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Biomedical subjects

L Griffiths

Publications and source records attributed to L Griffiths.

At least 37 records · Page 2Linked to original sources
PubMed1998

The influence of elevated levels of platelet-derived endothelial cell growth factor/thymidine phosphorylase on tumourigenicity, tumour growth, and oxygenation.

PURPOSE: Investigation of the effect of platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) on various aspects of tumour growth in a xenograft model, including growth rate, tumourigenicity and oxygenation levels. METHODS AND MATERIALS: MDA 231 breast cancer cells overexpressing PD-ECGF/TP protein were made by retroviral transduction. These cells were grown in vitro and in vivo as xenografts. Direct measurement of tumours was used to record growth parameters, while the comet assay with the bioreductive drug RSU 1069 was used to assess tumour cell oxygenation. RESULTS: We report that MDA 231 breast tumour cell lines expressing an increased range of levels of PD-ECGF/TP have increased tumourigenicity positively related to the level of PD-ECGF/TP when implanted in nude mice. As previously reported, tumours grown from these overexpressing cell lines grew faster than the parental line. These tumours expressed higher levels of TP activity and showed increased immunocytochemical staining for PD-ECGF. In addition, the rate of growth was found to be positively related to the level of PD-ECGF/TP expressed by the tumour cells. When the comet assay was used to compare the oxygenation status of cells between the parental and PD-ECGF/TP overexpressing tumours, the latter were found to have a larger proportion of well oxygenated cells. This is consistent with these tumours having an increased and functionally competent vascular supply in response to the expression of PD-ECGF/TP. CONCLUSION: PD-ECGF/TP appears to be capable of influencing tumourigenicity, angiogenesis and tumour growth in a proportional manner and can directly influence tumour oxygenation levels via its role in formation of functional vasculature.

Animals↗
PubMed1998

Patellar tendon ultrasonography in asymptomatic active athletes reveals hypoechoic regions: a study of 320 tendons. Victorian Institute of Sport Tendon Study Group.

OBJECTIVE: To compare patellar tendon sonographic findings in active, currently asymptomatic, elite athletes with those in nonathletic controls. DESIGN: Cross-sectional cohort study with convenience control sample. SETTING: The Victorian Institute of Sport Tendon Study Group, an institutional elite athlete study group in Australia. PATIENTS AND PARTICIPANTS: Two hundred elite male and female athletes from the sports of basketball, cricket, netball, and Australian rules football. Forty athletes who had current symptoms of jumper's knee were excluded from analysis, leaving 320 subject tendons in athletes who were currently asymptomatic. Twenty-seven nonathletic individuals served as controls. MAIN OUTCOME MEASURE: Sonographic patellar tendon appearance. We measured the dimensions of subject tendons and noted the presence or absence of hypoechoic regions and tendon calcification. Dimensions of hypoechoic regions were measured, and approximate cross-sectional areas were calculated. Chi-squared analysis was used to test the prevalence of hypoechoic regions in subjects and controls and men and women. RESULTS: In currently asymptomatic subjects, hypoechoic regions were more prevalent in athlete tendons (22%) than in controls (4%), in male subject tendons (30%) than in female subjects (14%), and in basketball players (32%) than in other athletes (9%) (all p < 0.01). Bilateral tendon abnormalities were equally prevalent in men and women but more prevalent in basketball players (15%) than in other athletes (3%) (p < 0.05). Sonographic hypoechoic regions were present in 35 of 250 (14%) patellar tendons in athletes who had never had anterior knee pain. CONCLUSIONS: Patellar tendon sonographic hypoechoic areas were present in asymptomatic patellar tendons of a proportion of elite athletes but rarely present in controls. This has implications for clinicians managing athletes with anterior knee pain.

Adult↗
PubMed1997

The influence of oxygen tension and pH on the expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast tumor cells grown in vitro and in vivo.

We report that hypoxia regulates and influences the level of the angiogenic enzyme platelet-derived endothelial cell growth factor (PD-ECGF), also called thymidine phosphorylase, in vitro and in vivo. Levels of PD-ECGF protein increased 6-fold in the breast cancer cell line MDA 231 after 16 h of growth in 0.3% oxygen. A simultaneous increase in enzyme activity was observed. Immunohistochemical staining of MDA 231 tumors grown in nu/nu mice showed increased expression of PD-ECGF in those parts of the tumor that are proximal to the areas of necrosis. In addition, increased and widespread staining for PD-ECGF protein was obtained when the tumor vascular supply was occluded for 2 h by clamping. Lowering the media pH to 6.3-6.7 in vitro also resulted in an increase in PD-ECGF protein levels. This study demonstrates that tumor microenvironmental factors can result in the specific up-regulation of an angiogenic enzyme that can also activate 5-fluorouracil prodrugs and hence is exploitable therapeutically.

