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Biomedical subjects

R Gregory

Publications and source records attributed to R Gregory.

At least 19 recordsLinked to original sources
PubMed2000

Anti-Gal antibodies in humans and 1, 3alpha-galactosyltransferase knock-out mice.

BACKGROUND: Due to the absence of alphaGAL epitopes, humans and galactosyltransferase knock-out (GALT/ KO) mice express high levels of anti-Gal antibodies. We describe the properties of mouse anti-GAL antibodies. METHODS: Anti-GAL IgG antibodies were quantified by affinity purification. Antibody affinities and avidities were determined in direct binding and competition assays. Antibody-mediated rejection was investigated using hyperimmunized GALT/KO mice as recipients of GAL+ heart allografts. RESULTS: In young GALT/KO mice the levels of anti-GAL antibodies were low. Immunization of GALT/KO mice resulted in increased anti-GAL antibody expression. In mouse serum 0.6% of IgG was specific for alphaGAL compared to 0.5% in human serum. The avidity of purified mouse and human anti-GAL IgG was 30 and 6 nM, the affinity 15 and 50 microM, respectively. The isotype distribution in mouse and human anti-GAL IgG appeared to be similar to the isotype distribution in normal sera. The affinity of mouse and human anti-GAL IgM was 150 and 750 microM, respectively. Immunized GALT/KO recipients of GAL+ heart transplants rejected their grafts within 2 hr although nonimmunized GALT/KO mice retained their grafts for up to 6 days. Immunohistological examination of the rejected GAL+ hearts revealed massive deposition of IgM and IgG on endothelial cells of the graft with a concomitant deposition of complement. CONCLUSIONS: Our studies demonstrate that anti-GAL antibodies from immunized GALT/KO mice bind alphaGAL with an avidity/affinity similar to human anti-GAL antibodies and are able to induce hyperacute rejection of GAL+ heart allografts.

Animals↗
PubMed2000

Opening up extra dimensions at ultralarge scales.

The standard picture of viable higher-dimensional theories is that direct manifestations of extra dimensions occur at short distances only, whereas long-distance physics is effectively four-dimensional. We show that this is not necessarily true in models with infinite extra dimensions. As an example, we consider a five-dimensional scenario with three 3-branes in which gravity is five dimensional at both short- and very long-distance scales, with conventional four-dimensional gravity operating at intermediate length scales. A phenomenologically acceptable range of validity of four-dimensional gravity extending from microscopic to cosmological scales is obtained without strong fine-tuning of parameters.

Journal Article↗
PubMed2000

Nonsingular global string compactifications

We consider an exotic "compactification" of spacetime in which there are two infinite extra dimensions, using a global string instead of a domain wall. By having a negative cosmological constant we prove the existence of a nonsingular static solution using a dynamical systems argument. A nonsingular solution also exists in the absence of a cosmological constant with a time-dependent metric. We compare and contrast this solution with the Randall-Sundrum universe and the Cohen-Kaplan spacetime and consider the options of using such a model as a realistic resolution of the hierarchy problem.

Journal Article↗
PubMed2000

Acute isolated cerebral mucormycosis in a patient with high grade non-Hodgkins lymphoma.

A 57-year-old female in complete remission of grade IV non-Hodgkin lymphoma whilst on intensive chemotherapy, suddenly developed unilateral hemispheric stroke with a fatal outcome in 3 days. She was apyrexial and had received antifungal prophylaxis during her treatment. Post-mortem examination showed complete thrombosis of the internal carotid artery leading to infarction in the territory of the middle and anterior cerebral arteries. Microscopic examination of the brain showed involvement of intra-cranial vessel walls and brain parenchyma by mucormyces, with no evidence of systemic mucormycosis. Isolated cerebral mucormycosis is a rare occurrence, more commonly found in intravenous drug abusers, but can occur in patients with haematological malignancy.

Central Nervous System Fungal Infections↗
PubMed1999

Effects of selected histamine H3 receptor antagonists on tele-methylhistamine levels in rat cerebral cortex.

