PubMed Health⌕ Search

Biomedical subjects

J R Griffiths

Publications and source records attributed to J R Griffiths.

At least 37 records · Page 2Linked to original sources
PubMed2002

The contribution of proton magnetic resonance spectroscopy (1HMRS) to clinical brain tumour diagnosis.

Proton magnetic resonance spectroscopy (1HMRS) provides biochemical information from tissue non-invasively, and has an evolving role in brain tumour diagnosis and management. We present 100 consecutive patients with brain tumours who had single voxel 1HMRS as part of their preoperative investigations. We report the histopathological findings and the diagnostic contribution of spectroscopy in an adjunctive role. On the basis of clinical and radiological information the preoperative diagnosis was unclear or inaccurate in 26 out of 100 cases. The discrepancy was of lesion grade in 17 cases and lesion type in 9 cases. In 6 of 100 patients with brain tumours 1HMRS could have made a significant contribution to the preoperative diagnosis if used as part of the routine assessment. There is therefore a useful role for 1HMRS in the evaluation of intracranial mass lesions.

Adolescent↗
PubMed2001

Effects of prior exercise on oxygen uptake and phosphocreatine kinetics during high-intensity knee-extension exercise in humans.

1. A prior bout of high-intensity square-wave exercise can increase the temporal adaptation of pulmonary oxygen uptake (.V(O2)) to a subsequent bout of high-intensity exercise. The mechanisms controlling this adaptation, however, are poorly understood. 2. We therefore determined the dynamics of intramuscular [phosphocreatine] ([PCr]) simultaneously with those of .V(O2) in seven males who performed two consecutive bouts of high-intensity square-wave, knee-extensor exercise in the prone position for 6 min with a 6 min rest interval. A magnetic resonance spectroscopy (MRS) transmit-receive surface coil under the quadriceps muscle allowed estimation of [PCr]; .V(O2) was measured breath-by-breath using a custom-designed turbine and a mass spectrometer system. 3. The .V(O2) kinetics of the second exercise bout were altered compared with the first such that (a) not only was the instantaneous rate of .V(O2) change (at a given level of .V(O2)) greater but the phase II tau was also reduced - averaging 46.6 +/- 6.0 s (bout 1) and 40.7 +/- 8.4 s (bout 2) (mean +/- S.D.) and (b) the magnitude of the later slow component was reduced. 4. This was associated with a reduction of, on average, 16.1% in the total exercise-induced [PCr] decrement over the 6 min of the exercise, of which 4.0% was due to a reduction in the slow component of [PCr]. There was no discernable alteration in the initial rate of [PCr] change. The prior exercise, therefore, changed the multi-compartment behaviour towards that of functionally first-order dynamics. 5. These observations demonstrate that the .V(O2) responses relative to the work rate input for high-intensity exercise are non-linear, as are, it appears, the putative phosphate-linked controllers for which [PCr] serves as a surrogate.

Adult↗
PubMed2001

Why are cancers acidic? A carrier-mediated diffusion model for H+ transport in the interstitial fluid.

31P MRS studies have shown that the intracellular compartment ot tumours is kept near neutrality, whereas the interstitial fluid is acidic (pH 6.5-6.8). Why is this compartment acidic? Balance studies confirm that tumours produce excessive lactic acid, although less than usually supposed, but this cannot be the whole story, since Tannock and co-workers have shown interstitial acidity in glycolysis-deficient tumours. Another major acid load is caused by hydration of CO2 molecules to carbonic acid, catalysed by carbonic anhydrase. The distance that H+ must diffuse from cancer cells to capillaries is further than in normal tissue and this will increase acidification near the cells. We show that previous quantitative models based on simple H+ diffusion are unsatisfactory. This is because most H+ ions cross the interstitial space bound to buffers such as inorganic phosphate. Although these protonated buffers (i.e. conjugate acids) diffuse much more slowly than H+ ions they carry most of the protons, so the pH predicted by this model is closer to neutrality for a given proton production rate than that predicted by the dissolved H+ model. We have developed a mathematical model of this carrier-mediated system that predicts pHe values as low as those observed in some tumours.

