I. Jane Cox

Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis and therapeutics

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide and, owing to changes in the prevalence of the two major risk factors, hepatitis B virus and hepatitis C virus, its overall incidence remains alarmingly high in the developing world and is steadily rising across most of the developed world. Early diagnosis remains the key to effective treatment and there have been recent advances in both the diagnosis and therapy of HCC, which have made important impacts on the disease. This review outlines the epidemiological trends, risk factors, diagnostic developments and novel therapeutics for HCC, both in the developing and developed world.

Proton MR spectroscopy of intracranial tumours: in vivo and in vitro studies.

Proton magnetic resonance spectroscopy (1H MRS) was used to investigate intracranial tumours in vitro and in vivo. Biopsy specimens were studied from 47 patients, 11 of whom were also examined in vivo. Analysis was based on the signals from N-acetylaspartate (NAA), phosphocreatine plus creatine (Cr), choline-containing compounds (Cho), alanine (Ala), and lactate. Biopsy data from 26 astrocytomas showed that the NAA/Cr ratio differs significantly in all grades from its value in normal white matter and that the Cho/Cr ratio differs significantly in grade IV tumours from its value in the other grades. Meningiomas have an unusually high Ala/Cr ratio. Spectra obtained in vivo are consistent with in vitro results from the same patients, and their lactate signal provides additional information about abnormal metabolism. We conclude that 1H MRS has a clear role in the diagnosis and biochemical assessment of intracranial tumours and in the evaluation and monitoring of therapy.

Characterization of Inflammatory Bowel Disease With Urinary Metabolic Profiling

OBJECTIVES:Distinguishing between the inflammatory bowel disease (IBD), Crohns disease (CD), and ulcerative colitis (UC) is important for both management and prognostic reasons. Discrimination using noninvasive techniques could be an adjunct to conventional diagnostics. Differences have been shown between the intestinal microbiota of CD and UC patients and controls; the gut bacteria influence specific urinary metabolites that are quantifiable using proton high-resolution nuclear magnetic resonance (NMR) spectroscopy. This study tested the hypothesis that such metabolites differ between IBD and control cohorts, and that using multivariate pattern-recognition analysis, the cohorts could be distinguished by urine NMR spectroscopy.METHODS:NMR spectra were acquired from urine samples of 206 Caucasian subjects (86 CD patients, 60 UC patients, and 60 healthy controls). Longitudinal samples were collected from 75 individuals. NMR resonances specific for metabolites influenced by the gut microbes were studied, including hippurate, formate, and 4-cresol sulfate. Multivariate analysis of all urinary metabolites involved principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA).RESULTS:Hippurate levels were lowest in CD patients and differed significantly between the three cohorts (P<0.0001). Formate levels were higher and 4-cresol sulfate levels lower in CD patients than in UC patients or controls (P=0.0005 and P=0.0002, respectively). PCA revealed clustering of the groups; PLS-DA modeling was able to distinguish the cohorts. These results were independent of medication and diet and were reproducible in the longitudinal cohort.CONCLUSIONS:Specific urinary metabolites related to gut microbial metabolism differ between CD patients, UC patients, and controls. The emerging technique of urinary metabolic profiling with multivariate analysis was able to distinguish these cohorts.

A 31P and 1H-NMR investigation in vitro of normal and abnormal human liver

Spectral changes in human hepatic tumours and possible systemic effects of tumour on host liver were assessed by 31P and 1H in vitro NMR spectroscopy. The 1H and 31P spectra from liver tumour biopsies showed significant elevation in phosphoethanolamine, phosphocholine, taurine, citrate, alanine, lactate and glycine, and significant reduction in GPE (glycerophosphoethanolamine), GPC (glycerophosphocholine), creatine and threonine compared to histologically normal tissue. 31P-NMR spectra obtained from histologically normal tissue within tumour-bearing livers showed significant elevation in phosphoethanolamine and phosphocholine compared to data from liver biopsies from nontumour-bearing patients (pancreatitis). These results suggest that alterations in membrane metabolism in host liver can be detected by 31P-NMR.

Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at 1 year of age

The aim of the study was to test the hypotheses that elevated cerebral lactate, detected by proton spectroscopy performed within 18 hours of suspected birth asphyxia, is associated with adverse outcome, and that increased lactate can be used to predict adverse outcome. Thirty-one term infants suspected of having had birth asphyxia and seven control infants underwent proton magnetic resonance spectroscopy, using three-dimensional chemical shift imaging, within 18 hours of birth. Adverse outcome was defined as death or neurodevelopmental impairment at 1 year of age or more. Nine infants had an adverse outcome. The other 22 and all of the control infants remained normal. Median (range) lactate/creatine plus phosphocreatine (lactate/creatine) ratios in the abnormal, the normal, and the control group were 1.14 (0.17 to 3.81), 0.33 (0 to 1.51), and 0.05 (0 to 0.6) respectively (P=0.003). Lactate/creatine >1.0 predicted neurodevelopmental impairment at 1 year of age with sensitivity of 66% and specificity of 95%, positive and negative predictive values of 86% and 88%, and a likelihood ratio of 13.2. Elevated cerebral lactate/creatine within 18 hours of birth asphyxia predicts adverse outcome.

Development and applications of in vivo clinical magnetic resonance spectroscopy.

4.1 CURRENT STATUS. While an extensive clinical literature of MRS of muscle, brain, heart and liver has been achieved, the MRS technique is not considered essential for routine diagnosis because it is inherently insensitive and metabolic changes tend to be small. However, MRS techniques have proven to be of considerable value for prognosis in some circumstances, notably for predicting outcome following hypoxic-ischaemic injury in the newborn and also in predicting graft viability following organ transplantation. The chemical specificity of MRS has been illustrated, and exploiting the non-invasive nature of the technique, metabolic fingerprinting of pathophysiological processes throughout the natural history of a wide variety of diseases is now being accomplished. Particularly exciting are the applications of 13C MRS for measuring hepatic and muscle glycogen levels, for example in diabetics, and the use of hepatic 31P MRS for assessing liver function in cirrhosis. Other areas of excitement are the applications of 1H MRS in assessing neuronal function in epilepsy and stroke, and for measuring the evolution of lactate in stroke and hypoxic-ischaemic encephalopathy. Emphasis on technique development continues, and applications still tend to be technology-led. The availability of routine clinical MRI systems with spectroscopy capabilities has given MRS studies wider applicability. The recent improvements in spatial resolution have been impressive and the technique is slowly becoming more quantitative. 4.2. FUTURE PERSPECTIVES. Given the flexibility of clinical magnetic resonance techniques, particularly magnetic resonance imaging, it is likely that MRI will be the diagnostic tool of choice in a wider range of diseases, such as multiple sclerosis, stroke, neurodegenerative conditions, sports injuries and in staging malignancies. Since proton magnetic resonance spectroscopy packages have become a routine addition to many MRI systems, it is feasible to select the MRI sequences of most value in highlighting anatomical and pathological abnormalities and to incorporate specifically selected MRS sequences to emphasize biochemical differences. Improvements in technical methodologies are central to further developments. For example, use of internal coils, such as implantable or endoscopic coils, will enable small regions of tissue to be studied in considerable detail, which may otherwise be inaccessible to measurement. Chemical MRS studies have benefited from the use of higher magnetic fields, and the same may be expected for clinical MRS studies. Whole-body magnets up to 4 T have been used in a few centres, and certainly 3 T systems are becoming more widely available with the recent tremendous interest in functional imaging. Certainly, better control of artefacts can be expected; for example, improved definition of spectral changes due to voluntary or involuntary movements. Wider use of proton decoupling methods will improve the specificity of the spectra, by allowing definitive assignments of overlapping resonances, as well as the sensitivity. Comparing PET and MRS studies, it is becoming increasingly obvious that both will be required in parallel to explore parameters of brain metabolism and function. The ability to measure 13C MR signals in the brain has been demonstrated, which allows measurements of glutamate and glucose turnover. MRS measurements have the advantage of not requiring a radioactive isotope, as well as being insensitive to activity-related changes in regional cerebral blood flow. Also the study of cerebral glucose metabolism by MRS is very promising, allowing a resolution and sensitivity comparable to PET. A combination of MRS and PET studies will allow the pathogenesis of neuropsychiatric disorders to be better understood. (ABSTRACT TRUNCATED)

