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Howard C Thomas

Publications and source records attributed to Howard C Thomas.

At least 19 recordsLinked to original sources
PubMed2006

Current and future applications of in vitro magnetic resonance spectroscopy in hepatobiliary disease.

Nuclear magnetic resonance spectroscopy allows the study of cellular biochemistry and metabolism, both in the whole body in vivo and at higher magnetic field strengths in vitro. Since the technique is non-invasive and non-selective, magnetic resonance spectroscopy methodologies have been widely applied in biochemistry and medicine. In vitro magnetic resonance spectroscopy studies of cells, body fluids and tissues have been used in medical biochemistry to investigate pathophysiological processes and more recently, the technique has been used by physicians to determine disease abnormalities in vivo. This highlighted topic illustrates the potential of in vitro magnetic resonance spectroscopy in studying the hepatobiliary system. The role of in vitro proton and phosphorus magnetic resonance spectroscopy in the study of malignant and non-malignant liver disease and bile composition studies are discussed, particularly with reference to correlative in vivo whole-body magnetic resonance spectroscopy applications. In summary, magnetic resonance spectroscopy techniques can provide non-invasive biochemical information on disease severity and pointers to underlying pathophysiological processes. Magnetic resonance spectroscopy holds potential promise as a screening tool for disease biomarkers, as well as assessing therapeutic response.

Bile↗
PubMed2006

Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence.

Persistent hepatitis B virus infection is a major risk factor for hepatocellular carcinoma, the most frequent cancer in some developing countries. Up to 95% of those infected at birth and 15% of those infected after the neonatal period fail to clear hepatitis B virus, together resulting in approximately 350 million persistent carriers worldwide. Via a whole genome scan in Gambian families, we have identified a major susceptibility locus as a cluster of class II cytokine receptor genes on chromosome 21q22. Coding changes in two of these genes, the type I IFN receptor gene, IFN-AR2, and the IL-10RB gene that encodes a receptor chain for IL-10-related cytokines including the IFN-lambdas, are associated with viral clearance (haplotype P value = 0.0003), and in vitro assays support functional roles for these variants in receptor signaling.

Carcinoma, Hepatocellular↗
PubMed2006

Hepatic vein transit time of SonoVue: a comparative study with Levovist.

PURPOSE: To prospectively compare transit times of Levovist and SonoVue in healthy volunteers and patients with biopsy-proved hepatitis C-related liver disease. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Forty patients and 25 healthy volunteers were examined. Subjects fasted, a bolus of SonoVue (0.6 mL) was injected into a cubital fossa vein, and hepatic venous time-intensity profiles were measured with spectral Doppler tracing. This was repeated with two injections of Levovist (2 g) and another injection of SonoVue. Time-intensity curves of spectral Doppler signals of right and middle hepatic veins were analyzed. A sustained signal intensity increase of 10% above baseline levels indicated hepatic vein transit time (HVTT). Carotid artery audio intensity was measured in volunteers. Analysis of variance and t tests were used for statistical analysis. RESULTS: Twelve patients had mild hepatitis; 18, moderate or severe hepatitis; and 10, cirrhosis. Mean HVTTs in control, mild hepatitis, moderate or severe hepatitis, and cirrhosis groups were 38.3 seconds +/- 2.4 (standard error), 47.5 seconds +/- 6.5, 29.5 seconds +/- 10.8, and 17.6 seconds +/- 5.0, respectively, with Levovist (P < .001) and 29.4 seconds +/- 6.9, 27.4 seconds +/- 9.3, 22.9 seconds +/- 4.7, and 16.4 seconds +/- 4.9, respectively, with SonoVue (P < .001). HVTT decreased as severity increased at imaging with both contrast agents. There was no significant difference in HVTT between mild and moderate hepatitis groups with SonoVue; however, there were significant differences in HVTT between all patient groups with Levovist. HVTT of SonoVue was shorter than that of Levovist in all groups (P < .001) except the cirrhosis group; in this group, HVTT of the two contrast agents was similar (P = .05). No difference was observed in mean cardiopulmonary transit time for SonoVue or Levovist (9.1 seconds +/- 2.4 [standard error] and 8.4 seconds +/- 2.5, respectively, P = .18). CONCLUSION: HVTT was significantly shorter with SonoVue than with Levovist; there was no significant difference in cardiopulmonary transit time.

Contrast Media↗
PubMed2006

The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice.

After liver injury, parenchymal regeneration occurs through hepatocyte replication. However, during regenerative stress, oval cells (OCs) and small hepatocyte like progenitor cells (SHPCs) contribute to the process. We systematically studied the intra-hepatic and extra-hepatic sources of liver cell replacement in the hepatitis B surface antigen (HBsAg-tg) mouse model of chronic liver injury. Female HBsAg-tg mice received a bone marrow (BM) transplant from male HBsAg-negative mice, and half of these animals received retrorsine to block indigenous hepatocyte proliferation. Livers were examined 3 and 6 months post-BM transplantation for evidence of BM-derived hepatocytes, OCs, and SHPCs. In animals that did not receive retrorsine, parenchymal regeneration occurred through hepatocyte replication, and the BM very rarely contributed to hepatocyte regeneration. In mice receiving retrorsine, 4.8% of hepatocytes were Y chromosome positive at 3 months, but this was frequently attributable to cell fusion between indigenous hepatocytes and donor BM, and their frequency decreased to 1.6% by 6 months, as florid OC reactions and nodules of SHPCs developed. By analyzing serial sections and reconstructing a 3-dimensional map, continuous streams of OCs could be seen that surrounded and entered deep into the nodules of SHPCs, connecting directly with SHPCs, suggesting a conversion of OCs into SHPCs. In conclusion, during regenerative stress, the contribution to parenchymal regeneration from the BM is minor and frequently attributable to cell fusion. OCs and SHPCs are of intrinsic hepatic origin, and OCs can form SHPC nodules.

