise for patients with panic disorder to a drug treatment of proven efficacy and to placebo. METHOD: Forty-six outpatients suffering from moderate to severe panic disorder with or without agoraphobia (DSM-III-R criteria) were randomly assigned to a 10-week treatment protocol of regular aerobic exercise (running), clomipramine (112.5 mg/day), or placebo pills. RESULTS: The dropout rate was 31% for the exercise group, 27% for the placebo group, and 0% for the clomipramine group. In comparison with placebo, both exercise and clomipramine led to a significant decrease in symptoms according to all main efficacy measures (analysis of variance, last-observation-carried-forward method and completer analysis). A direct comparison of exercise and clomipramine revealed that the drug treatment improved anxiety symptoms significantly earlier and more effectively. Depressive symptoms were also significantly improved by exercise and clomipramine treatment. CONCLUSIONS: These results suggest that regular aerobic exercise alone, in comparison with placebo, is associated with significant clinical improvement in patients suffering from panic disorder, but that it is less effective than treatment with clomipramine.
Adult↗
Termination of non-viable second trimester pregnancies.
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Abortifacient Agents↗
Octreotide as primary therapy for acromegaly.
The effects of octreotide (up to 5 yr) as primary treatment in 26 patients with acromegaly were compared with those in 81 patients with acromegaly who received octreotide as secondary or adjunctive therapy after previous surgery and/or pituitary radiation. These patients were part of a multicenter study that took place between 1989-1995. The study was divided into 3 phases beginning with a 1-month placebo-controlled treatment period followed by a 1-month washout period. In the second phase, patients were randomized to treatment with either 100 or 250 micrograms octreotide, sc, every 8 h for 6 months. Octreotide was then discontinued for 1 month and reinitiated at the lower dose for a total mean treatment duration of 39 months. The dose was titrated by each investigator to improve each patient's individual response, which included improvement in symptoms and signs of acromegaly as well as reduction of GH and insulin-like growth factor I (IGF-I) into the normal range. In the second phase of the study, in which patients were randomized to either 100 or 250 micrograms octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 +/- 5.2 to 6.0 +/- 1.7 micrograms/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3-60 months). The mean final daily dose was 777 micrograms. In the patients receiving secondary treatment, mean GH fell from 30.2 +/- 7.6 to 5.6 +/- 1.1 micrograms/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 micrograms daily). Mean IGF-I concentrations fell from 5.2 +/- 0.5 x 10(3) U/L (primary treatment group) and 4.7 +/- 0.4 x 10(3) U/L (secondary treatment group) to a mean of 2.2 +/- 0.3 x 10(3) U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group. Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups. Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50-100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62-88%. Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH. In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. (AB
Acromegaly↗
Oxygen therapy for children. Need-based preparation and evaluation of a self-instructional module for staff nurses on care of a child receiving oxygen therapy.
The present study was carried out with the objectives of determining the learning needs of Staff Nurses regarding care of children receiving Oxygen Therapy; finding association between learning needs and selected variables: age, total years of experience, experience in Paediatric Ward, married with or without children; determining validity of self-instructional module, on "care of child receiving Oxygen Therapy", and evaluating the effectiveness of the self-instructional module or SIM. The study was conducted in two phases. A survey approach was used for Phase-I and one group pre-test post-test design was adopted for Phase-II. The total sample of the study was 30 Staff Nurses, of 6 months experience in Paediatric Ward. The findings of the study showed high learning need status in most of the areas and the Staff Nurses also expressed the desirable need for learning in detail. It was found that age, total years of experience, experience in Paediatric Ward and married with or without children were independent of their learning need. SIM was effective in terms of gain in knowledge score as well as acceptability and utility scores of Staff Nurses.
Adult↗
A metalloprotease-inhibitor reduces pain associated behavior in mice with experimental neuropathy.
Tumor necrosis factor-alpha (TNF) is involved in the generation of inflammatory and neuropathic pain. The synthetic hydroxamic acid based metalloprotease inhibitor TAPI blocks cleavage of cell surface TNF and thus reduces levels of the mature 17-kDa TNF polypeptide in activated macrophages and T-cells. We have previously shown that pharmacologic inhibition of TNF production reduces pain related behaviors in mice with chronic constriction injury (CCI). Here we investigated whether blockage of TNF shedding by administration of TAPI would diminish hyperalgesia in animals with partial nerve injury. We injected 0.5 mg of the inhibitor epineurially once daily to mice with CCI for 7 days. The animals were tested for withdrawal thresholds to heat to test for thermal hyperalgesia and to von Frey hairs to assess mechanical allodynia. Mice with CCI developed thermal hyperalgesia and mechanical allodynia by day 3 after the injury. In mice treated with TAPI, a reduction of thermal hyperalgesia and mechanical allodynia of up to 50% occurred. Endoneurial TNF-immunoreactivity was reduced, but not immunoreactivity for IL-1alpha or IL-1beta. The numbers of degenerating axons and endoneurial macrophages were not affected by the treatment as compared to controls. We conclude that the metalloprotease inhibitor TAPI specifically reduces endoneurial TNF-levels after nerve injury and thereby may diminish neuropathic pain in the CCI-model.
Animals↗