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Biomedical subjects

M Michaelides

Publications and source records attributed to M Michaelides.

18 recordsLinked to original sources
PubMed2003

Cortical blindness and hepatic encephalopathy.

PURPOSE: To present a case of permanent cortical blindness (CB) following hepatic encephalopathy. METHODS: Systematic clinical examination and further investigations to elicit the diagnosis. CONCLUSION: Complete CB is an uncommon neurological disorder and is rarely persistent. In rare cases of hepatic encephalopathy, the visual cortex may be affected and CB may occur, which resolves following treatment of the hepatic encephalopathy. We report a previously unreported complication involving permanent CB following hepatic encephalopathy in a young man.

Adult↗
PubMed2003

The genetics of inherited macular dystrophies.

The inherited macular dystrophies comprise a heterogeneous group of disorders characterised by central visual loss and atrophy of the macula and underlying retinal pigment epithelium (RPE). The different forms of macular degeneration encompass a wide range of clinical, psychophysical and histological findings. The complexity of the molecular basis of monogenic macular disease is now beginning to be elucidated with the identification of many of the disease-causing genes. Age related macular degeneration (ARMD), the leading cause of blind registration in the developed world, may also have a significant genetic component to its aetiology. Genes implicated in monogenic macular dystrophies are good candidate susceptibility genes for ARMD, although to date, with the possible exception of ABCA4, none of these genes have been shown to confer increased risk of ARMD. The aim of this paper is to review current knowledge relating to the monogenic macular dystrophies, with discussion of currently mapped genes, chromosomal loci and genotype-phenotype relationships. Inherited systemic disorders with a macular dystrophy component will not be discussed.

Chromosome Mapping↗
PubMed2002

Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2).

OBJECTIVE: To determine the molecular basis for achromatopsia using autozygosity mapping and positional candidate gene analysis. DESIGN AND METHODS: A large consanguineous Pakistani family containing six subjects with autosomal recessive complete achromatopsia was ascertained. After excluding linkage to the two known achromatopsia genes (CNGA3 and CNGB3), a genome wide linkage screen was undertaken. RESULTS: Significant linkage was detected to a 12 cM autozygous segment between markers D1S485 and D1S2881 on chromosome 1p13. Direct sequence analysis of the candidate gene GNAT2 located within this interval identified a frameshift mutation in exon 7 (c842_843insTCAG; M280fsX291) that segregated with the disease. CONCLUSIONS: The GNAT2 gene codes for cone alpha-transducin, the G protein that couples the cone pigments to cGMP-phosphodiesterase in phototransduction. Although cone alpha-transducin has a fundamental role in cone phototransduction, mutations in GNAT2 have not been described previously. Since mutations in the CNGA3 gene may cause a variety of retinal dystrophies (complete and incomplete achromatopsia and progressive cone dystrophy), GNAT2 mutations may also prove to be implicated in other forms of retinal dystrophy with cone dysfunction.

Amino Acid Sequence↗
PubMed2001

Discovery of selective hydroxamic acid inhibitors of tumor necrosis factor-alpha converting enzyme.

Modification of the P(1)' substituent of macrocyclic matrix metalloproteinase (MMP) inhibitors provided compounds that are selective for inhibition of tumor necrosis factor-alpha converting enzyme (TACE) over MMP-1 and MMP-2. Several analogues potently inhibited the release of TNF-alpha in a THP-1 cellular assay. Compounds containing a trimethoxyphenyl group in the P(1)' substituent demonstrated TACE selectivity across several series of hydroxamate-based inhibitors.

ADAM Proteins↗
PubMed2001

Eclipse retinopathy.

PURPOSE: Solar retinopathy is a well-recognised clinical entity of macular damage caused by viewing the sun, induced by a photochemical process. The term 'eclipse retinopathy' is frequently employed when the condition is sustained as a result of viewing a solar eclipse. Considerable public excitement had been raised in anticipation of the full solar eclipse on 11 August 1999. Whilst experience has shown that visual morbidity is likely to be temporary, current evidence is anecdotal and restricted to isolated case reports and series. This study was conducted to establish the true visual morbidity associated with a solar eclipse, and whether it was temporary or permanent. METHODS: A 3 month active case ascertainment study was carried out from July to September 1999 to record cases presenting to ophthalmologists with visual symptoms arising from solar viewing. Further information about the cases was sought using a short questionnaire. A follow-up questionnaire requesting outcome data at 6 months was also employed. RESULTS: There were 70 reported cases of visual loss. The average age was 29.5 +/- 12.9 years. Half the cases presented to an ophthalmologist within 2 days of the eclipse. An abnormal macular appearance was reported in 84% of patients at presentation. There have been no reported cases of continued visual loss or symptoms at 6 months. CONCLUSIONS: This is the largest nationwide study of the visual effects of a solar eclipse ever undertaken. There were no recorded cases of permanent visual loss, which corroborates the previous evidence that visual morbidity is likely to be temporary. It would appear probable that public health education was most effective in reducing visual morbidity and hence keeping the consequent burden on the NHS to a minimum.

