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Biomedical subjects

A Guy

Publications and source records attributed to A Guy.

At least 19 recordsLinked to original sources
PubMed2006

Is there a minimum caseload that achieves acceptable operative mortality in abdominal aortic aneurysm operations?

BACKGROUND: Studies have shown correlation between operative workload and mortality for major operations. Is there a threshold for case volume that predicts an acceptable mortality for abdominal aortic aneurysm surgery? METHODS: Hospital Episode Statistics (HES) Data for England between 1997-2002 was analysed using ICD-10 codes I71.x and OPCS-4 codes L16.x-L26.x. Mortality was identified by the method of discharge. RESULTS: 31,078 operations on abdominal aortic aneurysms were studied in 223 NHS Trusts. 6,007 in-hospital deaths were identified in both elective and emergency cases (overall mortality rates 7.7% and 40%, respectively). Trusts with large elective workloads had reduced mortality for both elective and emergency operations. Using parabolic regression and logarithmic transformation, 14 elective operations per Trust per year was identified as a cut-off point above which the decrease in mortality rate with increasing case volume was relatively small. A similar effect was not seen with increasing emergency workload alone. CONCLUSION: HES data analysis suggests increasing elective workload correlates with lower in-hospital mortality for elective and emergency operations on abdominal aortic aneurysm. Data suggests a range of hospital caseload that correlate with an acceptable elective and emergency mortality rate.

Aortic Aneurysm, Abdominal↗
PubMed2005

Serum lactate and base deficit as predictors of mortality after ruptured abdominal aortic aneurysm repair.

OBJECTIVE: Whole body hypoperfusion and lower torso ischaemia-reperfusion contribute to post-operative organ dysfunction in patients undergoing repair of ruptured abdominal aortic aneurysm (AAA). Serum lactate and base deficit are markers of tissue ischaemia and are used to assess the adequacy of resuscitation. This study examines the prognostic value of immediate post-operative levels of serum lactate and base deficit in ruptured AAA. METHODS: Thirty patients (24 men and 6 women of median age 74, range 51-85, years) who survived to at least 12h after ruptured AAA repair were studied retrospectively. The relationship between immediate post-operative lactate, base deficit and mortality was determined. RESULTS: Fifteen patients (50%) died, all from organ failure. An elevated lactate (>2.1 mmol/l) and base deficit (<-2 mmol/l) were present in 20 (67%) and 27 (90%) patients, respectively. Lactate (p<0.001) and base deficit (p=0.003) were significantly higher in non-survivors compared with survivors. Lactate (p=0.021) and base deficit levels (p=0.028) were independently significant for predicting mortality and a significant interaction existed between lactate and base deficit levels for predicting mortality (p=0.027). The sensitivity and specificity of lactate > or =4.0 mmol/l was 13 of 15 (87%) and 12 of 15 (80%), respectively, and base deficit < or =-7 mmol/l was 12 of 15 (80%) and 12 of 15 (80%), respectively. The likelihood ratios for a positive result with the defined cut-off values for lactate and base deficit were 4.3 and 4.0, respectively. Lactate > or =4.0 mmol/l and base deficit or =-7 mmol/l were associated with a 4% probability of death. CONCLUSION: These data demonstrate that an immediate post-operative serum lactate > or =4.0 mmol/l and base deficit < or =-7 mmol/l are good predictors of outcome after ruptured AAA repair. The prognostic value of these simple and inexpensive tests require corroboration in a larger prospective study.

Acid-Base Imbalance↗
PubMed2003

A Q-methodological study of hearing voices: a preliminary exploration of voice hearers' understanding of their experiences.

Using Q-methodology and structured interviews, this preliminary study set out to explore how a diverse range of voice hearers construed their experience of hearing voices. Following factor analysis of 20 completed Q-sorts, six factors emerged. Pejorative media stereotypes about voice hearers were rejected, and despite the dominance of the biomedical model in our culture, on no factor did participants adhere to all of the biomedical concepts. All six factors endorsed some elements of psychological discourse on voice-hearing experiences. It is argued that attempting to understand voice hearers within a single theoretical framework may limit or adversely affect engagement and understanding of an individual. Consistent with previous research, users of mental-health services were more likely to find voices frightening and perceive them as negative experiences than non-users. However, some non-users found managing some of their voices difficult despite having seemingly positive beliefs about the experience of hearing voices. Comment is made on the potential therapeutic implications of this study along with some acknowledgement of its limitations.

