Decisions to remove asymptomatic third molars require rational criteria.
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Decision Making↗
Biomedical subjects
K G Smith
Publications and source records attributed to K G Smith.
Inhibition of the B cell by CD22: a requirement for Lyn.
Mice in which the Lyn, Cd22, or Shp-1 gene has been disrupted have hyperactive B cells and autoantibodies. We find that in the absence of Lyn, the ability of CD22 to become tyrosine phosphorylated after ligation of mIg, to recruit SHP-1, and to suppress mIg-induced elevation of intracellular [Ca2+] is lost. Therefore, Lyn is required for the SHP-1-mediated B cell suppressive function of CD22, accounting for similarities in the phenotypes of these mice.
Amino Acid Sequence↗
A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes.
Members of the tumour necrosis factor receptor family that contain a death domain have pleiotropic activities. They induce apoptosis via interaction with intracellular FADD/MORT1 and trigger cell growth or differentiation via TRADD and TRAF molecules. The impact of FADD/MORT1-transduced signals on T lymphocyte development was investigated in transgenic mice expressing a dominant negative mutant protein, FADD-DN. Unexpectedly, FADD-DN enhanced negative selection of self-reactive thymic lymphocytes and inhibited T cell activation by increasing apoptosis. Thus signalling through FADD/MORT1 does not lead exclusively to cell death, but under certain circumstances can promote cell survival and proliferation.
Adaptor Proteins, Signal Transducing↗
Affinity maturation of the primary response by V gene diversification.
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Animals↗
Suppression of the humoral immune response by mycophenolate mofetil.
BACKGROUND: No conventional immunosuppressive agent preferentially inhibits antibody production. Studies in experimental animals and in human cells in vitro suggested mycophenolate mofetil (MMF) might have such an effect. If this was the case in vivo it could have significant implications in terms of both MMF toxicity and the rational design of immunotherapeutic regimens. METHODS: Subjects were renal transplant recipients (25 patients treated with prednisolone, cyclosporine and azathioprine, and 13 treated with prednisolone, cyclosporine and MMF) and 20 normal controls. The three groups received influenza vaccination, and the antibody response to it was measured 4-6 weeks later using a standard haemagglutination assay. RESULTS: MMF profoundly suppressed the humoral immune response to influenza vaccination when added to prednisolone and cyclosporine. This effect could be seen when comparing the rise in the mean titre of antibody after vaccination. It was also reflected in the number of patients mounting responses deemed to be clinically protective by either demonstrating a 4-fold rise in titre or an increase in titre to > or = 40. CONCLUSIONS: Suppression of the humoral immune response by MMF has implications for the design of immunization protocols to protect the immunosuppressed, and raises the possibility that MMF use may be accompanied by more or different infections than complicate more conventional immunosuppression. More importantly, consideration should be given to harnessing the relatively specific effect of MMF on antibody production to treat antibody-mediated diseases.
Adolescent↗
How clinical research changed the habit of a lifetime.
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Dental Research↗
The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response.
Immunization with protein-containing antigens results in two types of antigen-specific B cell: antibody forming cells (AFCs) producing antibody of progressively higher affinity and memory lymphocytes capable of producing high affinity antibody upon re-exposure to antigen. The issue of the inter-relationship between affinity maturation of memory B cells and AFCs was addressed through analysis of single, antigen-specific B cells from the memory and AFC compartments during the primary response to a model antigen. Only 65% of splenic memory B cells were found capable of producing high affinity antibody, meaning that low affinity cells persist into this compartment. In contrast, by 28 days after immunization all AFCs produced high affinity antibody. We identified a unique, persistent sub-population of bone marrow AFCs containing few somatic mutations, suggesting they arose early in the response, yet highly enriched for an identical affinity-enhancing amino acid exchange, suggesting strong selection. Our results imply that affinity maturation of a primary immune response occurs by the early selective differentiation of high affinity variants into AFCs which subsequently persist in the bone marrow. In contrast, the memory B-cell population contains few, if any, cells from the early response and is less stringently selected.
Amino Acid Sequence↗
Online access to journal abstracts and articles.
Advances in information technology now offer several options for child and adolescent psychopharmacologists to navigate the increasingly complex terrain of scientific literature and keep abreast of the rapidly changing advances in our field. MEDLINE, the world's largest database of medical literature, can be accessed and searched by a variety of free or fee-based services. In addition to efficient retrieval of citations and abstracts based on subject, author, or title, many of these services now provide, for a fee, the entire text and graphics of articles (displayed on computer screen, faxed, or mailed). There are also current awareness services to alert the user when new requested literature become available as well as services to send via e-mail the tables of contents of requested journals (sometimes prior to paper publication). For online citation and abstract retrieval, we found that free services, such as PubMed, performed as good or better than fee-based services. Physicians' Online, sponsored by the pharmaceutical industry, offered the lowest price for full-text manuscript delivery. In this article, we review literature search, delivery, and update services and offer some tips on how to most effectively use these resources.
Child↗
Apoptosis and the B cell response to antigen.
