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Biomedical subjects

A M MacLeod

Publications and source records attributed to A M MacLeod.

At least 91 records · Page 5Linked to original sources
PubMed1991

The blood transfusion effect: clinical aspects.

In 1973, Opelz et al. demonstrated a one-year renal transplant survival of 29% in patients who had never been transfused and 66% in those receiving over ten units of blood before transplantation. Subsequent reports were contradictory, but by the early 1980s it was generally accepted that pretransplant blood transfusions were beneficial. By 1983 only 4% of patients awaiting transplantation were untransfused. Since 1985 the data have again become much less clear. In 1987, Opelz showed no improvement in transplant survival, irrespective of whether immunosuppression was with cyclosporin or with conventional therapy. Recently, however, several American studies have again shown beneficial effects of transfusions particularly in patients less well matched for HLA antigens with their donor. There is evidence also that blood transfusion from the specific donor improves survival of a transplant from a living related donor. The risk of sensitisation can be minimised by giving cyclosporin along with the transfusion. Mechanism of the transfusion effect is unclear, but the following have been suggested: (a) clonal deletion or inactivation; (b) the induction of suppressor lymphocytes; (c) the presence of blocking alloantibodies or anti-idiotypic antibodies. There is clearly a need to determine from large studies whether the beneficial transfusion effect still exists, and also to determine whether, for example, numbers of rejection episodes which require expensive therapy are different in transfused and non-transfused patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Anti-Idiotypic↗
PubMed1991

Tetrahydropyridyloxadiazoles: semirigid muscarinic ligands.

Recent studies have described novel azabicycle-based muscarinic agonists which readily penetrate into the central nervous system and are capable of displaying high efficacy at cortical sites. The current paper describes the synthesis and biochemical assessment of semirigid muscarinic ligands which were used to map the requirements of the cortical muscarinic receptor and to study the degree of conformational flexibility required to cause receptor activation. Analogues 6 and 9 provide high-efficacy muscarinic agonists at cortical sites; however, C-alkylation on the tetrahydropyridine ring resulted in more rigid analogues and showed lower predicted efficacy. Molecular mechanics calculations indicated a preference for the E rotameric form. This conformation was also observed in the X-ray crystal structure of ethenyloxadiazole 12. The new compounds were tested in a biochemical assay designed to measure receptor affinity and to predict cortical efficacy.

Animals↗
PubMed1991

Influence of antiidiotypic antibody activity on renal transplant outcome.

The presence of cytotoxic HLA antibodies (Ab1) against donor lymphocytes in pretransplant sera is almost always associated with rapid rejection of the renal transplant. We have investigated the possibility that antiidiotypic antibodies (Ab2) to cytotoxic HLA antibodies might modulate the immune response and favorably influence renal allograft outcome. The role of antibodies (Ab3) which potentiate the cytotoxic effect of Ab1 was also studied. Pretransplant sera from 63 patients were tested for inhibitory or potentiating activity in the short antiidiotypic assay. Inhibitory activity was detected in 30 patients and in 28 the transplant survived more than a year. Of patients without antibody activity 11 of 17 had grafts surviving more than one year, and of those showing potentiating activity 11 of 16 were functioning at a year. The difference in transplant survival between the first group and the other two groups was statistically significant (P less than 0.05). There was no significant difference in survival rates between the latter two groups. Potentiating activity is therefore not an independent predictor of transplant failure, whereas the presence of antiidiotypic antibody activity did correlate with improved allograft survival.

Antibodies, Anti-Idiotypic↗
PubMed1991

Effect of cyclosporin A on immunoglobulin class in patients receiving blood transfusions.