The H3 antagonist thioperamide is thought to act on brain H3 autoreceptors to increase both the release and metabolism of neuronal histamine (HA). Our studies investigated the effects of several new brain-penetrating H3 antagonists on rat cerebral cortical levels of the HA metabolite tele-methylhistamine (t-MH). Animals were pretreated with H3 antagonists (0.3 to 30 mg/kg; 1-4 hr; i.p.) in the presence or absence of the monoamine oxidase inhibitor pargyline to prevent metabolism of t-MH. Cortical t-MH levels were measured by both radioimmunoassay (RIA) and gas chromatography-mass spectrometry (GC-MS). Pargyline (60 mg/kg; 1 hr; i.p.) produced an approximately 2-fold increase in t-MH levels as measured by either GC-MS or RIA. Thioperamide (+/- pargyline) increased t-MH levels as measured by both GC-MS and RIA. In contrast, neither 5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one (GT-2016) (+/- pargyline), 4-(6-cyclohexylhex-cis-3-enyl)imidazole (GT-2227) (+/- pargyline), nor clobenpropit (minus pargyline) increased t-MH levels as measured by GC-MS. A good agreement was found between t-MH levels as determined by either RIA or GC-MS except after treatment with GT-2016, which increased apparent t-MH brain levels according to the former but not the latter method. Subsequent studies suggest the in vivo formation of a GT-2016 metabolite, which can cross-react in the t-MH RIA. Although all H3 receptor antagonists studied to date seem capable of enhancing brain HA release, only thioperamide presently was found to enhance cortical t-MH levels. Thus, H3 receptor antagonists may differentially affect HA release and turnover, and brain t-MH levels may not be reliable predictors of H3 agonist, partial agonist, or antagonist in vivo activity.

Analysis of Variance↗
PubMed1999

Design, synthesis, and structure-activity relationships of acetylene-based histamine H3 receptor antagonists.

New, potent, and selective histamine H3 receptor antagonists have been synthesized by employing the use of (1) an appropriately positioned nonpolar acetylene spacer group, (2) either a two-carbon straight chain linker or a conformationally restricting trans-cyclopropane ring between the C-4 position of an imidazole headgroup and the acetylene spacer, and (3) a Topliss operational scheme for side-chain substitution for optimizing the hydrophobic domain. Compounds 9-18 are examples synthesized with the two-carbon straight chain linker, whereas 26-31 are analogues prepared by incorporation of the trans-(+/-)-cyclopropane at the C-4 position of an imidazole headgroup. Synthesis of both the (1R,2R)- and (1S, 2S)-cyclopropyl enantiomers of the most potent racemic compound 31 (Ki = 0.33 +/- 0.13 nM) demonstrated a stereopreference in H3 receptor binding affinity for the (1R,2R) enantiomer 32 (Ki = 0.18 +/- 0.04 nM) versus the (1S,2S) enantiomer 33 (Ki = 5.3 +/- 0.5 nM). (1R,2R)-4-(2-(5,5-Dimethylhex-1-ynyl)cyclopropyl)imidazole (32) is one of the most potent histamine H3 receptor antagonists reported to date.

Acetylene↗
PubMed1999

The effect of gliclazide on plasma insulin, intact and 32/33 split proinsulin in South Asian subjects with Type 2 diabetes mellitus.

AIMS: Previous studies have shown that in Caucasian subjects with Type 2 diabetes mellitus (DM), the sulphonylurea glibenclamide increased insulin secretion without causing an increase in 32/33 split proinsulin secretion. South Asian subjects with Type 2 DM are thought to be more insulin resistant and the effect of sulphonylureas may be different. We therefore investigated the effect of sulphonylurea therapy with gliclazide on beta-cell function in South Asian subjects with newly diagnosed Type 2 DM. METHODS: Glucose, insulin, and intact and 32/33 split proinsulin were measured at diagnostic oral glucose tolerance test (OGTT). After 8-12 weeks on a conventional diet, subjects with a fasting glucose > 6 mmol/l (n = 16) were commenced on gliclazide. RESULTS: At diagnosis, those requiring gliclazide were more hyperglycaemic but there was no difference in weight or fasting insulin concentration than in the diet group. Following diet, in the gliclazide group, weight fell (P < 0.04) with no change in fasting glucose concentration. Fasting intact proinsulin, insulin and 32/33 split proinsulin remained unchanged. After gliclazide therapy weight remained unchanged, but fasting glucose fell (P < 0.003). Fasting insulin and intact proinsulin remained unchanged but 32/33 split proinsulin fell (P < 0.05). Fasting insulin to glucose ratio significantly improved after gliclazide (P < 0.006). CONCLUSIONS: In South Asian subjects treated with gliclazide the reduction in fasting glucose concentrations appears to be due to an improvement in insulin sensitivity as well as in beta-cell function.

