Biomedical subjects
M Kelleher
Publications and source records attributed to M Kelleher.
IASP task force on euthanasia and assisted suicide.
The first meeting of the IASP Task Force on Euthanasia and Assisted Suicide took place in Venice on June 7, 1995. Several interested observers were present. It was decided that at the public IASP meeting the following day each speaker should address, briefly, the current legal situation and the pressure for change, as well as give a personal statement. David Clark spoke for North America, Bob Goldney for Australia, Michael Kelleher for Britain and Ireland, Jerzy Wasserman for Scandinavia, and Hans Wedler for the German-speaking world. Their views are published in this article. Ad Kerkhof requested that the Dutch television film "Death on Request" be discussed. The committee was of the opinion that clear definitions were essential. In their view, these should take into account the differences between active and passive euthanasia, as well as between professionally assisted and lay-assisted suicide.
Sickle cell disease: a diagnostic dilemma.
The case history is described of a patient with sickle cell anaemia who developed a unilateral infarct of the mandible following a sickle cell crisis. The interruption of the blood supply resulted in an anaesthesia of the inferior dental nerve and pulpal necrosis of otherwise sound premolar and molar teeth. The diagnostic and management difficulties of the case are discussed, and recommendations are made for treatment of such patients in light of the problems encountered.
Lipophosphoglycan blocks attachment of Leishmania major amastigotes to macrophages.
Promastigotes of the intracellular protozoan parasite Leishmania major invade mononuclear phagocytes by a direct interaction between the cell surface lipophosphoglycan found on all Leishmania species and macrophage receptors. This interaction is mediated by phosphoglycan repeats containing oligomers of beta (1-3)Gal residues specific to L. major. We show here that although amastigotes also use lipophosphoglycan to bind to both primary macrophages and a cell line, this interaction is independent of the beta (1-3)Gal residues employed by promastigotes. Binding of amastigotes to macrophages could be blocked by intact lipophosphoglycan from L. major amastigotes as well as by lipophosphoglycan from promastigotes of several other Leishmania species, suggesting involvement of a conserved domain. Binding of amastigotes to macrophages could be blocked significantly by the monoclonal antibody WIC 108.3, directed to the lipophosphoglycan backbone. The glycan core of lipophosphoglycan could also inhibit attachment of amastigotes, but to a considerably lesser extent. The glycan core structure is also present in the type 2 glycoinositolphospholipids which are expressed on the surface of amastigotes at 100-fold-higher levels than lipophosphoglycan. However, their inhibitory effect could not be increased even when they were used at a 300-fold-higher concentration than lipophosphoglycan, indicating that lipophosphoglycan is the major macrophage-binding molecule on amastigotes of L. major. In the presence of complement, the attachment of amastigotes to macrophages was not altered, suggesting that lipophosphoglycan interacts directly with macrophage receptors.
Anti-galactosyl antibodies that react with unmodified agarose: a potential source of artifacts in immunoaffinity chromatography.
Rabbits were immunized with glycolipid and membrane glycoprotein extracts of the promastigotes of Leishmania major partially purified by two-phase extraction with Triton X-114. The resulting antibodies were affinity purified on agarose immunoadsorbents to which a recombinant DNA-produced L. major polypeptide had been coupled. In addition to the expected reaction with the polypeptide, it was found that the affinity-purified antibodies reacted strongly with lipophosphoglycan of L. major amastigotes and to a lesser extent with the lipophosphoglycan of promastigotes. Antibodies with this reactivity could be affinity purified on unmodified agarose and were probably directed against beta-1,3-galactosyl determinants shared between the agarose matrix and Leishmania. In this and other special situations the properties of the support matrix can be exploited to obtain antibodies of defined specificity which may be useful probes for the identification and characterization of carbohydrate structures. This work also points to a potential source of artifacts in affinity chromatography, in which the bead matrix is usually considered as inert. Carbohydrate antigens are ubiquitous, particularly in micro-organisms, and the presence of such antibodies may be more common than previously recognized.
Epitope mapping of monoclonal antibodies directed against lipophosphoglycan of Leishmania major promastigotes.