Diffusion↗
PubMed2001

BOLD MRI of human tumor oxygenation during carbogen breathing.

An MRI method is described for demonstrating improved oxygenation of human tumors and normal tissues during carbogen inhalation (95% O2, 5% CO2). T2*-weighted gradient-echo imaging was performed before, during, and after carbogen breathing in 47 tumor patients and 13 male volunteers. Analysis of artifacts and signal intensity was performed. Thirty-six successful tumor examinations were obtained. Twenty showed significant whole-tumor signal increases (mean 21.0%, range 6.5-82.4%), and one decreased (-26.5 +/- 8.0%). Patterns of signal change were heterogeneous in responding tumors. Five of 13 normal prostate glands (four volunteers and nine patients with nonprostatic tumors) showed significant enhancement (mean 11.4%, range 8.4-14.0%). An increase in brain signal was seen in 11 of 13 assessable patients (mean 8.0 +/- 3.7%, range 5.0-11.7%). T2*-weighted tumor MRI during carbogen breathing is possible in humans. High failure rates occurred due to respiratory distress. Significant enhancement was seen in 56%, suggesting improved tissue oxygenation and blood flow, which could identify these patients as more likely to benefit from carbogen radiosensitization.

Aged↗
PubMed2001

In vivo hyperpolarized 129Xe NMR spectroscopy in tumors.

The first in vivo hyperpolarized 129Xe NMR study in experimental tumors is presented. Hyperpolarized 129Xe was dissolved in solutions, and was injected intratumorally in GH-3 prolactinomas in rats and RIF-1 fibrosarcomas in mice. The 129Xe NMR spectra and apparent spin-lattice relaxation times in the two tumor types present characteristic differences. These differences are discussed in terms of xenon exchange between the carrier medium and the tissue compartments.

Animals↗
PubMed2001

Effects of different levels of hypercapnic hyperoxia on tumour R(2)* and arterial blood gases.

The hypercapnia induced by carbogen (95% O(2)/5% CO(2)) breathing, which is being re-evaluated as a clinical radiosensitiser, causes patient discomfort and hence poor compliance. Recent preclinical and clinical studies have indicated that the CO(2) content might be lowered without compromising increased tumour oxygenation and radiosensitisation. This preclinical study was designed to see if lower levels of hypercapnia could evoke similar decreases in the transverse relaxation rate R(2)* of rodent tumours to those seen with carbogen breathing. The response of rat GH3 prolactinomas to 1%, 212% and 5% CO(2) in oxygen, and 100% O(2) breathing, was monitored by non-invasive multi-gradient echo MRI to quantify R(2)*. As the oxygenation of haemoglobin is proportional to the blood p(a)O(2) and therefore in equilibrium with tissue pO(2), R(2)* is a sensitive indicator of tissue oxygenation. Hyperoxia alone decreased R(2)* by 13%, whilst all three hypercapnic hyperoxic gases decreased R(2)* by 29%. Breathing 1% CO(2) in oxygen evoked the same decrease in R(2)* as carbogen. The DeltaR(2)* response is primarily consistent with an increase in blood oxygenation, though localised increases in tumour blood flow were also identified in response to hypercapnia. The data support the concept that levels of hypercapnia can be reduced without loss of enhanced oxygenation and hence potential radiotherapeutic benefit.

Animals↗
PubMed2001

Genetic prodrug activation therapy (GPAT) in two rat prostate models generates an immune bystander effect and can be monitored by magnetic resonance techniques.

