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Biomedical subjects

C M Graham

Publications and source records attributed to C M Graham.

At least 19 recordsLinked to original sources
PubMed2001

Evidence from detrital zircons for the existence of continental crust and oceans on the Earth 4.4 Gyr ago.

No crustal rocks are known to have survived since the time of the intense meteor bombardment that affected Earth between its formation about 4,550 Myr ago and 4,030 Myr, the age of the oldest known components in the Acasta Gneiss of northwestern Canada. But evidence of an even older crust is provided by detrital zircons in metamorphosed sediments at Mt Narryer and Jack Hills in the Narryer Gneiss Terrane, Yilgarn Craton, Western Australia, where grains as old as approximately 4,276 Myr have been found. Here we report, based on a detailed micro-analytical study of Jack Hills zircons, the discovery of a detrital zircon with an age as old as 4,404+/-8 Myr--about 130 million years older than any previously identified on Earth. We found that the zircon is zoned with respect to rare earth elements and oxygen isotope ratios (delta18O values from 7.4 to 5.0%), indicating that it formed from an evolving magmatic source. The evolved chemistry, high delta18O value and micro-inclusions of SiO2 are consistent with growth from a granitic melt with a delta18O value from 8.5 to 9.5%. Magmatic oxygen isotope ratios in this range point toward the involvement of supracrustal material that has undergone low-temperature interaction with a liquid hydrosphere. This zircon thus represents the earliest evidence for continental crust and oceans on the Earth.

Journal Article↗
PubMed2000

Effects of glaucoma medications on the cardiorespiratory and intraocular pressure status of newly diagnosed glaucoma patients.

AIMS: To evaluate the short term cardiovascular, respiratory, and intraocular pressure (IOP) effects of four glaucoma medications in newly diagnosed glaucoma patients. METHODS: 141 newly diagnosed glaucoma patients were recruited and underwent a full ocular, cardiovascular, and respiratory examination, including an electrocardiogram (ECG) and spirometry. They were prescribed one of four topical glaucoma medications and reviewed 3 months later. One eye of each patient was randomly chosen for analysis, performed using analysis of variance and the chi(2) test. RESULTS: Latanoprost had the greatest mean IOP lowering effect in both the primary open angle glaucoma (POAG) (p = 0.005) and the "presumed" normal tension glaucoma (NTG) groups (p = 0.33), reducing the IOP by 8.9 mm Hg and 4.1 mm Hg respectively. Timolol was associated with lowered pulse rates and reductions in the spirometry measurements. 41% of patients using brimonidine complained of systemic side effects and over 55% of patients using betaxolol complained of ocular irritation. 28% of patients required an alteration in their glaucoma management. CONCLUSIONS: Latanoprost appears to be a useful primary treatment for glaucoma patients, in view of superior IOP control and a low incidence of local and systemic side effects. Timolol causes a reduction in measurements of respiratory function, a concern in view of the potential subclinical reversible airways disease in the elderly glaucoma population. Brimonidine is associated with substantial, unpredictable systemic side effects and betaxolol causes ocular irritation and weak IOP control. Spirometry is advised in all patients receiving topical beta blocker therapy to control their glaucoma.

Adrenergic alpha-Agonists↗
PubMed1998

Novel diversity in Th1, Th2 type differentiation of hemagglutinin-specific T cell clones elicited by natural influenza virus infection in three major haplotypes (H-2b,d,k).

We report novel diversity in the lymphokine (LK) secretion profile of hemagglutinin-specific, CD4+ T cell clones elicited by influenza virus infection in three major haplotypes: I-Ad- or I-Ed-restricted T cell clones obtained from individual BALB/c donors, and specific for three distinct antigenic peptides (p56-76, or p186-205 or p177-199), were uniformly Th1 type, releasing only IFN-gamma on activation. In contrast, extensive diversity was evident for the C57BL/10 or CBA/Ca repertoire. Sibling T cell clones, established from the same C57BL/10 donor and expressing identical TCR beta-chains in their recognition of p186-205, released either (IFN-gamma and IL-5) or (IFN-gamma and IL-4 and IL-5) or (IL-4 and IL-5 and IL-10) following Ag-specific or nonspecific stimulation. Similarly, I-Ak-restricted T cell clones, specific for p120-139 secreted either (IFN-gamma only) or (IFN-gamma and IL-5) or (IFN-gamma and IL-2 and IL-5) on activation. Despite such phenotypic diversity within the individual's repertoire, all clones had been maintained under identical in vitro culture conditions. Moreover, sequence analyses of TCR beta gene usage indicated that in most instances clones from the same donor expressed identical (VDJ)beta rearrangements, indicative of a common progenitor cell. FACS analysis of cytoplasmic cytokine production confirmed that for the novel phenotype (IFN-gamma and IL-5), both LKs were synthesized at the single cell level. Sibling families of T cell clones, established from a common donor following viral infection but differing in LK secretion, may offer a suitable model system for further studies of signal transduction mechanisms that discriminate between Th1- and Th2-specific responses to a well defined protective Ag.

