Biomedical subjects
Publications and source records attributed to J Davies.
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The aim of this study was to assess the change in workload in a general surgery department over 2 consecutive 1-year periods and document the impact of a high dependency unit (HDU) on hospital mortality. Data were collected on all admissions, the number and type of operations performed for a 1-year period before and after a purpose-built HDU was opened. During the study period, the total number of admissions increased by 15%, with a disproportionately large increase (27%) in the number of emergency admissions. This was reflected by increases in the emergency out-of-hours operating by 12%. During the study period, the overall in-patient mortality rose from 2.16% to 3.2%. Introduction of HDU facilities alone does not lead to a reduction in hospital mortality. Alterations in emergency workload and changes in case-mix are important in determining outcome. League tables of hospital mortality are likely to be difficult to interpret without adequate information about facilities and case-mix.
This review describes the technique of distraction osteogenesis, outlining its application and current developments for the correction of craniofacial anomalies. Also described are some of the difficulties and complications which can arise with speculation on how this may be overcome. Finally, there is an exploration of how this technique might be routinely used to deal with orthognathic, orthodontic and alveolar problems.
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The addition of the alpha-ketoaldehyde methylglyoxal (0.5 or 1 mmol/L) to single isolated rat pancreatic beta-cells caused a rapid, marked depolarization resulting in electrical activity. This effect of methylglyoxal on beta-cell was reversible upon removal of the alpha-ketoaldehyde, and could be inhibited by the anion channel blockers 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). Methylglyoxal also resulted in elevated cytosolic [Ca2+] and an intracellular acidification in intact rat islets. In perifused islets, methylglyoxal provoked a modest, transient stimulation of secretion but inhibited glucose-induced insulin release. Incubation of islets with methylglyoxal resulted in the formation of large quantities of D-lactate, indicating metabolism of the alpha-ketoaldehyde via the glyoxalase pathway. The effects of methylglyoxal on beta-cell membrane potential, cytosolic [Ca2+] and intracellular pH were also observed in response to phenylglyoxal which is also effectively metabolized via the glyoxalase pathway. However, t-butylglyoxal which is poorly metabolized via the glyoxalase pathway, caused neither depolarization of the membrane potential nor intracellular acidification, but did inhibit glucose-induced insulin release. These findings suggests that the depolarization and acidification evoked by methyl- and phenylglyoxal are dependent upon their metabolism via the glyoxalase pathway. The possible mechanisms coupling alpha-ketoaldehyde metabolism via the glyoxalase pathway with membrane depolarization are discussed.
The ability of bacteria to acquire and disseminate heterologous genes has been a major factor in the development of multiple drug resistance. A gene, intI4, was identified that encodes a previously unknown integrase that is associated with a "gene-VCR" organization (VCRs are Vibrio cholerae repeated sequences), similar to that of the well-characterized antibiotic resistance integrons. The similarity was confirmed by IntI1-mediated recombination of a gene-VCR cassette into a class 1 integron. VCR cassettes are found in a number of Vibrio species including a strain of V. metschnikovii isolated in 1888, suggesting that this mechanism of heterologous gene acquisition predated the antibiotic era.
Tetrahydrocyclopent[b]indoles, tetrahydrocarbazoles, and hexahydrocyclohept[b]indoles have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was compared in a radioligand binding assay using chicken brain membranes and agonist and antagonist potency measured in clonal Xenopus laevis melanophore cells. Comparison of the N-acyl-3-amino-6-methoxytetrahydrocarbazoles (2) with N-acyl-4-(aminomethyl)-6-methoxy-9-methyltetrahydrocarbazoles (9) showed that the latter have much higher binding affinities for the chicken brain receptor. Comparison of N-acyl-1-(aminomethyl)-7-methoxy-4-methyltetrahydrocyclopent[b]ind oles (10), 6-methoxytetrahydrocarbazoles (9), and N-acyl-10-(aminomethyl)-2-methoxy-5-methylhexahydrocyclohept[b]ind oles (11) showed that the tetrahydrocarbazoles had the highest binding affinity with the cyclohept[b]indoles and the cyclopent[b]indoles having rather lower affinities. All of these observations are in agreement with our postulated model of melatonin orientation at the binding pocket in which the 3-amidoethane side chain is in a conformation close to the 5-methoxyl group, as is shown in the X-ray crystallographic structure of 9m and in the energy-minimized computed structures. Separation of the enantiomers of members from each of these three systems was accomplished by chiral HPLC. It was found that in all cases the (-)-enantiomer had a higher binding affinity than the (+)-enantiomer. An X-ray crystallographic analysis of the two enantiomers of 9a showed that the (+)-enantiomer had the (R) absolute stereochemistry. Since the sign of the Cotton curves, determined from circular dichroism studies, was the same for all (+)-enantiomers, it is assumed that the absolute stereochemistry at these centers is identical. In the Xenopus melanophore assay, the tetrahydrocarbazoles 2 (R = H) were mainly weak antagonists, while those with R = OMe were agonists. The biological behavior of the tetrahydrocarbazoles 9 (R = H) depended on R1, some being agonists and some antagonists, whereas those with R = OMe were generally agonists. Variation of the R and R1 groups in compounds of type 9 produced both agonists and antagonists. The tetrahydrocylopentaindoles 10 had similar biological properties to the corresponding analogues of 9, but the hexahydrocycloheptaindoles 11 showed a much greater propensity to be antagonists. In all cases the (S)-enantiomers were found to be more potent agonists than the (R)-enantiomers.