Adult↗
PubMed1999

Surgical complications of functional neurosurgery treating movement disorders: results with anatomical localisation.

Thalamic and pallidal lesions can alleviate movement disorders, but to achieve this safely and efficaciously requires accurate target localization. We report the surgical complications encountered using an anatomical localization technique to create 121 thalamic and pallidal lesions in 79 consecutive patients over a 3 year period. There was no perioperative mortality, although there was one late death indirectly related to surgery. The risk of haemorrhage was 3.3% per lesion made. Anatomical localization offers a relatively safe way of identifying targets for functional neurosurgery, with complication rates which compare favourably with the published literature. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗
PubMed1999

A chimeric type 2 adenovirus vector with a type 17 fiber enhances gene transfer to human airway epithelia.

In studies of the genetic disease cystic fibrosis, recombinant adenovirus type 2 (Ad2) and Ad5 are being investigated as vectors to transfer cystic fibrosis transmembrane conductance regulator cDNA to airway epithelia. However, earlier work has shown that human airway epithelia are resistant to infection by Ad2 and Ad5. Therefore, we examined the efficiency of other adenovirus serotypes at infecting airway epithelia. We found that several serotypes of adenoviruses, in particular, wild-type Ad17, infected a greater number of cells than wild-type Ad2. The increased efficiency of wild-type Ad17 could be explained by increased fiber-dependent binding to the epithelia. Therefore, we constructed a chimeric virus, Ad2(17f)/betaGal-2, which is identical to Ad2/betaGal-2 with the exception of having the fiber protein of Ad17 replace Ad2 fiber. This vector retained the increased binding and efficiency of gene transfer to well-differentiated human airway epithelia. These data suggest that inclusion of Ad17 fiber into adenovirus vectors may improve the outlook for gene delivery to human airway epithelia.

Adenoviridae↗
PubMed1999

Parental allele-specific chromatin configuration in a boundary-imprinting-control element upstream of the mouse H19 gene.

The mouse H19 gene is expressed from the maternal chromosome exclusively. A 2-kb region at 2 to 4 kb upstream of H19 is paternally methylated throughout development, and these sequences are necessary for the imprinted expression of both H19 and the 5'-neighboring Igf2 gene. In particular, on the maternal chromosome this element appears to insulate the Igf2 gene from enhancers located downstream of H19. We analyzed the chromatin organization of this element by assaying its sensitivity to nucleases in nuclei. Six DNase I hypersensitive sites (HS sites) were detected on the unmethylated maternal chromosome exclusively, the two most prominent of which mapped 2.25 and 2.75 kb 5' to the H19 transcription initiation site. Five of the maternal HS sites were present in expressing and nonexpressing tissues and in embryonic stem (ES) cells. They seem, therefore, to reflect the maternal origin of the chromosome rather than the expression of H19. A sixth maternal HS site, at 3.45 kb upstream of H19, was detected in ES cells only. The nucleosomal organization of this element was analyzed in tissues and ES cells by micrococcal nuclease digestion. Specifically on the maternal chromosome, an unusual and strong banding pattern was obtained, suggestive of a nonnucleosomal organization. From our studies, it appears that the unusual chromatin organization with the presence of HS sites (maternal chromosome) and DNA methylation (paternal chromosome) in this element are mutually exclusive and reflect alternate epigenetic states. In addition, our data suggest that nonhistone proteins are associated with the maternal chromosome and that these might be involved in its boundary function.

Age Factors↗
PubMed1999

Remote village survey for agents causing hepatosplenic disease in the Republic of Yemen.