Animals↗
PubMed1997

Low-temperature carbonate concretions in the Martian meteorite ALH84001: evidence from stable isotopes and mineralogy.

The martian meteorite ALH84001 contains small, disk-shaped concretions of carbonate with concentric chemical and mineralogical zonation. Oxygen isotope compositions of these concretions, measured by ion microprobe, range from delta18O = +9.5 to +20.5 per thousand. Most of the core of one concretion is homogeneous (16.7 +/- 1.2 per thousand) and over 5 per thousand higher in delta18O than a second concretion. Orthopyroxene that hosts the secondary carbonates is isotopically homogeneous (delta18O = 4.6 +/- 1.2 per thousand). Secondary SiO2 has delta18O = 20.4 per thousand. Carbon isotope ratios measured from the core of one concretion average delta13C = 46 +/- 8 per thousand, consistent with formation on Mars. The isotopic variations and mineral compositions offer no evidence for high temperature (>650 degrees C) carbonate precipitation and suggest non-equilibrium processes at low temperatures (< approximately 300 degrees C).

Carbon Isotopes↗
PubMed1996

Viral peptide specific induction of MHC class II expression by murine T cell clones.

We report that I-Ab-restricted T cell clones, elicited by influenza infection of C57BL/10 mice and specific for the hemagglutinin peptide HA1 186-205, express class II. They respond to peptide stimulation by IL release (IL-3 or IFN-gamma) without a requirement for APC but do not proliferate. Moreover, surface expression of class II requires de novo synthesis in the presence of the stimulatory peptide and is inhibited by coculture with TCR-specific Ab, or brefeldin A or cycloheximide. Clonotypic specificity of peptide induction was confirmed by failure of other allele specific peptides to enhance class II expression. Addition of the viral peptide to T cells induced homotypic adhesion, which provides a physical basis for stabilization of class II-peptide complexes at the cell surface. Extinction of class II expression was evident in the corresponding T cell hybridomas, which might account for the failure to report class II expression by murine T cells. Control studies indicated that class II was not passively acquired from APC by demonstrating 1) failure of processed Ag to induce class II expression, 2) allo-class II (Ak) was not acquired by coculture with peptide and semisyngeneic (H-2 b/k) APC, 3) absence of class II expression by a NP peptide-specific Th2 clone under identical culture conditions, and most significantly, 4) reverse-transcriptase PCR amplification and surface expression of class II using highly purified preparations of FACS-selected CD4+ class II- cells cocultured with the stimulatory peptide.

Alleles↗
PubMed1996

Effects of active recovery on power output during repeated maximal sprint cycling.

The effects of active recovery on metabolic and cardiorespiratory responses and power output were examined during repeated sprints. Male subjects (n = 13) performed two maximal 30-s cycle ergometer sprints, 4 min apart, on two separate occasions with either an active [cycling at 40 (1)% of maximal oxygen uptake; mean (SEM)] or passive recovery. Active recovery resulted in a significantly higher mean power output (W) during sprint 2, compared with passive recovery [W] 603 (17) W and 589 (15) W, P < 0.05]. This improvement was totally attributed to a 3.1 (1.0)% higher power generation during the initial 10 s of sprint 2 following the active recovery (P < 0.05), since power output during the last 20 s sprint 2 was the same after both recoveries. Despite the higher power output during sprint 2 after active recovery, no differences were observed between conditions in venous blood lactate and pH, but peak plasma ammonia was significantly higher in the active recovery condition [205 (23) vs 170 (20) mumol .l-1; P < 0.05]. No differences were found between active and passive recovery in terms of changes in plasma volume or arterial blood pressure throughout the test. However, heart rate between the two 30-s sprints and oxygen uptake during the second sprint were higher for the active compared with passive recovery [148 (3) vs 130 (4) beats.min-1; P < 0.01) and 3.3 (0.1) vs 2.8 (0.1) l.min-1; P < 0.01]. These data suggest that recovery of power output during repeated sprint exercise is enhanced when low-intensity exercise is performed between sprints. The beneficial effects of an active recovery are possibly mediated by an increased blood flow to the previously exercised muscle.