Monoclonal antibodies (MAbs) were generated against Leishmania major promastigote lipophosphoglycan (LPG) to use as tools in defining functional epitopes of this major cell surface glycoconjugate. Epitope mapping of four MAbs, designated 4A2-A2, 2G11-A3, 5E6-D10 and 5E10-F2, revealed that the phosphorylated oligosaccharide repeat unit PO4-6[Gal(beta 1-3)]Gal(beta 1-4)Man alpha 1-, P3, is a highly immunogenic epitope which has previously been demonstrated, by chemical analyses, to be a repeat unit specific to L. major. Two antibodies, 4A2-A2 and 5E10-F2, also recognised the repeat unit PO4-6[Ara(beta 1-2)Gal(beta 1-3)]Gal(beta 1-4)Man alpha 1-, 4Pa, with less affinity than P3, while 2G11-A3 recognised P4a with greater affinity than for P3. The L. major metacyclic-specific antibody 3F12 only recognised repeat units terminating with arabinose residues. In particular, 3F12 recognised P4a, which is upregulated in metacyclic LPG compared to the procyclic form of the molecule. The oligosaccharides P3, P4a and P5a are specific to L. major LPG. The epitopes of 4A2-A2, 2G11-A3, 5E6-D10 and 5E10-F2 were found on the cell surface and in the flagellar pocket of both procyclic and metacyclic V121 promastigotes, but were only detected at very low levels on amastigotes. The repeat unit P3 is able to inhibit attachment of procyclic promastigotes to the midgut of the sandfly vector, but neither Fab fragments of the four antibodies nor purified P3 could inhibit attachment of metacyclic promastigotes to the macrophage cell line J774. It was also shown that human sera from patients with cutaneous leishmaniasis recognised purified P3. The data suggests that while P3 is an immunogen in the natural course of infection of the human host, P3 plays no role in attachment and internalisation of promastigotes into the macrophages of the mammalian host.
Ricin-resistant mutants of Leishmania major which express modified lipophosphoglycan remain infective for mice.
Glycosylation variants of the virulent Leishmania major clone V121 were generated by mutagenesis with N-methyl-N-nitroso-N-nitroguanidine and selected using the galactose-specific lectin Ricinus communis II (RCA II). Three mutants, 4B9, 1D1 and 1C12, which failed to bind RCA II, were found to have an altered expression of lipophosphoglycan (LPG), a molecule implicated in the attachment to host macrophages and survival within the phagolysosome. There were differences in the antigenicity, molecular weight and localization of LPG from mutant parasites as compared to V121. Expression of gp63, a surface molecule also implicated in attachment to macrophages, was unaltered. All 3 mutants caused disease when injected into genetically susceptible BALB/c mice but lesions developed at a much slower rate than those caused by the virulent V121 clone. This slow rate of lesion development did not correlate with promastigotes' ability to invade macrophages in vitro. Karyotype analysis showed that there was a reduction in the size of chromosome band number 2 in all 3 mutants. The differences in LPG and chromosome band 2 were retained by mutant clones following passage through mice, suggesting that these phenotypes are stable. Although the mutant parasites were infective and caused lesions, the changed structure of the LPG appeared to influence the virulence of the parasites.
The aetiology and management of localized anterior tooth wear in the young adult.
This article reviews the aetiology and clinical features of the increasingly common problem of localized loss of anterior tooth tissue in the young adult. The management of the problem is highlighted, with emphasis placed on preservation of the tooth structure and the use of modern materials and techniques.
Case report: the use of indirect composite for the management of extensive erosion.
Erosive tooth surface loss due to acidic soft-drinks has been well documented. Unfortunately, the erosive danger, especially to young patients, of low calorie beverages seems less well appreciated. A clinical case is reported to highlight the problems that can occur with excessive exposure to such beverages. A method of restoring the damaged dentition using indirect composite is described. It is concluded that indirect composite may be particularly suited for the restoration of eroded dentitions, especially in young patients where aesthetics and repairability are important. Further clinical studies are necessary to assess the performance of these and other materials currently used in the management of erosive tooth wear.
Back pain: the history and physical examination.
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Identification of a macrophage-binding determinant on lipophosphoglycan from Leishmania major promastigotes.
Leishmania are obligatory intracellular parasites in mammalian macrophages that gain entry by receptor-mediated phagocytosis. Their major cell surface glycoconjugate, lipophosphoglycan (LPG), has been implicated in this process. A monoclonal antibody specific for Leishmania major LPG (WIC 79.3), which has been shown to block promastigote attachment to macrophages, was used to identify a macrophage-binding determinant of LPG. WIC 79.3 bound exclusively to the phosphorylated repeats of LPG and not to the saccharide core or lipid anchor. Furthermore, the epitope recognized by WIC 79.3 mapped to the phosphorylated oligosaccharide P5b, PO4-6[Gal(beta 1-3)Gal(beta 1-3)Gal(beta 1-3)]Gal(beta 1-4)Man(alpha 1-, which is unique to the LPG of promastigotes of L.major. Phosphorylated oligosaccharides P3, PO4-6[Gal(beta 1-3)[Gal(beta 1-4) Man(alpha 1-, and P4b, PO4-6[Gal(beta 1-3)Gal(beta 1-3)] Gal(beta 1-4)Man(alpha 1-, were also recognized by WIC 79.3 but with considerably lower (approximately 100-fold) affinities. The phosphorylated oligosaccharide P5b inhibited attachment of promastigotes of L. major to the macrophage cell line J774 to the same degree as phosphoglycan (derived from LPG) and Fab fragments of WIC 79.3, suggesting that P5b is a site of L. major LPG that is recognized by macrophage receptor(s) and is an important determinant in the attachment of promastigotes to host macrophages and initiation of infection.