Adult↗
PubMed2000

Tandem mass spectrometric quantification of 8-iso-prostaglandin F2alpha and its metabolite 2,3-dinor-5,6-dihydro-8-iso-prostaglandin F2alpha in human urine.

Whole body synthesis of F2-isoprostanes, a family of cyclooxygenase-independent eicosanoids formed by free-radical catalysed peroxidation, should be best assessed by quantifying their urinary metabolites. Two methods for the quantitative determination of F2-isoprostane metabolites in human urine performing either thin-layer chromatography (TLC) (method A) or high-performance liquid chromatography (HPLC) (method B) prior to GC-tandem MS are described. Method A allows for simultaneous quantification of 8-iso-PGF2alpha, one prominent member of the F2-isoprostane family, and its major urinary metabolite, 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha. Mean excretion was found to be 223 and 506 pg/mg creatinine of 8-iso-PGF2alpha and 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha, respectively (n=14). A tight correlation existed between the urinary excretion of these two isoprostanes (r=0.86). Method B enables quantification of dinor-dihydro metabolites of various F2-isoprostanes including 8-iso-PGF2alpha. 2,3-Dinor-5,6-dihydro-8-iso-PGF2alpha was found to be an abundant dinor-dihydro F2-isoprostane metabolite. Validity of method A was proven by a combination of HPLC with TLC prior to GC-tandem MS analysis. A correlation was observed between the urinary concentrations of 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha measured by GC-MS and GC-tandem MS (r=0.84).

Adult↗
PubMed2000

Structure of an oligonucleotide containing a N-(2-deoxy-beta-D-erythro-pentofuranosyl)formamide residue facing a guanine.

Formamide residue is a major oxidative DNA damage product from ionizing radiation on thymine residues in DNA. We report NMR and molecular modeling studies on a DNA duplex structure which contains guanine opposite formamide residue. Formamide residue exists as either the cis and trans isomer. For the trans and the cis isomers, we find that guanine and formamide are stacked inside the helix and are hydrogen bonded. The oligonucleotide adopts globally a B form structure for the two isomers. Conformational changes are observed between the two isomers.

Formamides↗
PubMed1999

Identification and measurement of endogenous beta-oxidation metabolites of 8-epi-Prostaglandin F2alpha.

F2-isoprostanes are prostaglandin-like compounds derived from nonenzymatic free radical-catalyzed peroxidation of arachidonic acid. 8-epi-Prostaglandin (PG) F2alpha, a major component of the F2-isoprostane family, can be conveniently measured in urine to assess noninvasively lipid peroxidation in vivo. Measurement of major metabolites of endogenous 8-epi-PGF2alpha, in addition to the parent compound, may be useful to better define its formation in vivo. 2,3-Dinor-5,6-dihydro-8-epi-PGF2alpha is the only identified metabolite of 8-epi-PGF2alpha in man, but its endogenous levels are unknown. In addition to this metabolite, we have identified another major endogenous metabolite, 2,3-dinor-8-epi-PGF2alpha, in human and rat urine. The identity of these compounds, present at the pg/ml level in urine, was proven by a number of complementary approaches, based on: (a) immunoaffinity chromatography for selective extraction; (b) gas chromatography-mass spectrometry for structural analysis; (c) in vitro metabolism in isolated rat hepatocytes; and (d) chemical synthesis of the enantiomer of 2,3-dinor-5, 6-dihydro-8-epi-PGF2alpha as a reference standard. In humans, the urinary excretion rate of both dinor metabolites is comparable with that of 8-epi-PGF2alpha. Both metabolites increase in parallel with the parent compound in cigarette smokers, and they are not reduced during cyclooxygenase inhibition. Another beta-oxidation product, 2, 3,4,5-tetranor-8-epi-PGF2alpha, was identified as a major product of rat hepatocyte metabolism. In conclusion, at least two major beta-oxidation products of 8-epi-PGF2alpha are present in urine, which may be considered as additional analytical targets to evaluate 8-epi-PGF2alpha formation and degradation in vivo.