Adolescent↗
PubMed1996

ABT-431: the diacetyl prodrug of A-86929, a potent and selective dopamine D1 receptor agonist: in vitro characterization and effects in animal models of Parkinson's disease.

(-)-Trans 9,10-hydroxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5- azacyclopent-1-ena[c]phenanthrene hydrochloride (A-86929) is a potent and selective full agonist at the dopamine (DA) D1-like receptor. Judging by its binding affinities to the D1 and D2 classes of receptors, the compound is approximately 20-fold D1 receptor-selective, whereas relative potencies based on functional in vitro assays indicate that A-86929 is greater than 400-fold D1-selective. A-86929 has moderate to weak (Ki > 1 microM) affinity at other monoaminergic and peptidergic receptors, at ion channels and at monoamine uptake sites. The catechol of A-86929 was bis-acetylated to produce the prodrug, (-)-trans 9,10-acetoxy-2-propyl-4,5,5a,6,7,11-b-hexahydro-3-thia- 5-azacyclopent-1-ena[c]phenanthrene hydrochloride (ABT-431), which is more chemically stable yet is rapidly converted to the parent compound with a half-life of less than 1 min in plasma. Both A-86929 and ABT-431 produced contralateral rotation in rats bearing unilateral 6-hydroxydopamine lesions, with ED50 values of 0.24 mumol/kg s.c. and 0.54 mumol/kg s.c., respectively. A-86929 and ABT-431 improved behavioral disability scores and increased locomotor activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of Parkinson's disease in a dose-dependent manner (the minimum effective dose was 0.10 mumol/kg s.c.). When administered three times daily for 30 consecutive days to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmosets, A-86929 significantly improved disability scores throughout the duration of the study. Current Parkinson's disease therapy includes L-dopa, which stimulates both classes of DA receptors by virtue of its conversion to DA in vivo, and direct-acting D2-selective agonists. Stimulation of the D2 receptor, which is associated with all current DA agonist-based therapies, may contribute to their dose-limiting side effects. An agent such as A-86929 (or its prodrug ABT-431), which selectively stimulates the D1 receptor, may represent a novel mechanism for Parkinson's disease therapy with the potential for an improved side-effect profile and, consequently, improved patient compliance.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

A phase I/II SECSG (Southeastern Cancer Study Group) pilot study of surgical adjuvant immunotherapy with vaccinia melanoma oncolysates (VMO).

Forty-eight patients with nonrecurrent high risk Stage I and II malignant melanoma were treated with Vaccinia Melanoma Oncolysates (VMO). Six different dose levels and two different treatment regimens were tested. Thirty-two out of 48 patients completed the 12 months of therapy. Side effects were mild to moderate. Twenty-eight out of 48 patients remain free from disease with a mean survival of 19 months, while 20/48 patients have recurred with a mean time to recurrence of 6 months.

Adjuvants, Immunologic↗
PubMed1984

Studies of murine lymphocytes and alloantigens. I. Ly-6 mitogen and MLR responses.

Antisera to the mouse lymphocyte surface alloantigens Ly-6.1 and Ly-6.2 were used to further study the functional distribution of these antigens. After selective depletion with antiserum + rabbit complement (RC), lymph node or spleen cells from Ly-6 congenic (C3H and C3H.B6-Ly-6b) and noncongenic strains of mice were tested for: (a) their proliferative responses to T- and B-cell mitogens; and (b) their proliferative responses to alloantigens, or ability to stimulate in the MLR. Lymphoid cells required in the proliferative responses to the mitogens leucoagglutinin, concanavalin A (Con A), lipopolysaccharide (LPS), and pokeweed mitogen (PWM) were Ly-6+. Lymph node responder cells in the mixed lymphocyte reaction (MLR) were also Ly-6+, whereas spleen stimulator cells were Ly-6-. Treatment of lymph node cells with anti-Ly-6 sera in the absence of RC had no specific blocking effect on the response to any of these mitogens. The studies indicate that the Ly-6 antigen is a potentially valuable marker for distinguishing between functionally distinct Ly-1+ T-cell subsets.