A bleomycin-binding protein (BLMA) produced by bleomycin-producing Streptomyces verticullus was crystallized in a form suitable for X-ray diffraction analysis using the vapor-diffusion method. Crystals were grown at pH 5.7, in 0.2 M NH4 actate and 0.1 M Na acetate, using 30% PEG 4000 as a precipitant. They belong to the orthorhombic system, with space group P21212, cell dimensions a = 54. 90, b = 67.94, c = 35.60 A, and one BLMA molecule in the asymmetric unit. The crystals diffract X-rays well and the diffraction intensity data was collected up to 1.5 A resolution with a merging R value of 0.054 at beamline 6B of the Photon Factory. The diffraction data set is 94% complete.
1. The human pur H (ATIC) gene encoding a bifunctional protein, hPurH, which carries the penultimate and final enzymatic activities of the purine nucleotide synthesis pathway, AICARFT & IMPCH, has been cloned and sequenced. The gene product, hPurH has been overexpressed in E. coli, purified to homogeneity and crystallized. 2. The human pur H gene lies on chromosome 2, between band q34 and q35. There is at least one intron of 278 bp near the 5' end. 3. Truncation mutant studies demonstrate two non-overlapping functional domains in the protein arranged as indicated in Figure 5. The existence of a linker or interaction region between the catalytic domains remains to be established. 4. Cleland-type kinetic inhibition experiments indicate that the AICARFT reaction is of the ordered, sequential type with the reduced folate cofactor binding first. 5. The reaction has a broad pH optimum in the alkaline range, with a maximum at about pH 8.2. 6. Preliminary transient phase kinetic studies show the presence of a "burst" indicating that a late step in the reaction sequence is rate limiting. 7. A PurH crystal structure is that of a dimer, with a putative single binding site for the reduced folate cofactor formed using elements from each of the monomer subunits. Probable binding sites for AICAR and FAICAR can be identified on each monomer. 8. Equilibrium sedimentation studies show hPurH apoprotein to be a monomer:dimer equilibrium mixture with a kD of 0.55 uM. 9. The crystal structure has permitted identification of a number of candidate amino acid residues likely to be involved in catalysis and/or substrate binding. Among these, we have thus far completed studies on two, Lysine 265 and Histidine 266. These appear to be critically involved in the AICARFT reaction, although whether their role(s) are in catalysis or binding remains to be determined.
The aim of this study was to compare quality of life after total gastrectomy (TG) with that after subtotal gastrectomy (STG) for gastric carcinoma. The value of the routine use of TG de principe in the treatment of gastric carcinoma, wherever the tumor may be sited in the stomach, remains controversial. The advocates of TG contend that when it can be performed safely, with relatively low operative mortality and morbidity, it yields better long-term survival than STG. Most surgeons, however, believe that the routine use of TG increases both operative mortality and morbidity and the risk of nutritional deficiency in the long term, without improving survival. TG may also be associated with poorer outcome in terms of quality of life (QOL), but the evidence for this is tenuous. Forty-seven consecutive patients who had undergone potentially curative (R0) gastric resection for carcinoma were studied: 26 had undergone TG and 21 STG. A radical D2 lymph node dissection had been performed in each, and all patients were free from recurrence at the time of the study. QOL was measured before operation and 1, 3, 6, and 12 months after operation by means of five questionnaires to measure functional outcome: the Rotterdam symptom checklist (RSCL), the Troidl index, the hospital anxiety and depression (HAD) scale, activities of daily living score, and Visick grades. Before operation there was no significant difference in QOL between the two groups of patients. At 1 year after operation, however, patients who had undergone STG had a significantly better QOL than patients who had undergone TG: Their median RSCL score was lower (10 versus 19 respectively, p < 0.05), and their Troidl index was higher (11 versus 9 respectively, p < 0.05). The QOL of patients who underwent STG was also significantly better after operation than it had been before operation, whereas the QOL of the TG group was not significantly better after operation than before operation. The QOL of patients was found to be significantly better after STG than after TG for gastric carcinoma. Because operative mortality is greater and long-term survival is no better after TG than after STG, the latter is recommended as the treatment of choice for tumors of the distal stomach.