The objective of this study was to epidemiologically describe potential infectious agents among rural people in the Republic of Yemen. This would aid clinicians in designing empirical therapy and public health officials in planning disease prevention. We sought to examine evidence for the geographical distribution of pathogens causing human hepatic and splenic disease among villagers and domestic animals living in three remote areas with differing altitudes. In June 1992, a cross-sectional survey was conducted at three survey sites of differing altitudes: 3080, 1440 and 250 m above sea level. Questionnaires, parasitic and serological tests were administered to 627 human volunteers. Additionally 317 domestic animals were studied. Malaria, schistosomiasis, and hepatitis B and C infections were found to be likely causes of human hepatic or splenic disease. Additionally, evidence of human and animal infections with the agents of brucellosis and Q fever was found: IgG antibodies against hepatitis E virus were discovered in two (2.0%) of the 100 volunteers. The prevalence of markers for human and animal disease was often lowest at the village of highest elevation, suggesting that increasing altitude, as a surrogate or a true independent risk factor, was protective against infection with the agents studied.

Adolescent↗
PubMed1999

Identification and pharmacological characterization of a series of new 1H-4-substituted-imidazoyl histamine H3 receptor ligands.

A new series of 1H-4-substituted imidazole compounds were synthesized and identified as potent and selective histamine (HA) H3 receptor ligands. These ligands establish that HA H3 antagonists exhibit stereoselective and conformational preferences in their binding to the HA H3 receptor. Structure-activity relationships were determined in vitro by HA H3 receptor-binding affinities using [3H]Nalpha-methylhistamine and rat cerebral cortical tissue homogenates. Several derivatives containing olefin, amide, and acetylene functional groups were identified as potent HA H3 receptor ligands. In the olefin series, GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) was identified as a potent HA H3 receptor ligand with a Ki of 4.2 +/- 0.6 nM, while the trans isomer (GT-2228) displayed a reduced potency (Ki = 15.2 +/- 2.4 nM). GT-2227 was also found to have excellent central nervous system penetration in an ex vivo binding paradigm (ED50 = 0.7 mg/kg i.p.). In the acetylene series, GT-2260 and GT-2286 both exhibited high affinity (Ki = 2.9 +/- 0.2 and 0.95 +/- 0.3 nM) and excellent central nervous system penetration profiles (ED50 = 0.43 and 0.48 mg/kg i.p., respectively). As a prototype for the series, GT-2227 showed high affinity for the human HA H3 receptor (3.2 nM) and minimal affinity for the human HA H1 (Ki = 13,407 +/- 540 nM) and H2 (Ki = 4,469 +/- 564 nM) receptor subtypes. GT-2227 also showed good selectivity for the HA H3 receptor over a broad spectrum of other neurotransmitter receptors (IC50 >/= 1 microM). Furthermore, GT-2227 improved acquisition in a cognitive paradigm without behavioral excitation or effect on spontaneous locomotor activity. In summary, the present studies demonstrate the development of novel HA H3-selective ligands, and lend support for the use of such agents in the treatment of disorders associated with cognitive or attentional deficits.

Animals↗
PubMed1999

Development of trans-2-[1H-imidazol-4-yl] cyclopropane derivatives as new high-affinity histamine H3 receptor ligands.

Previously, a novel series of 1H-4-substituted imidazole compounds were described as potent and selective histamine (HA) H3 receptor ligands (Yates et al., 1999). The present studies extend the structure-activity relationships for optimal HA H3 receptor affinity and central nervous system penetration by incorporation of a conformationally restricted cyclopropane nucleus. Moreover, the current studies extend our understanding of ligand-receptor interactions at the HA H3 receptor with the development of high affinity HA H3 receptor antagonists containing a stereochemical presentation. Structure-activity relationships were established from in vitro HA H3 receptor-binding affinities using [3H]Nalpha-methylhistamine and rat cortical tissue homogenates. Systematic optimization of multiple structural features critical for HA H3 receptor affinity provided some of the most potent HA H3 receptor agents described. For example, GT-2331 was determined to bind to a single population of HA H3 receptors with a Ki of 0.125 nM. In vivo, GT-2331 has a favorable central nervous system penetration profile with an ED50 of 0.08 mg/kg (i.p.) in rats and a long duration of action (T1/2 > 4 h). In addition, GT-2331 was extremely selective for the HA H3 receptor versus other HA receptors and a battery of neurotransmitter, neuropeptide, hormone, or enzyme systems. Several compounds were tested in vitro which suggested HA H3 receptor heterogeneity and are discussed in terms of structure-activity relationships for the HA H3 receptor.

Animals↗