Treatment of hormone refractory prostate cancer requires new treatment strategies. Genetic prodrug activation therapy (GPAT) may provide a new therapeutic avenue. In this study the antitumour efficacy of the gene encoding herpes simplex virus thymidine kinase (HSVtk) activating the prodrug ganciclovir (GCV) was compared in two models of ectopic (subcutaneous) rat prostate cancer. Both models, which differ in their characteristics, were previously shown to be weakly immunogenic but susceptible to immunotherapy. Tumour cell lines were stably transfected with HSVtk and were rendered highly sensitive to GCV. Little or no bystander killing effect was observed by tk-transfected cells on wild-type cells in vitro. However, a significant in vivo bystander effect was observed suggesting an immune-mediated response. Indeed, such an immune response was capable of slowing the growth of distant wild-type tumours and increased overall animal survival. A T helper 1 immune response was generated as a result of GCV activation and cell kill, demonstrated by the secretion of IFNgamma by cultured splenocytes in response to tumour cells. BrDU staining of tk-transfected cells treated with GCV in vitro suggested apoptotic cell death, but Annexin V staining was less marked for one of the cell lines. Serial in vivo monitoring by non-invasive magnetic resonance spectroscopy (MRS) of the tk-transfected MATLyLu tumours demonstrated a decreased ATP/Pi ratio (a measure of cell energy status) during growth and an increase in the ATP/Pi ratio during regression initiated by treatment with GCV. Further, significant differences were found in the phosphomonester (PME) to total phosphate (SigmaP) ratios in treated compared with untreated tumours, a result rarely seen in animal models, but commonly observed in patients. This study showed that a Th1-biased immune response generated by killing prostate tumour cells with tk/GCV can kill distant as well as local wild-type tumour cells. These findings suggest that GPAT may have a potential application in patients with both confined and metastatic prostate cancer and MRS may provide a method of monitoring response to treatment.

Animals↗
PubMed2001

Issues of normal tissue toxicity in patient and animal studies--effect of carbogen breathing in rats after 5-fluorouracil treatment.

Non-invasive magnetic resonance spectroscopy (MRS) can be used in the clinic to monitor the pharmacokinetics of the chemotherapeutic drug 5-fluorouracil (5-FU) and the effects of modifiers. We report two studies of 5-FU toxicity in normal tissue--one with patients and the other an animal study. 1) 19F MRS signals from fluoronucleotides, cytotoxic anabolites of 5-FU metabolism, were observed in the livers of two patients treated with 5-FU for colorectal cancer, shown by computed tomography (CT) and ultrasound (US) to have no liver metastases. This is the first report of non-invasive monitoring of toxic 5-FU metabolites in normal human tissues. 2) In animals, carbogen-breathing enhances tumour uptake and the efficacy of 5-FU, and the method is under trial in patients. This study demonstrates that there were no significant effects of carbogen breathing on the levels of 5-FU and its metabolites in normal rat tissues, or on the histology of the tissues assessed after treatment.

Adenocarcinoma↗
PubMed2001

In-vivo intracellular pH at rest and during exercise in patients with essential hypertension.

BACKGROUND: Several studies in isolated cells have reported that intracellular pH (pHi) in individuals with essential hypertension may be relatively alkaline compared to normotensive individuals. Such an abnormality of pHi in hypertension would be consistent with enhanced sodium-hydrogen exchanger activity and may provide potential mechanisms by which hypertension and its complications could develop. OBJECTIVES: To determine in-vivo intracellular pH of skeletal muscle at rest and during recovery from exercise-induced acidosis in hypertensive and normotensive subjects. METHODS: Using 31-phosphorus magnetic resonance spectroscopy, pHi of the dominant flexor digitorum superficialis was measured in 20 Caucasian subjects (14 male) with essential hypertension and 20 normotensive controls matched for gender, age, race and body mass index. Measurements were made at rest and during the exercise and recovery periods of a stepped incremental maximal exercise protocol. The rate of pHi recovery from exercise-induced acidosis was calculated by linear regression over the first 210 s of recovery from the pHi time plots of respective subjects. RESULTS: Mean resting pHi in the hypertensive (7.05 +/- 0.04) and normotensive groups (7.06 +/- 0.04) were not significantly different. There was a significant effect of gender on pHi: mean pHi was 7.07 +/- 0.03 in males and 7.02 +/- 0.03 in females, respectively (P < 0.0005). The mean intracellular pH achieved by exercise was 6.74 +/- 0.31 in hypertensive individuals and not significantly different in normotensive individuals (6.68 +/- 0.19; P = 0.4). The mean rate of pHi recovery in the hypertensives was 0.08 +/- 0.03 pH units/min and not significantly different in normotensives (0.08 +/- 0.02; P = 0.4). CONCLUSIONS: These results contrast with previously documented abnormalities in the control of pHi in hypertension and demonstrate the absence of major in-vivo disturbances of pHi in skeletal muscle, both at rest and during recovery from exercise-induced acidosis, in essential hypertension. Therefore, it is possible that previously documented abnormalities of pHi and activity of the exchanger may be either specific to cell type or not present under in-vivo conditions.