The primary B cell response to T cell dependent antigens comprises two pathways of differentiation; one resulting in formation of foci of antibody forming cells in the extrafollicular regions of secondary lymphoid organs and the other giving rise to germinal centers within the follicles. Foci of antibody forming cells are detectable for only a limited time, before involuting due to apoptosis of the plasma cells. Similarly in the germinal center, regulation of cell number, selection of high affinity variants generated by somatic hypermutation, and the resolution of the germinal center itself all involve the death of unwanted B cells. In this review we describe recent experiments which have allowed determination of the role of certain forms of apoptosis in the B cell response to antigen.
Animals↗
CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (Fas/APO-1)-transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease.
The cysteine protease interleukin-1beta converting enzyme (ICE) is implicated as an effector of apoptosis in mammalian cells. Proteolytic activity of ICE can be blocked in vitro by the cytokine response modifier A (crmA), a serpin-like protease inhibitor encoded by cowpox virus. Here we show that CD2 enhancer-driven expression of crmA in T lymphocytes of transgenic mice (CD2-crmA mice) reduces CD95 (Fas/APO-1)-transduced apoptosis in vitro to the level seen in CD95-deficient mutant lpr mice, but does not protect against gamma-radiation or corticosteroid-induced cell death. Unlike lpr mice, CD2-crmA transgenic mice developed neither T cell hyperplasia nor serum autoantibodies. These results provide evidence that the phenotype of lpr mice is not simply due to failure of CD95 to trigger T cell apoptosis mediated by ICE.
Animals↗
Lingual nerve damage during lower third molar removal: a comparison of two surgical methods.
The high incidence of lingual sensory disturbance following lower third molar removal in the UK may be due to the elevation of a lingual flap and insertion of a Howarth's periosteal elevator, in an attempt to protect the lingual nerve. We have therefore studied the validity of this technique by recording the incidence of temporary and permanent lingual nerve injury during 771 operations randomly allocated to be carried out with or without lingual flap retraction. Surgery with lingual flap retraction resulted in lingual sensory disturbance in 6.9% and this persisted, requiring lingual nerve repair, in 0.8%. Surgery without lingual flap retraction resulted in lingual sensory disturbance in 0.8% (P < 0.0001) and this persisted, requiring lingual nerve repair, in 0.3%. We conclude that avoidance of lingual retraction reduces the incidence of temporary lingual nerve disturbance and does not increase the incidence of permanent damage. This indicates that use of the Howarth's in this way is invalid, and suggests that for the majority of cases, lingual retraction should be avoided.
Humans↗
The phenotype and fate of the antibody-forming cells of the splenic foci.
The first product of the humoral response to antigen is low-affinity antibody, produced by extrafollicular foci of antibody-forming cells (AFC) in organs such as spleen and lymph node. These cells proliferate rapidly but then undergo an equally rapid decline, so that they are present in only small numbers 14 days after immunization. We have used 6-parameter flow cytometry to isolate and examine the characteristics of (4-hydroxy-5-nitrophenyl)acetyl-specific AFC, looking in particular for those markers that might differentiate them from cells of the intrafollicular (germinal center) arm of the T-dependent immune response. At day 7 of the primary response, most AFC were found to express surprisingly low levels of B220, high levels of syndecan, and retain significant levels of surface IgG1. We then used enzyme-linked immunospot assays to demonstrate that the rapid decline of these cells was not likely to be due to migration to organs such as the bone marrow. Their decline could, however, be explained by apoptosis in situ, which was demonstrated immunohistologically by nick-end labeling.
Animals↗
Surgical anatomy of the buccal nerve.
The buccal nerve may be damaged during surgical procedures which require an incision along the external oblique ridge of the mandible and this study was undertaken to clarify its surgical anatomy. The course and relationships of the nerve were determined in 20 formalin-fixed cadaver specimens. The number of major branches of the nerve ranged from 4 to 8 and a mean of 3 branches was present as the nerve crossed the external oblique ridge. In 14 dissections the main trunk of the nerve crossed the external oblique ridge within 3 mm of the deepest concavity, but in the other 6 it was 7-12 mm below this point. We conclude that incisions even 12 mm below the deepest concavity in the external oblique ridge could result in buccal nerve damage.
Aged↗
A study on the efficacy of late lingual nerve repair.
The level of sensory recovery was studied in 13 consecutive patients who had undergone lingual nerve repair after a delay of 7-32 (mean 16) months since the initial injury. In all patients the damaged segment of nerve was excised and the cut ends directly apposed by 6-10 (mean 7) epineurial sutures. The final outcome was assessed 12-24 months after repair. Preoperatively none of the patients could detect light touch stimuli in the denervated area, whereas 10 patients could detect some stimuli after repair. Pin-prick was detected in 6 preoperatively and in some areas by all 13 patients after repair. Two-point discrimination thresholds decreased after repair in 10 patients and in four of these became the same as on the uninjured side. Gustatory stimuli showed that there had been some return of taste sensation in 6 patients, and there were responses to electrogustometry in 12 patients. The patients' subjective assessment of the value of repair (scale 0-10) ranged from 0-10 (median 7). These results show that most patients undergo significant and worthwhile recovery after late lingual nerve repair.