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Thiol-disulphide exchanges are involved in many important biological processes; they are normally regulated by the glutaredoxin and thioredoxin systems. The thioredoxin system (TX) is composed of thioredoxin (TrxA) and thioredoxin reductase (TrxB) and requires NADPH as a cofactor. The thioredoxin genes trxA and trxB of Mycobacterium smegmatis mc2(6) were cloned and sequenced. The complete nucleotide sequences revealed that the TX genes of M. smegmatis were clustered, similar to the organization of trxA and trxB of S. clavuligerus, M. tuberculosis and M. leprae. Alignment with the M. tuberculosis and M. leprae protein sequences showed that the deduced amino acid sequences for M. smegmatis trxA and trxB have a very high degree of similarity. Sequence alignments and phylogenetic analysis of known TrxAs and TrxBs clearly identify the two gene products of M. smegmatis as members of the TX family grouped with other mycobacteria.
We surveyed centres collaborating in two trials in lung cancer (LU12, LU13) and one in lung and head and neck cancer (CHART) to find out how QL questionnaires were being administered, with the aim of standardising procedures and improving compliance. Dedicated local trials staff were funded for CHART but not for the other trials. In all three trials, patients completed a Rotterdam Symptom Checklist (RSCL) and a Hospital Anxiety and Depression Scale (HADS) at specified times. 17 of 22 LU12 centres, 9 of 11 LU13 and all 10 CHART centres returned survey forms. In LU12 and LU13, the category of staff responsible for questionnaires varied widely; in CHART, only research staff were involved. This led to more consistency in CHART centres in the administration and collection of questionnaires, and more frequent checking of forms. However, even the CHART administration, although better than in the other two trials, could not be regarded as standardised. All centres were equally affected by logistical problems. These embraced organisational deficits (e.g. unavailability of staff, lack of questionnaires) and patient-related factors (e.g. patient deemed to be too ill, had difficulty reading or left before completing the form). Patient refusals were an uncommon reason for non-compliance and patients were considered to be generally in favour of QL assessment. As a result of these findings, a number of measures have been put in place to increase standardisation of procedures and improve compliance. These include publishing guidelines for protocol writing, providing centres with guidelines for QL administration and information leaflets for patients, together with introducing staff training.
Here I am, rushed into your Accident and Emergency department, unconscious but not exactly dead. What are you going to do about it? As I write this, ahead of time, obviously, we are in Holby (scene of Casualty, for non-TV-watching readers) because that is the closest that most members of the general public come to knowing about such places.
TGF-beta1, expressed in the pancreatic islets, protects the nonobese diabetic (NOD) mouse from insulin-dependent diabetes mellitus (IDDM). The islet antigen-specific T cell response of ins-TGF-beta1 mice relied on different antigen-presenting cells (APC) from those used by NOD T cells. T cells from NOD mice utilized B cells to present islet antigen, whereas T cells from ins-TGF-beta1 mice utilized macrophages. In addition, the islet antigen-specific T cell repertoire of ins-TGF-beta1 mice was distinct and deviated toward an IL-4-producing Th2 phenotype. When ins-TGF-beta1 mice were treated with anti-iL-4 antibody, islet antigen-specific IFNGamma-producing Th1 cells were unleashed, and the incidence of diabetes increased to the level of NOD mice. This suggests active suppression of a diabetogenic T cell response. This study describes a novel mechanism in which expression of TGF-beta1 in the context of self-antigen shifts APC preference, deviating T cell responses to a Th2 phenotype, preventing IDDM.