Exercise↗
PubMed2001

Sensitivity of quantitative (1)H magnetic resonance spectroscopy of the brain in detecting early neuronal damage in systemic lupus erythematosus.

OBJECTIVE: To quantify N-acetylaspartate (NAA), total creatines (tCr), total cholines (tCho), and myo-inositol (mI) levels in normal and abnormal appearing white matter of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) in order to determine the specific changes in metabolite concentrations. METHODS: Axial proton density and T(2) weighted magnetic resonance images, and short echo time (TE 30 ms) (1)H spectra were acquired with a GE SIGNA 1.5 T magnetic resonance system. Concentrations of NAA, tCr, tCho, and mI were determined, using brain tissue water as a reference, from nine patients (seven female, mean age 40.3 years, range 16-65) with NPSLE and eight healthy women (mean age 43 years, range 31-65). RESULTS: A significant rise of tCho (12.4%, p<0.05) and mI (31.4%, p<0.005) and a significant reduction in NAA (-12%, p<0.05) was found in normal appearing white matter compared with controls. Analysis according to severity of the clinical NPSLE features (subgrouped as major or minor) showed that SLE major had reduced NAA compared with SLE minor (-18.4%, p<0.05) and controls (-20%, p<0.005). The SLE major group showed a significant rise of mI (32%, p<0.01) and the SLE minor group a significant increase in tCho (18.6%, p<0.05) compared with controls. Longitudinal analysis of brain metabolites in normal appearing white matter showed consistent abnormalities in NAA, tCho, and mI in a patient with stable clinical features and a constant rise of tCho, but transient rise of mI was seen during a flare of disease in another patient. CONCLUSION: Quantitative (1)H magnetic resonance spectroscopy (MRS) suggests a particular course of neurometabolite changes that precedes irreversible reductions in NAA and permanent neuronal loss. Initially, in patients with SLE minor, there is a significant rise in tCho and a trend (reversible) for mI also to be raised. In patients with SLE major the NAA is significantly and permanently reduced and mI is significantly raised, whereas the tCho levels are near normal. Further investigations are needed to determine how specific MRS is as a clinical marker for brain disturbance in SLE.

Adolescent↗
PubMed2000

Intersample fluctuations in phosphocreatine concentration determined by 31P-magnetic resonance spectroscopy and parameter estimation of metabolic responses to exercise in humans.