Adult↗
PubMed1995

Immunodominance with progenitor B cell diversity in the neutralizing antibody repertoire to influenza infection.

We report striking immunodominance in the neutralizing antibody responses of major histocompatibility complex congenic mice to natural infection with influenza virus (H3N2 subtype), as deduced by sequencing the hemagglutinin (HA) genes of monoclonal antibody (mAb)-selected mutant viruses. A majority of mAb, established from individual BALB/c (H-2d) mice, select mutant viruses containing the same single amino acid substitution in the membrane distal ecto-domain, HA1 198 A-->E, whereas changes at either HA1 158 G-->E or HA1 198 A-->E are selected for by mAb from BALB.K (H-2k) donors. The structural basis for immunodominance, and potential diversity of progenitor B cells, was investigated by sequence analysis of H and L chain gene rearrangements in mAb specific for HA1 158 or HA1 198. No correlation was found between antibody specificity and VH or VL gene usage, and a minimum of three to six progenitor cells contributed to the individual's repertoire for a single antigenic site. However, in a further analysis of the HA1 158-specific antibody response of CBA/Ca (H-2k) donors, there was highly restricted light chain gene usage. Focusing of the immune repertoire to limited regions of the HA molecule during a primary viral infection may be a significant factor in immune pressure for antigenic variation, particularly since there is no evident restriction in the antibody response to immunization.

Animals↗
PubMed1995

Immune receptor repertoire for influenza haemagglutinin.

An extensive analysis was made of receptor specificity and gene usage in the neutralising antibody (mAb) and Class II-restricted T cell responses to influenza haemagglutinin (HA) following natural infection of MHC (H-2(k) or H-2(d)) congenic mice with X31 virus (H3N2 subtype). Despite the diversity of available antigenic sites on the HA1 subunit, there was striking immunodominance in the mAb response as deduced by sequencing the HA genes of escape mutants and the corresponding antibody H and L chain gene rearrangements. Similarly, Class II restricted T cell responses of individual donors focused on a single antigenic site, or immunodominant peptide; and PCR sequence analysis of T cell receptor (alpha beta) gene usage indicated that T cell memory was derived from a single progenitor cell. Focusing of the immune repertoire to limited regions of the HA molecule during a primary viral infection may be a significant factor in immune pressure for antigenic variation.

Amino Acid Sequence↗
PubMed1995

Comparison of continuous spinal and epidural analgesia for pain relief in labour.

We have compared continuous spinal analgesia with continuous epidural analgesia for pain relief in labour. Twenty-six women were randomly allocated to receive either epidural 0.25% bupivacaine 5-10 ml via a 20 gauge catheter inserted through a 16 gauge Tuohy needle or intrathecal 0.25% bupivacaine 0.5-1.0 ml via a 32 gauge catheter inserted through a 24 gauge Sprotte needle. This was supplemented with fentanyl 5-10 mcg (spinal) or 1 mcg per kg (epidural) if analgesia was unsatisfactory. Outcome was measured by the success and timing of the procedure, time to analgesia, amount of drug given, visual analogue scoring of pain relief by the patient and an observer and degree of motor block. Onset time and dosage were significantly reduced in the continuous spinal group. Two catheters failed to feed in the spinal group. One catheter became displaced in each group. Pain relief was satisfactory in all patients and none had post-dural puncture headache. Continuous spinal analgesia may offer significant advantages over epidural analgesia but technical difficulties remain with the present equipment. The reasons for the withdrawal of the spinal catheters in the United States of America are discussed.

Journal Article↗
PubMed1995

The practical use of axillary brachial plexus block for hand surgery.

A retrospective study of 178 patients undergoing axillary brachial plexus block (ABPB) for hand surgery used information gathered by a computer-aided anaesthetic record keeping system. The practical use of local techniques to augment the block meant that only two of the 178 patients required a general anaesthetic, giving a success rate of 98.8%. There were no significant complications.