Adult↗
PubMed1999

Substituent effects in the selective reductive opening of epoxides with borohydrides in the presence of beta-cyclodextrin

The opening of ortho-substituted phenyl oxiranes by borohydrides is described both in aqueous and solid phases. Some remarkable differences in the regioselectivity and inversion of enantioselectivity of oxirane ring-opening are reported. The results obtained are compared with previous studies and have allowed some factors governing the reactivity, the regio- and stereoselectivity of this reaction to be evaluated. Preferential orientations of the substrate included inside the cyclodextrin are proposed from these results. Copyright 1999 Wiley-Liss, Inc.

Journal Article↗
PubMed1999

Assessing surgical patients' expectations and subsequent perceptions of pain in the context of exploring the effects of preparatory information: raising issues of gender and status.

The present study explored both patients' expectations and experiences of pain in the context of utilizing an established research procedure, which previously reported a significant effect of instructional information on post-surgical recovery. No research to date has systematically attempted to identify pre-operative expectations of post-operative pain, nor has it compared pre- and post-operative ratings. A further variable scrutinized during the study was patient gender.Thirty-two males and 31 females undergoing two types of elective surgery were randomly allocated into experimental and control conditions by a third party. Patients in the experimental group received additional instruction information pre-operatively from the anaesthetist and the control group received the routine pre-operative visit. Using a numerical pain scale, all participants provided ratings of expected pain levels and subsequently rated their pain following surgery.Results obtained were contrary to expectations with respect to the effects observed by the established study as instructional information had no significant effect on recovery variables. However, the study did suggest that pre- and post-operative pain ratings were broadly equivalent. A significant gender difference was also found with male patients expecting less pain than they perceived and an opposite pattern for females. Measuring both pain expectations and perceptions is considered a useful technique to inform pain management and is worthy of further investigation. The inconsistent effect of instructional information and the gendered rating patterns are considered in relation to gender and status differentials between health providers and have important implications for future research. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

Journal Article↗
PubMed1998

Repair and mutagenic potency of 8-oxoG:A and 8-oxoG:C base pairs in mammalian cells.

Replication of the oxidative lesion 8-oxo-7,8-dihydroguanine (GO) leads to the formation of both 8-oxo-7,8-dihydroguanine:adenine (GO:A) and 8-oxo-7,8-di-hydroguanine:cytosine (GO:C) pairs. The repair and mutagenic potency of these two kinds of base pairs were studied in simian COS7 and human MRC5V1 cells using the shuttle vector technology. Shuttle vectors carrying a unique GO residue opposite either a C or an A were constructed, then transfected into recipient mammalian cells. DNA repair resulting in G:C pairs and mutation frequency, were determined using resistance to digestion by the Ngo MI restriction enzyme for screening and DNA sequencing of suspect mutants. Results showed that the GO:C mismatch was well repaired since almost no mutations were detected in the plasmid progeny obtained 72 h after cell transfection. The GO:A pair was poorly repaired since only 32-34% of the plasmid progeny contained G:C whereas two thirds contained A:T at the original site. Repair kinetics measured with a non-replicating vector deleted by 13 bp at the SV40 replication origin, showed that GO:A was slowly repaired. Only 30% of the mispairs were corrected in 12 h. During this time 100% of the plasmids containing GO:A pairs were replicated as seen by the replication kinetics in a vector with an intact SV40 replication origin. These results show that, under our experimental conditions, replication is occurring before completion of DNA repair which explains the high mutagenic potency of the GO:A mispair.

Animals↗
PubMed1998

Solution structure of N-(2-deoxy-D-erythro-pentofuranosyl)urea frameshifts, one intrahelical and the other extrahelical, by nuclear magnetic resonance and molecular dynamics.