Animals↗
PubMed1984

Skin graft rejection and delayed-type hypersensitivity responses to H-Y in an I-Ab mutant.

Based on graft rejection in C57BL/6 and B10.A(4R), but not in B10.A mice, skin graft rejection and delayed-type hypersensitivity (DTH) responses to the male HY antigen were considered to be under the control of the "IBb" gene in the mouse H-2 complex. These two phenomena were re-examined in the B6.C-H-2bm12 mutant strain [mutation in the A beta gene in IA leading to an alteration in Iab serologically detected specificities and the inability to generate cytotoxic T (Tc) cells to H-Y]. In this study the bm12 mutant was shown to produce weak DTH responses to H-Y. By contrast, bm12 female mice were unable to reject male skin grafts unless they had received prior footpad priming of male spleen cells, when graft rejection occurred, albeit slowly. In C57BL/6 mice the response to the HY antigen therefore appears to be solely under the control of the IAb gene. In other strains, response/nonresponse is presumably dictated by the ability of IA/IE interactions to produce T-helper responses.

Animals↗
PubMed1984

Serologic response to human melanoma lines from patients with melanoma undergoing treatment with vaccinia melanoma oncolysates.

Specific active tumor immunotherapy methods offer the possibility of increasing the immunogenicity of tumor cells. One of these methods is viral oncolysis, in which tumor cells are modified by viral infection. We prepared vaccinia melanoma oncolysates (VMO) from human melanoma lines infected with vaccinia virus. In a preliminary trial at Washington University, sera from 12 patients with melanoma with stage I and II disease were obtained before and during treatment with VMO. The reactivity of these sera to melanoma lines was examined with a Staphylococcus protein A assay that detects most human IgGs. Our data demonstrate that, during treatment with VMO, sera from all 12 patients developed reactivity to melanoma lines. Selected sera were also tested in a double blind study by the C3-mixed hemadsorption assay, which detects mostly IgM. Results from this assay were in complete agreement with those obtained by the Staphylococcus protein A assay: Pretreatment sera were generally negative and sera obtained during treatment were positive. The specificity of these responses is presently under investigation. Our findings indicate that, as a consequence of treatment with VMO, a reactivity develops in the patients' sera. This reactivity is probably due to both IgG and IgM antibodies and its directed toward antigens expressed on human melanoma lines.

Adult↗
PubMed1984

Studies of murine lymphocyte alloantigens Ly-7.2.

The Ly-7.2 alloantigen has previously been defined by an alloantiserum and shown to be expressed on T and B cells; it is now studied for its distribution on responder and stimulator cells in the mixed lymphocyte reaction, on cells responding to mitogens and on mitogen-induced blast cells. In the mixed lymphocyte reaction, the responder cells were Ly-7.2+; stimulator cells were Ly-7.2-. The Ly-7.2 antigen also had an unusual distribution on cells responding to mitogens: leucoagglutinin-responsive cells were Ly-7.2-, concanavalin A Ly-7.2+, pokeweed mitogen Ly-7.2+/-, and lipopolysaccharide Ly-7.2-, i.e., Ly-7 can distinguish between subpopulations of T cells which respond to mitogens (phytohaemagglutinin and concanavalin A). Ly-7.2 was present on approximately 60% of blast cells induced by all mitogens indicating that both Ly-7.2+ and Ly-7.2- cells could be activated to become Ly-7.2+. Further characterization of concanavalin A and leucoagglutinin-stimulated Ly-7.2+ and Ly-7.2- T blast cells with anti-Ly-2.1 and anti-Ia. 17 monoclonal antibodies demonstrated the presence of several T lymphocyte subsets as both Ly-7+ and Ly-7- blast cells contained Ly-2+, Ly-2-, Ia+ and Ia- cells. Ly-7.2 therefore has a heterogenous distribution on normal and activated T and B cell subpopulations, and is a potentially important antigenic marker for studies of lymphocyte differentiation and function.

Animals↗
PubMed1982

The detection of public Ia antigens on the surface of B6-C.H-2bm12 blast cells.