Animals↗
PubMed1997

Characterisation of Escherichia coli K-12 mutants defective in formate-dependent nitrite reduction: essential roles for hemN and the menFDBCE operon.

Three Escherichia coli mutants defective in formate-dependent nitrite reduction (Nrf activity) were characterised. Two of the mutants, JCB354 and JCB356, synthesized all five c-type cytochromes previously characterised in anaerobic cultures of E. coli. The third mutant, JCB355, was defective for both cytochrome b and cytochrome c synthesis, but only during anaerobic growth. The insertion sites of the transposon in strains JCB354 and JCB356 mapped to the menFDBCE operon; the hemN gene was disrupted in strain JCB355. The mutation in strain JCB354 was complemented by a plasmid encoding only menD; strain JCB356 was complemented by a plasmid encoding only menBCE. A mutant defective in the methyltransferase activity involved in both ubiquinone synthesis and conversion of demethylmenaquinone to menaquinone expressed the same Nrf activity as the parental strain. The effects of men, ubiA and ubiE mutations on other cytochrome-c-dependent electron transfer pathways were also determined. The combined data establish that menaquinones are essential for cytochrome-c-dependent trimethylamine-N-oxide reductase (Tor) and Nrf activity, but that either menaquinone or ubiquinone, but not demethylmenaquinone, can transfer electrons to a third cytochrome-c-dependent electron transfer chain, the periplasmic nitrate reductase.

Anaerobiosis↗
PubMed1997

"Ruling in" and "ruling out": two approaches to the micro-rationing of health care.

Much of the implicit rationing said to characterise British health care occurs as doctors decide what resources to allocate to individual patients. This paper examines this process using data from case studies of selection of patients for cardiac surgery and admission to a specialist neurological rehabilitation centre. The analysis focuses on cardiac catheterisation conferences in which cardiologists present surgical candidates to a cardiac surgeon, and neuro-rehabilitation admissions conferences in which a multidisciplinary team assess the suitability of head injury and stroke patients referred by hospital doctors. For much of the time participants in both settings discuss patients within a clinical discourse that relies on technical assessments of coronary anatomy, ADL scores and the like. However, there are many examples where the discourse "frame" shifts to address patient characteristics of a social or moral nature. Information of this kind tends to be deployed in two ways: it can be used to signal the patient's unsuitability, usually on the basis that past behaviour implies poor prognosis ("ruling out"), or it can be used to suggest that a patient is especially deserving of help ("ruling in"). Analysis of the data suggests that "ruling out" is more salient within the cardiac catheterisation conferences, and "ruling in" within the neuro-rehabilitation admissions conferences. The authors suggest that this reflects differences in the work organisation of the two specialties, including the division of labour, the organisation of waiting lists as a queue or a pool, and the putative significance of patient agency in the genesis of disease and recovery.

Adult↗
PubMed1997

Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumour growth and response to therapy.

Angiogenesis plays an important role in the growth and metastasis of solid tumours. Platelet-derived endothelial cell growth factor (PD-ECGF) is known to be chemotactic for endothelial cells in vitro and angiogenic in vivo. It is also known as gliostatin, a factor promoting neuronal survival, and thymidine phosphorylase (dThdPase), which catalyses the reversible phosphorylation of thymidine to thymine and 2-deoxyribose-1-phosphate. This enzymatic activity is critical for angiogenic activity. PD-ECGF protein is highly expressed in tumours compared with most normal tissues and has been correlated with tumour growth, invasion and metastasis in clinical studies. In addition, dThdPase activity (by inference PD-ECGF) has been found to be a major determinant of the toxicity of 5-fluorouracil and its prodrugs, which are extensively studied clinically as anti-cancer agents. This review attempts to summarize recent gains in understanding the nature, location and action of PD-ECGF and its specific relevance to tumour biology.

Antineoplastic Agents↗
PubMed1997

Nurses ... not victims.

Assault of nurses by patients is not an unavoidable work hazard, but an important occupational health and safety issue. The Association has recently been involved in negotiations with WorkCover over such a case in an inner-city psychiatric unit.

Australia↗
PubMed1996

Escherichia coli K-12 genes essential for the synthesis of c-type cytochromes and a third nitrate reductase located in the periplasm.