Brain alkaline intracellular pH after neonatal encephalopathy

Experimental studies demonstrate an alkaline shift in brain intracellular pH (pHi) after hypoxia‐ischemia (HI). In infants with neonatal encephalopathy after HI, our aims were to assess (1) brain pHi during the first 2 weeks after birth in infants categorized according to magnetic resonance imaging (MRI) during the first 2 weeks after birth and at more than 3 months of age, and neurodevelopmental outcome at 1 year; (2) the relationship between brain pHi and lactate/creatine; and (3) duration of alkaline brain pHi. Seventy‐eight term infants with neonatal encephalopathy were studied using MR techniques. One hundred and fifty‐one studies were performed throughout the first year including 56 studies of 50 infants during the first 2 weeks after birth. pHi was calculated using phosphorus‐31 MR spectroscopy and lactate/creatine was measured using proton MRS. The mean (standard deviation [SD]) brain pHi during the first 2 weeks after birth in infants with severely abnormal versus normal MRI was 7.24 (SD, 0.17) versus 7.04 (SD, 0.05; p < 0.001); in infants who subsequently developed cerebral atrophy versus those who did not: 7.23 (SD, 0.17) versus 7.06 (SD, 0.06; p < 0.05); in infants who died or had a severe neurodevelopmental impairment versus normal outcome: 7.28 (SD, 0.15) versus 7.11 (SD, 0.09; p < 0.05). Brain alkalosis was associated with increased brain lactate/creatine (p < 0.001). pHi remained more alkaline in the severe outcome group up to 20 weeks after birth (p < 0.05). Ann Neurol 2002;52:000–000

Abnormal cerebral phospholipid metabolism in dyslexia indicated by phosphorus-31 magnetic resonance spectroscopy

It has recently been suggested that many of the features of dyslexia may be explicable in terms of an abnormality of membrane phospholipid metabolism. To investigate this we studied 12 dyslexic and 10 non‐dyslexic adults using in vivo cerebral phosphorus‐31 magnetic resonance spectroscopy (31P MRS), as the phosphomonoester (PME) and phosphodiester (PDE) peaks include indices of membrane phospholipid turnover. Spectral localization was achieved using four‐dimensional chemical shift imaging methods. The PME peak area was significantly elevated in the dyslexic group, as evidenced by higher ratios of PME/total phosphorus (F=9.5, p<0.006), PME/NTP (F=17.5, p<0.001) and PME/PDE (F=6.9, p<0.02). No other spectral measurements differed significantly between the groups. These findings are consistent with the hypothesis that membrane phospholipid metabolism is abnormal in dyslexia. The PME peak is multicomponent, but predominantly consists of phosphoethanolamine (PE) and phosphocholine (PC), which are precursors of membrane phospholipids. Our finding of raised PME in dyslexia could therefore reflect reduced incorporation of phospholipids into cell membranes, although definitive interpretation must await further evidence.

Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function

Proton pump inhibitors (PPI) have been associated with infectious complications in cirrhosis, but their impact on distal gut microbiota composition and function is unclear. We aimed to evaluate changes in stool microbiota composition and function in patients with cirrhosis and healthy controls after omeprazole therapy. Both 15 compensated cirrhotic patients and 15 age-matched controls underwent serum gastrin measurement, stool microbiota profiling with multitagged pyrosequencing, and urinary metabolic profiling with NMR spectroscopy to assess microbial cometabolites before/after a 14-day course of 40 mg/day omeprazole under constant diet conditions. Results before (pre) and after PPI were compared in both groups, compared with baseline by systems biology techniques. Adherence was >95% without changes in diet or MELD (model for end-stage liver disease) score during the study. Serum gastrin concentrations significantly increased after PPI in cirrhosis (pre 38.3 ± 35.8 vs. 115.6 ± 79.3 pg/ml P < 0.0001) and controls (pre 29.9 ± 14.5 vs. 116.0 ± 74.0 pg/ml, P = 0.001). A significant microbiota change was seen in both controls and cirrhosis after omeprazole (QIIME P < 0.0001). Relative Streptococcaceae abundance, normally abundant in saliva, significantly increased postomeprazole in controls (1 vs. 5%) and cirrhosis (0 vs. 9%) and was correlated with serum gastrin levels (r = 0.4, P = 0.005). We found significantly reduced hippurate in cirrhosis vs. controls both pre- and postomeprazole and increased lactate in both groups post vs. preomeprazole, whereas dimethylamine (DMA) decreased in cirrhosis only. On correlation network analysis, significant changes in linkages of bacteria with metabolites (hippurate/DMA/lactate) were found postomeprazole, compared with pre-PPI in cirrhosis patients. In conclusion, omeprazole is associated with a microbiota shift and functional change in the distal gut in patients with compensated cirrhosis that could set the stage for bacterial overgrowth.

Experimental sulphur-33 nuclear magnetic resonance spectroscopy

The potential of sulphur-33 n.m.r. spectroscopy for chemical applications is explored. Data are presented for a range of compounds. Spectra have been obtained using both high-power and high-resolution systems. Moderately high field strengths were used (7.05 and 4.70 T), together with a special pulse sequence to reduce the effects of the dead-time. Lines as wide as 5 kHz can be readily observed. A scalar sulphur–hydrogen coupling is reported for the first time.