The B6-C.H-2bm12 (bm12) strain has previously been described as a spontaneously occurring mutant wherein the parental (C57BL/6 Iab specificities (Ia.3, 8, 9, 15 and 20) are absent or reduced in amount. To further characterize the bm12 mutant the antigenic phenotype of LPS-activated bm12 blast cells was determined with monoclonal and conventional anti-Ia antibodies. By direct testing and absorption the public Ia.8, 9 and 15 specificities were readily detected on both parental C57BL/6 and mutant bm12 blast cells, and the amounts of these antigens on activated bm12 cells were similar to or less than those found on C57BL/6 blast cells. The findings demonstrate that the Ia-I mutation has not resulted in an absolute loss of these specificities, but has altered their expression, or their accessibility to antibody on resting cells. By contrast, the private Ia. 20 specificity and another specificity (designated Iab) could not be detected on bm12 blast cells.

Absorption↗
PubMed1981

Ir gene function in an I-A subregion mutant B6.C-H-2bm12.

The B6.C-H2bm12 (bm 12) strain has a mutation in the I-A subregion of the murine H-2 complex and is characterized by a loss of serologically detected Ia antigens and a strong graft rejection and mixed lymphocyte response between parent and mutant. It was presumed that the mutation affected the Ia-1 gene and to determine the relationship of Ia antigens and Ir genes, the immune responses of mutant and parent were compared. The immune responses to poly(L-Tyr,LGlu)-poly(DLAla)--poly(LLys), poly(Phe,Glu)-poly(DLAla)--poly(LLys), and poly(His,Glu)-poly(DLAla)--poly(LLys) in parent and mutant were same, indicating the Ia-1 and the Ir genes for these antigens are not identical. By contrast, although C57BL/6 gave a good response, the mutant strain was unable to generate cytotoxic T lymphocytes to the male-specific H-Y antigen--a response under I-A subregion Ir gene control, which now must be considered to be the Ia-1 gene. In addition, complementary Ir genes in the H-2b haplotype for the H-Y immune response could be detected when the bm12 mutant was used.

Animals↗
PubMed1981

The immunosuppressive effect of monoclonal anti-Lyt-1.1 antibodies in vivo.

Monoclonal anti-Lyt-1.1 alloantibody was produced as tissue culture supernatant and administered to mice. The antibody, given intraperitoneally, resulted in the suppression of all T cell functions studied, but was without direct effect on B cells. Thus, skin and tumour allograft survival was prolonged and there was suppression of the delayed-type hypersensitivity response; T cell help inthe anti-sheep red blood cell antibody response, responder cells in the mixed lymphocyte reaction (MLR), leucoagglutinin-responsive cells, cytotoxic T cell (Tc) function and the induction of Tc were either totally or partially suppressed, all these responses being mediated by Lyt-1+2- or Lyt-1+2+ cells in CBA/H mice. By contrast, there was no inhibitory effect on the MLR-stimulating or lipopolysaccharide-responsive cells. The administration of the anti-Lyt-1.1 antibody was accompanied by a depletion of Lyt-1.1+ T cells from both spleen and lymph node. These studies indicate that the monoclonal anti-Lyt-1.1 antibody is active in vivo with a selective effect on T cells. The results also have important implications for studies of T cell interactions in the mouse in vivo, and for similar studies in man.

Agglutinins↗
PubMed1981

Detection of Ia alloantigens on phytohemagglutinin-stimulated T blast cells.

The expression of Ia antigens on leukoagglutinin-induced blast cells was studied using a sensitive protein A-rosetting technique and quantitative absorption with conventional and monoclonal Ia antibodies. By direct testing, 40 to 60% of CBA (Iak) blast cells were shown to be Ia+ (Iak+, Ia.17+, and Ias-), expressing both glycoprotein and glycolipid Ia.17 determinants. The strong reactivity of the Thy-1.2 and Lyt-1.1 antibodies with leukoagglutinin blast cells (85%+) suggested that most of the Ia+ cells were T cells. Absorption studies confirmed the expression of Ia antigens on blast cells and excluded the possibility that the reaction of the Iak antiserum with blast cells represented antiviral reactivity. The Ia+-rosetting and Ia--nonrosetting blast cells were separated on a Percoll density gradient and typed with monoclonal anti-T cell antibodies. Both Ia+ and Ia- populations contained at least two T cell subpopulations: one Lyt-1.1+, 2.1+ and the other Lyt-1.1+, 2.1-. These studies indicate that during activation, certain T cell subpopulations express Ia antigens not found on resting T cells and emphasize the importance of such findings in determining the role of Ia antigens in immune responses.

Animals↗