IgG antibodies detected by flow cytometry in sera from potential renal transplant recipients are associated with an increased number of rejection episodes and impaired graft function. Furthermore, cytotoxic antibodies may develop if pre-transplant blood transfusions are given to such patients. We have investigated the effect of cyclosporin A on the development of IgM and IgG antibodies detected by flow cytometry after blood transfusions in 16 previously untransfused dialysis patients. Eight (group 1) received three to five third-party blood transfusions at two weekly intervals and the remaining eight (group 2) received transfusions with concomitant cyclosporin A therapy (10 mg/kg/day). Sera obtained after each transfusion were tested using flow cytometry against lymphocytes from six normal donors. In all 462 serum/cell combinations were tested. Sera from six out of eight patients in group 1 showed IgG antibody activity following blood transfusions and none developed IgM antibodies alone. In contrast IgG antibody activity was detected in one serum sample from only one of the eight patients in group 2 (P less than 0.02); a further three patients developed IgM but not IgG antibody activity during the transfusion protocol. IgG antibodies were found in 25/228 serum/cell combinations in group 1 but in 1/234 in group 2 (P less than 0.001). The patient in group 2 who developed IgG antibodies in one serum/cell combination was known to have red cell autoantibodies. This IgG activity was removed by red cell absorption, suggesting that the autoreactive red cell antibody cross-reacted with lymphocytes. Cytotoxic antibodies were detected in two serum/cell combinations in group 1 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody Formation↗
PubMed1991

Prenatal diagnosis of nuchal cystic hygroma.

Twenty-seven cases of nuchal cystic hygroma were diagnosed prenatally over a 5-year period at the Birmingham Maternity Hospital. Karyotypes were obtained in 20 cases, of which 14 (70%) were abnormal. Two-thirds of these represented various trisomy syndromes in contrast to other series where cases of Turner's syndrome have predominated. Twenty pregnancies were terminated. There was one intra-uterine death and two neonatal deaths. Hydrops was present in 15 cases, none of which survived to term. Associated structural abnormalities, mainly skeletal, renal and cardiac, were present in 18 cases. There were four long-term survivors with good quality of life, including both normal and abnormal karyotypes. In utero regression of the hygroma was documented in five cases, total in three and subtotal in two cases born with residual neck webbing.

Adolescent↗
PubMed1990

Novel quinuclidine-based ligands for the muscarinic cholinergic receptor.

Recent clinical studies on Alzheimer's patients have implied that only agents displaying high efficacy at the cortical muscarinic receptor have yielded encouraging results. This paper describes the design, synthesis, and biochemical characterization of novel quinuclidine-based muscarinic agonists which can readily penetrate into the central nervous system and which are capable of displaying high efficacy at cortical sites. With use of a biochemical assay capable of measuring receptor affinity and predicting cortical efficacy, it has been discovered that an oxadiazole ring and related heterocycles can function as bioisosteric replacements for the ester moiety found in several known muscarinic ligands. Within this series there exist compounds which span the efficacy range from high-efficacy agonist through partial agonists to antagonists with affinity comparable or superior to that of classical quaternary ammonium ligands. Consistent with recent molecular biology studies, structure-activity trends are interpreted in terms of separate binding sites for agonists and antagonists with H-bonding interactions characterizing agonist behavior and lipophilic binding characterizing antagonist behavior. Thus the aminooxadiazole moiety has structural features which are optimized for an agonist profile.

Animals↗
PubMed1990

Synthesis and muscarinic activities of 1,2,4-thiadiazoles.

A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and 1-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hydrolysis and decarboxylation. The receptor-binding affinity and efficacy of these compounds as muscarinic ligands was assessed by radioligand binding assays using [3H]-N-methylscopolamine and [3H]oxotremorine-M. Optimal agonist affinity was observed for 3'-methyl compounds. Smaller substituents (H) retained efficacy with reduced affinity while larger groups led to substantially lower efficacy. The observed binding affinity was influenced both by the conformational energy of rotation around the C3-C5' bond and the steric requirement of the mono- or bicyclic amine.

Animals↗
PubMed1990

Synthesis and biological activity of 1,2,4-oxadiazole derivatives: highly potent and efficacious agonists for cortical muscarinic receptors.

The synthesis and biochemical evaluation of novel 1,2,4-oxadiazole-based muscarinic agonists which can readily penetrate into the CNS is reported. Efficacy and binding of these compounds are markedly influenced by the structure and physicochemical properties of the cationic head group. In a series of azabicyclic ligands efficacy and affinity are influenced by the size of the surface area presented to the receptor, at the active site, and the degree of conformational flexibility. The exo-1-azanorbornane 16a represents the optimum arrangement, and this compound is one of the most efficacious and potent muscarinic agonists known. In a series of isoquinuclidine based muscarinic agonists efficacy and affinity are influenced by the geometry between the cationic head.group and hydrogen bond acceptor pharmacophore and steric bulk in the vicinity of the base. The anti configuration represented by 22a is optimal for muscarinic activity. Ligands with pKa below 6.5 show poor binding to the muscarinic receptor as exemplified by the diazabicyclic derivative 42.