Alcohol-free beer and the irreversible monoamine oxidase inhibitors.
Three cases of vascular crises associated with the use of MAOIs and the ingestion of alcohol-free beer are reported.
Lipophosphoglycan expression and virulence in ricin-resistant variants of Leishmania major.
Lipophosphoglycan (LPG) of Leishmania is a polymorphic molecule comprising an alkylglycerol anchor, a conserved oligosaccharide core and a species-specific polymer of oligosaccharide repeats jointed by phosphodiester bonds. This molecule, together with the membrane polypeptide gp63, has been implicated as a parasite receptor for host macrophages. To examine the role of LPG in parasite infectivity glycosylation variants of Leishmania major were generated by chemical mutagenesis of a virulent cloned line V121 and variants with modified LPG selected using the galactose-specific lectin Ricinus communis II (RCA II). Twenty RCA II-resistant primary clones were generated. Analysis of LPG profile by immunoblotting using LPG-specific monoclonal and polyclonal antibodies revealed that some of the clones were LPG-deficient. Three clones that did not bind any LPG-specific antibodies but expressed normal levels of the Mr 63,000 glycoprotein (gp63), a second parasite receptor for host, were chosen for detailed studies. All three clones expressed, at least to some extent, a surface molecule which could be labeled by mild periodate oxidation and sodium borotritide and behaved like LPG by hydrophobic interaction chromatography. All clones also bound a well-characterized monoclonal antibody L157 directed to the core oligosaccharide of LPG, but did not bind another monoclonal antibody, CA7AE, to an epitope on a repeating unit shared by Leishmania donovani and L. major LPG. A third monoclonal antibody, 5E6, recognizing LPG on the surface of wild-type V121 promastigotes bound only to RCA II-resistant clone 3A2-C3 and was restricted to an internal structure. The LPG molecule that this clone expressed was a form of LPG by its chromatographic behavior and by its monosaccharide and alkylglycerol composition. Clone 3A2-C3 was the only one to infect mice in vivo and survive in macrophages in vitro, albeit at a much reduced rate compared to wild-type V121 promastigotes. The data suggest that some form of LPG may be necessary to ensure parasite infectivity.
Treatment of hepatic epithelioid hemangioendothelioma with liver transplantation.
Ten patients received liver transplants for unresectable epithelioid hemangioendothelioma (EHE). At the time of transplantation, four patients had microscopic metastases to the hilar lymph nodes, and one of the four also had metastases to a rib. The fifth patient had metastases to the lung, pleura, and diaphragm. The remaining five patients were believed to be free of metastatic disease. Two of these five patients died of metastatic disease at 3 and 16 months, respectively, after transplantation. Interestingly, all five patients with metastatic involvement are currently alive 40.6 +/- 22 months (mean +/- standard error of mean [SEM]) after transplantation, although one of these patients currently has metastatic disease to the lungs and mediastinum. Thus, the projected 5-year actuarial survival rate is 76%, with two patients at risk after the third year. In conclusion, liver transplantation is a reasonable procedure for bulky, otherwise unresectable, EHE even in the presence of metastatic disease.
Airway effects of monosodium glutamate in subjects with chronic stable asthma.
We studied the effect of oral monosodium glutamate (MSG) on airways function in 12 subjects with a history of chronic stable asthma in a double-blind, randomized, crossover protocol. Subjects ingested either 25 mg/kg of MSG or sodium chloride (equimolar to MSG) following a 6-hour fast. Spirometry [forced expiratory volume in 1 second (FEV1) and forced vital capacity] was performed before administration of the test substances and for a minimum of 4 hours thereafter. At no time during the observation period was the mean change in FEV1 more negative following MGS than following placebo. MSG is unlikely to be a contributing factor in bouts of bronchospasm in subjects with asthma, and routine avoidance of MSG by individuals with asthma need not be advised.
The increase in the suicide rate in Ireland.
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Microbial examination of kidney lithotripter tub water and epidural anesthesia catheters.
Kidney lithotripsy patients frequently receive epidural anesthesia via indwelling epidural catheters. In our hospital, patients are immersed in a tub of warm, continuously-flowing tap water. The epidural catheter-entry site is covered by a transparent occlusive dressing. To determine the risk of microbial colonization of the epidural catheter during lithotripsy, we performed quantitative cultures of tub water and semiquantitative cultures of catheters in 63 lithotripsy procedures. Most of the tub water organisms were typical tap water and skin flora isolates. Total colony counts were generally low with no significant progression during the course of serial procedures. Forty-two epidural catheters were cultured; 34 (81%) were sterile, 8 (19%) were colonized with small numbers of flavobacteria or coagulase-negative staphylococci. Only four catheters had organisms present on catheter segments covered by the transparent occlusive dressing (in each case there was a single colony forming unit per semiquantitative plate) and these organisms were probable contaminants. We conclude that with our current lithotripsy procedures, the risk for the development of epidural catheter-associated infection seems to be low.