The ATP turnover rate during constant-load exercise is often estimated from the initial rate of change of phosphocreatine concentration ([PCr]) using 31P-magnetic resonance spectroscopy (MRS). However, the phase and amplitude characteristics of the sample-to-sample fluctuations can markedly influence this estimation (as well as that for the time constant (tau) of the [PCr] change) and confound its physiological interpretation especially for small amplitude responses. This influence was investigated in six healthy males who performed repeated constant-load quadriceps exercise of a moderate intensity in a whole-body MRS system. A transmit- receive surface coil was placed under the right quadriceps, allowing determination of intramuscular [PCr]; pulmonary oxygen uptake (VO2) was simultaneously determined, breath-by-breath, using a mass spectrometer and a turbine volume measuring module. The probability density functions (PDF) of [PCr] and VO2 fluctuations were determined for each test during the steady states of rest and exercise and the PDF was then fitted to a Gaussian function. The standard deviation of the [PCr] and VO2 fluctuations at rest and during exercise (sr and sw, respectively) and the peak centres of the distributions (xc(r) and xc(w)) were determined, as were the skewness (gamma1) and kurtosis (gamma2) coefficients. There was no difference between sr and sw for [PCr] relative to the resting control baseline (s(r) = 1.554 %delta (s.d. = 0.44), s(w) = 1.514 %delta (s.d. = 0.35)) or the PDF peak centres (xc(r) = -0.013 %delta (s.d. = 0.09), xc(w) -0.197 %delta (s.d. = 0.18)). The standard deviation and peak centre of the 'noise' in VO2 also did not vary between rest and exercise (sr = 0.0427 l min(-1) (s.d. = 0.0104), s(w) = 0.0640 l min(-1) (s.d. = 0.0292); xc(r) = -0.0051 l min(-1) (s.d. = 0.0069), xc(w) 0.0022 l min(-1) (s.d. = 0.0034)). Our results demonstrate that the intersample 'noise' associated with [PCr] determination by 31P-MRS may be characterised as a stochastic Gaussian process that is uncorrelated with work rate, as previously described for VO2. This 'noise' can significantly affect the estimation of tau[PCr] and especially the initial rate of change of [PCr], i.e. the fluctuations can lead to variations in estimation of the initial rate of change of [PCr] of more than twofold, if the inherent 'noise' is not accounted for. This 'error' may be significantly reduced in such cases if the initial rate of change is estimated from the time constant and amplitude of the response.

Adenosine Triphosphate↗
PubMed2000

Poor regression of myocardial hypertrophy following concomitant chronic alcohol ingestion and angiotensin converting enzyme (ACE) inhibition.

In the following study we examined the combined effect of chronic alcohol administration and anti-hypertensive drug treatment in spontaneously hypertensive rats (SHR). SHR were fed alcohol for six weeks while taking the angiotensin converting enzyme (ACE) inhibitor lisinopril. After six weeks, protein synthesis rates, contractile protein levels and protease activities were examined in control; alcohol; control+lisinopril; alcohol+lisinopril groups. Lisinopril treatment significantly reduced left ventricular mass, protein content and contractile proteins in control rats, but these effects were not as pronounced in alcohol+lisinopril rats. Protein synthesis rates in both mixed and myofibrillar fractions were not significantly different in any of the 4 groups. The enzyme activities of the proteases cathepsin D and dipeptidyl aminopepetidase I increased in control+lisinopril rats, however, this effect was not evident in alcohol+lisinopril rats. Contractile proteins identified by one-dimensional electrophoresis showed that lisinopril treatment reduced all contractile proteins in control rats. However, in alcohol+ lisinopril rats, myosin heavy chain was higher than in control+lisinopril rats. In summary, alcohol ingestion impairs the regression of the hypertrophic myocardium in SHR on ACE-inhibitor treatment, which was reflected by altered protein metabolism. This study suggests that successful anti-hypertensive treatment may not be achieved if alcohol misuse is evident.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Metabolites of 2'-fluoro-2'-deoxy-D-glucose detected by 19F magnetic resonance spectroscopy in vivo predict response of murine RIF-1 tumors to 5-fluorouracil.