Adult↗
PubMed1995

The use of Bier's block for day case surgery.

With the increasing popularity of day case surgery it is important to ensure that safe and appropriate techniques are being used. We retrospectively reviewed a large series of 732 patients who underwent planned day case hand surgery under intravenous regional anaesthesia (modified Bier's block) over a 5-year period. We found a modified Bier's block to be ideally suited to day case surgery with no deaths, minimal morbidity and a success rate in excess of 98%.

Adult↗
PubMed1994

Productive re-arrangement at both alleles of the T-cell receptor beta-chain locus in CD4 T-cell clones specific for influenza haemagglutinin.

T-cell receptor (TcR) beta-chain usage, and VDJ junctional region sequences thereof in a panel of CD4+ T-cell clones Ad-, or Ak- or Ek-restricted for major antigenic sites of influenza haemagglutinin (H3 subtype), were investigated. Direct sequencing of cDNA, obtained by polymerase chain reaction, revealed that the majority of T-cell clones contained both productive and non-productive rearranged transcripts. Moreover, T-cell clones specific for p206-227 (Ad) or p245-265 (AK) contained double-productive re-arranged transcripts (V beta 6 J beta 2.6, V beta 4, J beta 1.2) and (V beta 6 J beta 1.3, V beta 8.2, J beta 1.5) respectively. However, FACS analysis with V beta-specific monoclonal antibodies established that, for each of these T-cell clones, only a single beta-chain was expressed at the cell surface, thereby indicating post-transcriptional editing.

Alleles↗
PubMed1994

Immunodominance correlates with T-cell receptor (alpha beta) gene usage in the class II-restricted response to influenza haemagglutinin.

Class II-restricted T-cell clones elicited by natural infection with influenza A virus (H3N2 subtype) exhibit extensive diversity in their recognition specificity for the envelope glycoprotein, haemagglutinin, and focus on hypervariable regions of the HA1 subunit that feature in antigenic drift. However, T-cell clones established from the same individual focus on a single antigenic site with differing fine specificity for mutant viruses. We wished to determine whether such diversity of the haplotype and contrasting immunodominance of the individual's repertoire was mirrored in T-cell receptor (TcR) gene usage. A structural analysis was undertaken of the alpha and beta chains of TcR from a panel of CD4+ T-cell memory clones established in vitro after natural infection with X31 virus and specific for eight distinct antigenic sites of the HA1 subunit: p48-67 (Ak), p58-73 (Ad), p120-139 (Ak), p177-199 (Ad), p186-200 (Ad), p226-245 (Ek), p246-265 (Ek) and p269-288 (Ak). Direct sequencing of the alpha and beta chains, using the polymerase chain reaction, revealed that T-cell clones derived from the same donor used identical V beta D beta J beta and V alpha J alpha elements. Moreover there was extensive diversity in usage of V beta (V beta 1 or V beta 4 or V beta 8) genes between individual mice, in association with diverse J beta and V alpha J alpha elements for the recognition of a common antigenic peptide. We conclude that the CD4+ T-cell memory repertoire of the individual, following primary exposure to infectious virus, is oligoclonal and recruited from a limited number of precursor cells.

Amino Acid Sequence↗
PubMed1993

Normal trachea during forced expiration: dynamic CT measurements.

The purpose of this study was to define the range of normal intrathoracic tracheal diameters and cross-sectional areas during forced respiration. A report of tracheomalacia is also presented. Ten volunteers were studied in the supine position with dynamic computed tomography (CT), at a level at or between the brachiocephalic vein and the aortic arch, with 3-mm collimation and with image reconstruction by means of a high-spatial-frequency algorithm. Ten 100-msec dynamic scans were obtained at 500-msec intervals during a 6-second period as the patient performed forced inspiration and expiration vital capacity maneuvers. The mean cross-sectional area of the trachea decreased dynamically from 280 mm2 at end inspiration (standard deviation, 50.5; range, 221-388 mm2) to 178 mm2 at end expiration (standard deviation, 40.2; range, 115-236 mm2; P < .001) (mean decrease, 35% between inspiration and expiration; standard deviation, 18%; range, 11%-61%). The percentage decrease in cross-sectional area of the trachea correlates well with the decrease in the anteroposterior and coronal diameters of the trachea from maximum inspiration to maximum expiration (r = .879 and .916 and P = .0018 and .0002, respectively).