The presence of a N-(2-deoxy-D-erythro pentofuranosyl)urea (henceforth referred to as deoxyribosylurea) residue, ring fragmentation product of a thymine, in a frameshift situation in the sequence 5'd(AGGACCACG).d(CGTGGurTCCT) has been studied by 1H and 31P nuclear magnetic resonance and molecular dynamics. At equilibrium, two species are found in slow exchange. We observe that the deoxyribosylurea residue can be either intra- or extrahelical within structures which otherwise do not deviate strongly from that of a B-DNA as observed by NMR. Our study suggests that this is determined by the nature and number of hydrogen bonds which this residue can form as a function of two possible isomers. There are two possible structures for the urea side chain, either cis or trans for the urido bond which significantly changes the hydrogen bonding geometry of the residue. In the intrahelical species, the cis isomer can form two good hydrogen bonds with the bases on the opposite strand in the intrahelical species, A4 and C5, which is not the case for the trans isomer. This results in a kink in the helical axis. For the major extrahelical species, the situation is reversed. The trans isomer is able to form two good hydrogen bonds, with G13 on the same strand and A7 on the opposite strand. For the extrahelical species, the cis isomer can form only one hydrogen bond. In this major structure the NMR data show that the bases which are on either side of the deoxyribosylurea residue in the sequence, G14 and T16, are stacked over each other in a way similar to a normal B-DNA structure. This requires the formation of a loop for the backbone between these two residues. This loop can belong to one of two families, right- or left-handed. In a previous study of an abasic frameshift [Cuniasse et al. (1989) Biochemistry 28, 2018-2026], a left-handed loop was observed, whereas in this study a right-handed loop is found for the first time in solution. The deoxyribosylurea residue lies in the minor groove and can form both an intra- and an interstrand hydrogen bond.

Computer Simulation↗
PubMed1995

Sodium-independent carrier-mediated inositol transport in cultured renal epithelial (LLC-PK1) cells.

In addition to the concentrative, Na(+)-dependent inositol transport system demonstrated in many cell types, carrier-mediated, Na(+)-independent inositol transport is also shown to exist in LLC-PK1 renal epithelia. Inhibition of inositol uptake in Na(+)-free saline by 0.1 mM phloretin, and self-inhibition by net concentrations of inositol exceeding 10 mM, demonstrate the carrier-mediation of the Na(+)-independent uptake and distinguish it from flux through anion channels. The Na(+)-dependent uptake exhibits higher affinity for inositol, as seen by the stronger self-inhibition at lower inositol concentrations in Na+ saline. Kinetic analyses indicate a Km of 178 microM and a Vmax of 2447 pmol/min per microgram DNA for the Na(+)-dependent system, whereas the lower affinity, lower capacity Na(+)-independent system manifests a Km of 5.2 mM and a Vmax of 249 pmol/min per microgram DNA. the Na(+)-independent uptake further differs from the Na(+)-dependent transport by the lack of inhibitory effect of 10 microM glucose, and the greater relative inhibition of phloretin compared to that of phlorizin. Both types of uptake appear to localize predominantly to the basal-lateral cell surface. The Na(+)-independent transport is bidirectional, functioning in efflux as well as influx of inositol.

Animals↗
PubMed1993

The crystal structure of N4-methylcytosine.guanosine base-pairs in the synthetic hexanucleotide d(CGCGm4CG).

The structure of d(CGCGm4CG) were m4C = N4-methylcytosine has been determined by crystallographic methods. The crystals are multifaced prisms, with orthorhombic space group P2(1)2(1)2(1) and unit cell dimensions of a = 17.98, b = 30.77 and c = 44.75A. The asymmetric unit consists of one duplex of hexanucleotide and 49 waters. The R-factor is 0.189 for 1495 reflections with F > or = sigma(F) to a resolution limit of 1.8A. The double helix has a Z-DNA type structure which appears to be intermediate in structure to the two previously characterised structure types for Z-DNA hexamers. The two m4C.G base-pairs adopt structures that are very similar to those of the equivalent base-pairs in the structure of the native sequence d(CGCGCG) except for the presence of the methyl groups which are trans to the N3 atoms of their parent nucleotides and protrude into the solvent region. The introduction of the modified base-pairs into the d(CGCGCG) duplex appears to have a minimal effect on the overall base-pair morphology of the Z-DNA duplex.

Base Composition↗
PubMed1993

Turning intermittent regimens into daily regimens using blister-packs. An exploration in murine tuberculosis.