There is a clinical need for early detection of tumor response to therapy. This study aimed to determine whether metabolites of fluorodeoxyglucose (FDG) detected in solid mouse tumors in situ by I9F magnetic resonance spectroscopy (19F MRS) correlated with response to 5-fluorouracil chemotherapy. After injection of FDG (1.4 mmol/kg i.p.), uptake and metabolism was monitored for 2 h in RIF-1 tumors. FDG was detectable immediately, and after 10 min, a second broad peak was detected 5-6 ppm upfield. 19F MRS analysis of cell and tumor extracts in vitro showed that the upfield peak (> or =15% of the total detectable 19F signal) consisted of the epimer alpha-fluorodeoxymannose (FDM) and various conjugates. Mice treated with 5-fluorouracil (130 mg/kg) received, 48 h later, a repeat dose of FDG. The change in the rate of FDM formation, but not the FDG or total 19F signal, correlated significantly with the response to 5-fluorouracil (P = 0.032), suggesting that 19F MRS of FDM metabolism in vivo may be a novel means of predicting tumor response.

Animals↗
PubMed2000

Monitoring pharmacokinetics of anticancer drugs: non-invasive investigation using magnetic resonance spectroscopy.

Magnetic resonance spectroscopy (MRS) offers the unique advantage of detecting, identifying and quantifying chemicals deep within the living body in a totally non-invasive manner. In studies on pharmacology and toxicology of anticancer drugs, MRS and the closely related technique magnetic resonance imaging (MRI) have many uses. MRS in particular, despite its low sensitivity, offers unique insights into pharmacokinetics (the changing concentration of the drug at its site of action) which can be monitored, and metabolism (both activation and detoxification) can be detected in real time. This review considers some recent work on (19)F, (31)P, (1)H and (13)C MRS of anticancer drugs. Future possibilities for (13)C MRS and (1)H MRS studies of drugs and their metabolites are considered in detail.

Antineoplastic Agents↗
PubMed2000

A comparative investigation into the effect of chronic alcohol feeding on the myocardium of normotensive and hypertensive rats: an electrophoretic and biochemical study.

We investigated whether the imposition of chronic alcohol in hypertension leads to greater biochemical and cellular abnormalities of the myocardium than those arising in normotension. Fifteen-week-old spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were fed ethanol-containing diets for six weeks. Particular attention was focused on the composition of contractile proteins identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), fractional rate of protein synthesis, and synthesis rates relative to RNA (RNA activity) or DNA (cellular efficiency). In addition, myocardial enzymes and adenine nucleotides were measured. In both SHR and WKY rats chronic ethanol caused a general decrease in the contents of all nine contractile proteins with myosin heavy chain predominantly affected. Fractional rates of mixed (i.e., total) and myofibrillary proteins remained unaltered in both WKY rats and SHR, as were cellular efficiencies. The RNA activity was significantly reduced in ethanol-treated SHR but not in WKY rats. In ethanol-treated SHR, cardiac creatine kinase (CK) and malate dehydrogenase (MDH) activities were increased, AMP levels were elevated, whilst ATP levels and the energy charge were reduced. In WKY rats, the only significant change related to increased aspartate aminotransferase activities in response to alcohol feeding. Although there were only subtle differences between the response of the normotensive and hypertensive rats due to ethanol dosage, the reduced ATP levels and increased CK and MDH activities in SHR may reflect a greater susceptibility to ischaemic damage. Reduced contractile protein content, particularly myosin heavy chain, may contribute to contractile defects, a common feature of subclinical and clinical alcoholic cardiomyopathy.

Adenosine Diphosphate↗
PubMed2000

Causes and consequences of tumour acidity and implications for treatment.

Tumour cells have a lower extracellular pH (pHe) than normal cells; this is an intrinsic feature of the tumour phenotype, caused by alterations either in acid export from the tumour cells or in clearance of extracellular acid. Low pHe benefits tumour cells because it promotes invasiveness, whereas a high intracellular pH (pHi) gives them a competitive advantage over normal cells for growth. Molecular genetic approaches have revealed hypoxia-induced coordinated upregulation of glycolysis, a potentially important mechanism for establishing the metabolic phenotype of tumours. Understanding tumour acidity opens up new opportunities for therapy.

Animals↗