The 'aeg46.5' operon was originally detected as an 'anaerobically expressed gene' located at minute 46.5 on the Escherichia coli linkage map. Subsequent results from the E. coli Genome Sequencing Project revealed that the 'aeg46.5' promoter was located in the centisome 49 (minute 47) region. Downstream from this promoter are 15 genes, seven of which are predicted to encode a periplasmic nitrate reductase and eight encode proteins homologous to proteins essential for cytochrome c assembly in other bacteria. All of these genes, together with the 'aeg46.5' promoter, have been subcloned on a 20kb EcoRI fragment from Kohara phage 19D1. Evidence is presented that, as predicted, the region includes structural genes for two c-type cytochromes of mass 16kDa and 24 kDa, which are transcribed from the previously described 'aeg46.5' promoter, and that the first seven genes encode a functional nitrate reductase. We, therefore, propose that they should be designated nap (nitrate reductase in the periplasm) genes. Plasmids encoding the entire 20kb region, or only the downstream eight genes, complemented five mutations resulting in total absence of all five known c-type cytochromes in E coli, providing biochemical evidence that these are ccm (for cytochrome c maturation) genes. The ccm region was transcribed both from the FNR-dependent, NarL- and NarP-regulated nap promoter (formerly the 'aeg46.5' promoter) and from constitutive or weakly regulated promoters apparently located within the downstream nap and ccm genes.

Amino Acid Sequence↗
PubMed1995

The pharmacokinetics and cardiovascular pharmacodynamics of HP 749 (besipirdine HCl) and metabolite P86-7480 in the conscious monkey.

HP 749 was absorbed slowly in the conscious monkey after single oral doses (10, 20, and 40 mg/kg), with gradual metabolism to the N-despropyl metabolite, P86-7480. The tmax was 2 to 4 hours after dosing, with nonlinear increases in Cmax and the AUC0-4th for HP 749. The calculated elimination half life (t1/2) after oral administration was 7.4 +/- 2.1 hours; however, absorption appeared to influence the terminal phase because the t1/2 after intravenous administration of 10 mg/kg was 1.5 hours. Plasma concentration of HP 749 2 minutes after intravenous bolus was 26.08 micrograms/mL. The HP 749 was rapidly distributed (t1/2 alpha = 0.064 +/- 0.033 hours) after intravenous administration, and displayed a VZ of 2.6 +/- 0.85 L/kg. The CL of HP 749 was 20.8 +/- 6.9 mL/min/kg, whereas renal clearance (CLR) of unchanged drug was only 0.13 +/- 0.04 mL/min/kg. Thus, only about 1% of the administered dose was excreted unchanged by the kidney. The P86-7480 also was rapidly distributed and eliminated after an intravenous bolus, but was less extensively distributed than HP 749. HP 749 administered either as an intravenous bolus or orally caused a significant pressor effect soon after dosing. A significant tachycardia resulted from intravenous administration, but not after oral administration of the drug. An intravenous bolus of P86-7480 (0.1 mg/kg) resulted in an immediate increase in MAP and decreased heart rate. The duration of these cardiovascular events was significantly shorter after intravenous administration of P86-7480 than with intravenous or oral administration of the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

An essential role for DsbA in cytochrome c synthesis and formate-dependent nitrite reduction by Escherichia coli K-12.

An Escherichia coli K-12 mutant, isolated on the basis of its inability to catalyze formate-dependent nitrite reduction, was characterized. The mutant was defective in the synthesis of all known c-type cytochromes during anaerobic growth. The mutation was localized by conjugation, transduction, and Southern blotting experiments to the dsbA gene at minute 87 on the E. coli chromosome and was complemented by the wild-type allele. Both DsbA and the recently described DipZ protein were shown to be essential for cytochrome c synthesis, suggesting that they act sequentially in a pathway for cytochrome c assembly in the E. coli periplasm.

Bacterial Proteins↗
PubMed1995

Health care contracts in Britain and the United States: a case for technology transfer?

One unexpected point of convergence between the British and North American health care systems is the increased use of negotiated contracts to govern relationships between purchasers and providers. In Britain, the internal market reforms introduced a special regime of National Health Service (NHS) contracts; in the United States there has been a move from disorganization towards integration with the emergence of larger purchasing coalitions and provider organizations. While, in the past, US patients were simply billed for services or assigned claims to the provider, it is now common for payment to be made directly from purchaser to provider and for the terms of these transactions to be set out in contracts. This paper draws on the reading of contracts, interviews with contracting parties, and ongoing research on NHS contracting in Wales to compare contracting practice within the two systems. It examines how the very different environments of the public, hierarchically-regulated NHS and the private health care market of the US influence the detailed content of contract clauses. The analysis passes over similarities, different solutions to common problems, and fundamental differences of approach, before considering the possibilities for transfers of contracting 'technology'.

Contract Services↗
PubMed1995

The British health care reforms, the American health care revolution, and purchaser/provider contracts.