Adult↗
PubMed1992

Do antigenic drift residues in influenza hemagglutinins of the H3 subtype qualify as contact sites for MHC class II interaction?

We have previously reported that a majority of hemagglutinin-specific and class II (Ak or Ad)-restricted T cell clones, elicited by natural infection with X31 virus (H3N2 subtype), focus on regions of the HA1 subunit that have featured in antigenic drift and exhibit extensive diversity in their ability to discriminate between variant viruses with amino acid substitutions in these sites. The structural basis for the loss of recognition of a major antigenic site, HA1 120-139, was investigated by (i) comparing the effects of amino acid substitutions in mutant hemagglutinins (HA1 129 Gly----Glu; 132 Gln----Glu; 135 Gly----Arg) with the corresponding substitutions in synthetic peptides or (ii) by assessing the effects of single amino acid substitutions (to Ala) in the alpha k chain (residues 50-79) on the ability of Ak transfectants to present peptides. Despite the failure to recognise mutant viruses, mutant peptides were recognised as efficiently as wild-type peptides in association with wild-type Ak. However, the mutant Ak transfectants identified a different set of alpha k residues (positions 56, 65, and 72) as being critical for presentation of mutant peptides. Taken together with our previous findings that defects in antigen presentation of mutant hemagglutinin are reversed by single substitutions in the alpha k chain (residues 56 and 62), it would seem that the antigenic drift residues in mutant hemagglutinins alter the profile of contact sites with class II.

Amino Acid Sequence↗
PubMed1990

The role of the endoplasmic reticulum in antigen processing. N-glycosylation of influenza hemagglutinin abrogates CD4+ cytotoxic T cell recognition of endogenously processed antigen.

Evidence is presented for an endogenous route of Ag processing for CD4+ T cell recognition of influenza hemagglutinin that requires obligatory traffic of de novo synthesized hemagglutinin across the lumen of the endoplasmic reticulum for processing in a cytosolic compartment. I-Ad-restricted T cell clones that recognize synthetic peptides corresponding to two distinct antigenic regions of the HA1 subunit, HA1 56-76 and HA1 177-199, are cytotoxic and, dependent on epitope specificity can recognize endogenously processed Ag and lyse class II+ target cells infected with a recombinant vaccinia-X31 HA virus. HA1 56-76 specific T cell clones fail to recognize (target cells infected with) influenza X31 viruses, containing a single residue change, HA1 63 Asp----Asn that introduces an oligosaccharide attachment site: Asp63Cys64Thr65. Recognition is restored, however, by tunicamycin treatment of mutant virus infected target cells. Inasmuch as N-glycosylation of nascent hemagglutinin polypeptides occurs in the lumen of the endoplasmic reticulum, this indicates a route of endogenous processing for hemagglutinin, requiring transport across the endoplasmic reticulum, which has been confirmed by the failure of CD4+ T cells to recognize a recombinant VACC-hemagglutinin virus in which the same single residue change, HA1 63 Asp----Asn has been introduced by site directed mutagenesis.

Amino Acid Sequence↗
PubMed1990

Single amino acid residues in a synthetic peptide of influenza haemagglutinin, HA 1 177-199, distinguish I-Ad- and I-Ed-restricted T-cell epitopes.

A majority of Iad-restricted, CD4+ T-cell clones, derived from BALB/c mice infected with X31 (H3N2) influenza virus and specific for the HA 1 subunit of the viral haemagglutinin (HA), has previously been shown to recognize the synthetic peptide HA 1 177-199, corresponding to the primary amino acid sequence of a major antibody binding site. Here it is demonstrated that both I-Ad- and I-Ed-restricted T-cell clones recognize HA 1 177-199, and that inter- and intra-allelic differences in Iad-restricted recognition are defined by single amino acid residues. A panel of truncated HA 1 synthetic peptides defined three distinct but overlapping CD4+ epitopes within the common antigenic site (HA 1 177-199): two I-Ad-restricted epitopes mapped within HA 1 186-198 and HA 1 177-199, and peptide HA 1 178-195 identified an I-Ed-restricted epitope. Moreover, fine specificity differences in the recognition of synthetic peptides, truncated at the carboxy terminus of HA 1 177-199, identified residues HA 1 A 198 and HA 1 S 199 as being critical for defining inter- and intra-allelic differences, respectively, in the Iad-restricted T-cell recognition of HA.

Amino Acids↗