SETTING: Blisterpacks might be used to present low cost intermittent regimens while maintaining an easily remembered daily frequency of opening blisters, by alternating blisters containing 2 of the drugs of a 4-drug regimen with blisters containing the remaining 2 drugs. OBJECTIVE: The efficacy of the alternating regimens was examined in murine tuberculosis. DESIGN: 2 weeks after infection with Mycobacterium tuberculosis H37Rv, groups of mice were treated with rifampicin (R) 15 mg/kg, isoniazid (H) 25 mg/kg, pyrazinamide (Z) 300 mg/kg, ethambutol (E) 100 mg/kg three times weekly (RHZE3); RH/ZE, an alternating regimen of RH on days 1, 3 and 5 of the week and ZE on days 2, 4 and 6, RZ/HE or RE/HZ. RESULTS: Spleen and lung bacillary counts at 7 and 12 weeks indicated large differences in the efficacy of the regimens: RZ/HE > RE/HZ > RHZE3 > RH/ZE. Serum assays showed that Rifampicin (RMP) levels were much lower after HRZE and slightly lower after RZ, RE and RH than after R alone, whereas levels were similar when R was given before the remaining drugs; also, the absorption of Z was slightly increased by R. A second experiment used the same 4 regimens but gave R before other drugs. The organ colony forming units counts at 6 and 12 weeks were then similar. A third experiment examined continuation phase regimens of R3, R2, R2H2 and R2H6 given after daily RHZ treatment for 4 weeks. It found R2H2 only slightly superior to R2H6 and R3 much better than R2. CONCLUSION: 1. Alternating initial phase regimens were as effective as conventional intermittent regimens. 2. R3H6 might be an optimal continuation phase regimen for blisterpacks.

Animals↗
PubMed1992

Solution conformation of an oligonucleotide containing a urea deoxyribose residue in front of a thymine.

Urea residues are produced by ionizing radiation on thymine residues in DNA. We have studied an oligodeoxynucleotide containing a thymine opposite the urea residue, by one and two dimensional NMR spectroscopy. The urea deoxyribose exists as two isomers with respect to the orientation about the peptide bond. For the trans isomer we find that the thymine and urea site are positioned within the helix and are probably hydrogen bonded. The oligonucleotide adopts a globally B form structure although conformational changes are observed around the mismatch site. A minor species is observed, in which the urea deoxyribose and the opposite base adopt an extrahelical position and this corresponds to the isomer cis for the peptide bond.

Base Sequence↗
PubMed1992

Chemical synthesis of a biologically active natural tRNA with its minor bases.

The complete chemical synthesis of an E. coli tRNA(Ala) with its specific minor nucleosides, dihydrouridine, ribothymidine and pseudouridine, is reported. The method makes use of protected 2'-O-tertiobutyldimethylsilyl-ribonucleoside-3'-O-(2-cyanoethyl-N- ethyl-N- methyl)phosphoramidites. The exocyclic amino functions of the bases were protected by the phenoxyacetyl group for purines and acetyl for cytosine. The assembling has been performed on a silica support with coupling yield better than 98% within 2 min of condensation. Triethylamine tris-hydrofluoride allowed a clean and complete deprotection of the tBDMS groups. The synthetic tRNA(Ala) has been transcribed into cDNA by reverse transcriptase and sequenced. With E. coli alanyl-tRNA synthetase the alanyl acceptance activity and kcat/Km were 672 pmol/A260 and 6 x 10(4)M-1s-1, respectively.

Alanine-tRNA Ligase↗
PubMed1992

Conformation of guanine-8-oxoadenine base pairs in the crystal structure of d(CGCGAATT(O8A)GCG).

The structure of the synthetic deoxydodecamer d(CGCGAATT(O8A)GCG)2 (O8A = 8-oxoadenine) has been determined by single-crystal X-ray diffraction techniques. The oligonucleotide crystallizes in the orthorhombic space group P2(1)2(1)2(1) with cell dimensions of a = 25.48 A, b = 41.84 A, and c = 64.91 A. The refinement has converged with an R-factor of 0.151 for 1119 reflections in the resolution range 8.0-2.25 A. Sixty-seven solvent molecules were located during the course of the refinement. The B-DNA helix consists of ten Watson-Crick base pairs and two guanine-8-oxoadenine (G.O8A) base pairs. In order to achieve hydrogen-bonding complementarity between the two bases, an unusual G(anti).O8A-(syn) wobble conformation is adopted. It is proposed that the G.O8A mispairs are held together by a network of four interbase hydrogen bonds which are the result of the formation of two reverse three-center hydrogen-bonding systems. These involve one carbonyl oxygen lone pair interacting with two hydrogen atoms. In a departure from previous observations of the characteristics of purine-purine anti-syn base pairs, lambda 1 and lambda 2, the angles between the glycosidic bonds and the C1'-C1' vector, are symmetric. A reassessment of the other purine-purine mispairs suggests that similar three-center hydrogen bonds may occur and make a contribution to stabilizing other base pairings.

Adenine↗