The health care systems of the United States and the United Kingdom are changing rapidly. After the Thatcher government's 1989 white paper, the formerly unified British National Health Service (NHS) was split into purchaser and provider sides, with the NHS District Health Authorities becoming purchasers, and the NHS hospitals, now reconstructed as independent NHS trusts, becoming providers. The U.S. health care system, driven by market forces rather than government fiat, has been moving rapidly toward integration, with increasingly formalized purchaser and provider relationships. Contracts are found at the purchaser/provider interface in both systems. We reviewed American and British purchaser/provider contracts. The contracts address similar issues but often take disparate approaches. These dissimilarities illuminate the profound, continuing differences between the two systems. They also, however, offer possibilities to transfer contracting "technology" between the two contracting cultures.

Competitive Bidding↗
PubMed1994

A reassessment of the range of c-type cytochromes synthesized by Escherichia coli K-12.

Five different c-type cytochromes have been detected during anaerobic growth of various Escherichia coli strains in different media. None of these cytochromes was detectable in aerobically-grown cultures. Only a single, 43 kDa cytochrome was synthesized in response to the presence of trimethylamine-N-oxide: synthesis of this cytochrome was unaffected by the presence of nitrate or nitrite, was repressed by oxygen, but was dependent upon a functional tor operon located at minute 22 (coordinate 1070 kb) on the E. coli chromosome. The other four cytochromes, masses 16, 18, 24 and 50 kDa, were induced by nitrite coordinately with formate-dependent nitrite reductase activity, but repressed by oxygen and nitrate. As only the 18 kDa and 50 kDa cytochromes are encoded by the nrf operon located at minute 92 (coordinate 4366 kb), there must be other loci, possibly essential for formate-dependent nitrite reduction, encoding the 16 kDa and 24 kDa cytochromes. No other c-type cytochrome was detected under any growth condition tested.

Anaerobiosis↗
PubMed1994

A seven-gene operon essential for formate-dependent nitrite reduction to ammonia by enteric bacteria.

The DNA sequence of the regulatory region and the structural gene, nrfA, for cytochrome c552 of Escherichia coli K-12 have been reported. We have now established that nrfA is the first gene in a seven-gene operon, designated the nrf operon, at least five of which are essential for formate-dependent nitrite reduction to ammonia. This operon terminates just upstream of the previously sequenced gltP gene encoding a sodium-independent, glutamate and aspartate transporter. Expression of lac fused to nrfA, nrfE or nrfG is regulated by oxygen repression, FNR-dependent anaerobic induction, nitrite induction and nitrate repression during anaerobic growth, exactly as previously reported for the nrfA promoter. In contrast, expression of the gltP-lac fusion was FNR-independent. The open reading frame immediately downstream of nrfA encodes NrfB, a hydrophilic, penta-haem cytochrome c with an M(r) of 20,714. The structure of the N-terminal region is typical of a signal peptide for a periplasmic protein: cleavage at the putative signal peptide cleavage site, Ala-26, would result in a periplasmic cytochrome with a molecular mass of 18 kDa. The NrfC polypeptide, M(r) 24,567, contains 16 cysteine residues arranged in four clusters typical of the CooF super-family of non-haem iron-sulphur proteins. The NrfD sequence predicts a 318-residue hydrophobic protein with a distribution of acidic and basic amino acids which suggests that NrfD is an integral transmembrane protein with loops in both the periplasm and the cytoplasm. Proteins most similar to NrfD include the PsrC subunit of polysulphide reductase from Wolinella, but, as seven of the 10 most similar proteins are NADH-ubiquinone oxidoreductases, we propose that NrfD participates in the transfer of electrons from the quinone pool into the terminal components of the Nrf pathway. NrfE, M(r) 60,851, is predicted to be another hydrophobic, integral membrane protein homologous to the CdI1 protein of Rhodobacter capsulatus, which has been implicated in the assembly of periplasmic c-type cytochromes. The sequence of the 127 residue NrfF polypeptide, M(r) 14,522, is strikingly similar to the CcI2 protein of R. capsulatus, especially in the putative haem-binding motif, RCPQCQNQN.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1994

The prevalence of latent Equid herpesviruses in the tissues of 40 abattoir horses.

Equid herpesviruses 1 or 4 (EHV-1 or -4) were isolated by cocultivation from 60% of 40 horses examined at slaughter. The lymph nodes draining the respiratory tract were the most common source of virus. EHV-1 or EHV-4 was never isolated from the trigeminal ganglia (SLG). The polymerase chain reaction (PCR) detected virus in 87.5% of bronchial lymph nodes and a similar level in the trigeminal ganglia that were examined. By both assays approximately one third of the positive animals harboured both viruses. Equid herpesvirus 2 (EHV-2) was isolated from all but one of the horses and from > 75% of the lymph nodes draining the respiratory tract; alpha viruses were isolated only in the presence of EHV-2. The results indicate that latent EHV-1 and EHV-4 are widespread in the equine population and that the primary site of latency is the lymph nodes of the respiratory tract.

Abattoirs↗