Adult↗
A quantitative morphological comparison of cat lingual nerve repair using epineurial sutures or entubulation.
Since lingual nerves may be transected during a variety of oral surgical procedures, including third molar removal, we have investigated two possible methods of repair. Quantitative morphological observations were made on feline chorda tympani and lingual nerves proximal and distal to transection injuries repaired either by epineurial suturing or by insertion of the cut ends into a perforated silicon tube. Proximal to the repair, the most prominent difference was an increase in the number of myelinated axons in the lingual nerve following epineurial suturing but not entubulation. Proximal to the repair site, the number of nonmyelinated axons increased in comparison with controls in both chorda tympani and lingual nerves after both procedures, though the difference was statistically significant only in the lingual nerve proximal to entubulation. Distal to the injury, both types of repair showed a reduction in the number, size, and sheath thickness of myelinated axons in comparison with unoperated controls, but the difference in numbers was statistically signIficant only distal to repair by entubulation. The number of non-myelinated axons distal to the repair sites was much higher than that in controls, the difference being greater distal to entubulation repair. There were more axons per Remak bundle distal to entubulation repair than to epineurial suturing, suggesting, perhaps, that fewer axons would ultimately become myelinated. Though the morphological differences between the two repair techniques are not as striking as the parallel electrophysiological differences reported previously (Smith and Robinson, 1995a,b), they are consistent with them and support the conclusion that, for transected lingual and chorda tympani nerves, epineurial suturing is the preferred approach.
Animals↗
A quantitative morphological study of the recovery of cat lingual nerves after transection or crushing.
The morphological changes were examined proximal and distal to crush and transection injuries of the lingual/chorda tympani nerve. Under general anaesthesia the nerve was transected unilaterally in 6 adult cats and crushed with watchmakers forceps in 6 others. After 12 wk, again under general anaesthesia, the injured and contralateral (control) nerves were removed, fixed and embedded for histological examination. Sections were cut from sites proximal and distal to the injury and from a site equivalent to that of the injury on the control side. Using systematic randomised sampling techniques the number of nonmyelinated axons and the number and size of myelinated axons in each nerve at each location was estimated. In addition, the mean number of nonmyelinated axons in each Schwann cell unit was determined. The only significant difference between control and injured nerves proximal to either injury was a reduction in the number of myelinated axons in the chorda tympani after transection, and an increase in their mean size. This indicates a selective loss of smaller fibres and is consistent with the poor recovery of gustatory and thermosensitive fibres previously reported (Robinson, 1989). Distal to both types of injury there was an increase in the number of fascicles. The mean number of myelinated axons was reduced distal to a crush injury but unchanged distal to transection. The number of nonmyelinated axons distal to a transection injury was 5 times control counts and after a crush injury double. These findings suggest that sprouting persists 12 wk after both injuries but is much greater after transection.
Animals↗
Effects of viral inhibitors of apoptosis in models of mammalian cell death.
Apoptotic cell death is used as a defence against infection by viruses. To counter this protective mechanism, some viruses carry genes whose products can inhibit progression of the apoptotic process in the host cell. As it is clear that the core cell death mechanisms have been conserved through evolution, viral genes from various sources can be used to unravel these mechanisms in mammalian cells. We have produced transgenic mice that express the cowpox gene crmA in their T cell compartment, and analysed their susceptibility to apoptosis. We have studied the effects of the baculovirus genes p35 from Autographa californica nuclear polyhedrosis virus and IAP from Orgyia pseudotsugata nuclear polyhedrosis virus on cell death induced in HeLa cells by over-expression of interleukin-1 beta converting enzyme (ICE), overexpression of the CD95-associated protein FADD, or cell death induced by treatment with TNF plus cycloheximide. These experiments indicate that viral anti-apoptosis proteins target both the activation and effector phases of the physiological cell death process.
Animals↗
FAS is highly expressed in the germinal center but is not required for regulation of the B-cell response to antigen.
In establishing the memory B-cell population and maintaining self-tolerance during an immune response, apoptosis mediates the removal of early, low-affinity antibody-forming cells, unselected germinal center (GC) cells, and, potentially, self-reactive B cells. To address the role of the apoptosis-signaling cell surface molecule FAS in the B-cell response to antigen, we have examined the T-cell-dependent B-cell response to the carrier-conjugated hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) in lpr mice in which the fas gene is mutated. High levels of FAS were expressed on normal GC B cells but the absence of FAS did not perturb the progressive decline in numbers of either GC B cells or extrafollicular antibody-forming cells. Furthermore, the rate of formation and eventual size of the NP-specific memory B-cell population in lpr mice were normal. The accumulation of cells with affinity-enhancing mutations and the appearance of high-affinity anti-NP IgG1 antibody in the serum were also normal in lpr mice. Thus, although high levels of FAS are expressed on GC B cells, FAS is not required for GC selection or for regulation of the major antigen-specific B-cell compartments. The results suggest that the size and composition of B-cell compartments in the humoral immune response are regulated by mechanisms that do not require FAS.
Amino Acid Sequence↗