Animals↗
PubMed1990

Results of management of facial palsy with microvascular free-muscle transfer.

This paper reports our experience in facial reanimation using free innervated muscle transfer in 69 patients with long-term facial palsy. The majority of patients were treated in two stages with cross-facial nerve graft as the first stage and microvascular muscle transfer at the second stage. The gracilis muscle was used in 62 patients. A system of grading results has been utilized in the long-term evaluation. The overall final result was excellent or good in 51 percent of 47 patients who were available for follow-up. Although the results are not completely satisfactory, they justify the use of this approach to a difficult clinical problem. The results are improving as technical modifications to the procedure have evolved. The gracilis muscle is a reliable free transfer with internal anatomy conductive to use for reanimation of the paralyzed face. This type of transfer, in our experience, has proved superior to nonmicrosurgical methods for treatment of complete and severe incomplete facial palsy. The seventh cranial nerve is used in the innervation of the transferred muscle, the ipsilateral being preferable if available. The authors believe that use of the same cranial nerve is superior to methods that involve other cranial nerves, where spontaneity is often not achieved.

Adult↗
PubMed1989

Glutaraldehyde-tanned microvascular grafts.

In this study the efficacy of preserving microvascular heterografts with glutaraldehyde tanning was investigated. These were compared with glutaraldehyde-tanned autografts. Previous studies have found that untreated autograft veins maintain a 95% patency rate, whilst untreated heterograft veins (Group 1) had a 15% patency rate at 4 weeks in this study. Autogenous glutaraldehyde-tanned rabbit carotid arterial grafts (Group 2) and glutaraldehyde-tanned human chorionic veins (Group 3) were interposed in rabbit femoral or carotid arteries. Fifty per cent and 75% patency rates were achieved respectively at 4 weeks. The low patency rate of the autogenous group suggests that the glutaraldehyde tanning technique itself is largely responsible for the low patency of glutaraldehyde-tanned human chorionic veins rather than any immunological response. Therefore if human chorionic veins are to be used as a readily available preserved microvascular graft, further investigation is required to develop another technique which will reduce antigenicity without promoting thrombosis.

Animals↗
PubMed1989

An assessment of different types of anastomosis with significant vessel disproportion using thin-walled interposition vein grafts.

The microvascular anastomosis of vessels with a diameter difference in the range of 3:1 can be a difficult surgical exercise, with the risk of bleeding or thrombosis. Five different techniques for dealing with such asymmetries were investigated in a series of autogenous rabbit vein grafts. An assessment was made of patency rates and of factors involved in the performance of the anastomoses. It is concluded that the end-to-end with oblique cut procedure is the most suitable for the clinical situation.

Anastomosis, Surgical↗
PubMed1989

Immunological studies of trophoblast antigens: no evidence for human leucocyte antigen (HLA) linkage.

Parental disparity for trophoblast-lymphocyte crossreactive (TLX) antigens may promote successful pregnancy. A TLX antigen system has been defined on peripheral blood lymphocytes by heteroantisera. More recently, we have reported additional activity against antigens on B lymphocytes alone termed trophoblast-B lymphocyte crossreactive (TBX) antigens. In the present study we have investigated ten TLX sera in order to determine if their target antigens are linked to the human leucocyte antigen (HLA) gene complex. The sera showed no selective activity when tested against target B lymphocytes from ten normal donors. Cytotoxic activity of TLX antisera against peripheral blood lymphocytes from six normal donors was not reduced when the class I HLA antigens of the target cells were blocked with a monoclonal antibody (PA 2.6). Similarly the cytotoxic activity of both TBX antisera against B lymphocytes from six normal donors was not decreased when class II HLA antigens were blocked by a monoclonal antibody (FMC 4). Within a family the cytotoxic activity of the TLX antisera was absorbed equally by lymphocytes from siblings who shared neither HLA haplotype. Antibody content in TLX and TBX antisera is not directed toward the classically defined HLA class I or class II antigens and is not linked to the HLA gene complex.

Animals↗