Animals↗
PubMed2006

Variations due to analysis technique in intracellular pH measurements in simulated and in vivo 31P MR spectra of the human brain.

PURPOSE: To investigate variation in pH generated by different analysis techniques and to find the most robust method, 31P MR brain spectra were acquired in vivo. Three different methods were used to measure the chemical shift of inorganic phosphate (Pi) relative to phosphocreatine (PCr). MATERIALS AND METHODS: Eight healthy volunteers were scanned four times, and manual measurement of the chemical shift in a frequency domain spectrum using the manufacturer's software was compared with values produced by a frequency-domain analysis method (NMR1) and a prior-knowledge-based time-domain technique (MRUI). To explain the in vivo data, simulations of brain spectra, modified in ways typical of real variations in vivo, were produced and the pH was measured using manual measurement and MRUI. RESULTS: Different measurement techniques produced systematically different pH values, with manual measurement producing the lowest variability (manual measurement: pH = 6.999, CoV = 0.297; NMR1: pH = 7.042, CoV = 0.501; MRUI: pH = 7.036, CoV = 0.606). While MRUI more accurately measured the pH of unaltered simulations, it was systematically affected by altering the simulated spectra. Manual measurement was unaffected. CONCLUSION: Manual measurement produces the most consistent pH value, and there is no benefit in using more complex automated spectral fitting methods to measure the pH.

Adult↗
PubMed2006

Central nervous system changes in hepatitis C virus infection.

Patients with chronic hepatitis C virus (HCV) infection frequently describe neuropsychological symptoms. Although hepatic encephalopathy is the best established neurological association of HCV infection, there is a growing body of literature on cerebral dysfunction, occurring at an early stage of chronic HCV infection, well before the development of cirrhosis. In this review we describe recent studies that have documented mild, but significant neurocognitive impairment in HCV infection. These deficits in patients with minimal or absent liver disease do not appear to be attributable to a history of substance abuse, coexistent depression or hepatic encephalopathy. Recent studies employing in-vivo magnetic resonance spectroscopy have suggested that a biological mechanism associated with the virus may be responsible. The hypothesis that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment is supported by molecular virological studies of post-mortem brain tissue.

Brain↗
PubMed2006

Analysis of p53 mutations for a mutational signature in human intrahepatic cholangiocarcinoma.

Cholangiocarcinoma development may be related to cholangiocyte DNA damage from genotoxic compounds in bile. We have previously shown that human biliary tissue is exposed to genotoxic agents, as evidenced by the presence of DNA adducts. Establishing the presence of a 'mutational signature' in tumour suppressor genes from tumour tissue provides a means of linking cause and effect in human cancer. Inactivation of p53, known to have 'hot-spots' for particular chemical carcinogens, has previously been linked to human cholangiocarcinoma. However, previous p53 studies have focused on exons 5-8, potentially missing gene alterations at other sites. This study examined the putative link between environmental carcinogens and intrahepatic cholangiocarcinoma by analysing DNA from 31 patients for complete p53 mutational signatures, using single strand conformational polymorphism and polymerase chain reaction. All mutations found were compared to known p53 mutations in cholangiocarcinoma and to mutations induced by environmental mutagens, as described in p53 databases. Five non-silent p53 mutations were found, including three new frameshift mutations and two new intron mutations which have not previously been reported in cholangiocarcinoma. Two frameshifts were due to deletions and the third due to an insertion in exon 5. There was no predominant mutational spectrum amongst the set of cholangiocarcinoma samples studied, or on combining these mutations with the dataset of known p53 mutations in cholangiocarcinoma. Several reasons may explain this, including lack of data outside exons 5-8, bias in mutation reporting, the involvement of mutations in non-coding regions or genes other than p53, or the possibility that there is no carcinogenic specific agent and therefore no signature.

Base Sequence↗
PubMed2005

Cholangiocarcinoma.

Cholangiocarcinoma is a devastating malignancy that presents late, is notoriously difficult to diagnose, and is associated with a high mortality. The incidence of intrahepatic cholangiocarcinoma is increasing worldwide. The cause for this rise is unclear, although it could be related to an interplay between predisposing genetic factors and environmental triggers. MRI and CT with endoscopic ultrasound and PET provide useful diagnostic information in certain patients. Surgical resection is the only chance for cure, with results depending on careful technique and patient selection. Data suggest that liver transplantation could offer long-term survival in selected patients when combined with neoadjuvant chemoradiotherapy. Chemotherapy and radiotherapy have been ineffective for patients with inoperable tumours. For most of these patients biliary drainage is the mainstay of palliation. However, controversy exists over the type and positioning of biliary stents. Photodynamic treatment is a new palliative technique that might improve quality of life.

Bile Duct Neoplasms↗
PubMed2005

Complement inhibition rescued mice allowing observation of transgene expression following intraportal delivery of baculovirus in mice.

BACKGROUND: The baculovirus Autographa californica nucleo-polyhedrosis virus (AcNPV) is an alternative to other viral vectors for hepatic gene delivery. A barrier to AcNPV being used in vivo is its susceptibility to inactivation by serum complement 1. In vivo utility has only been demonstrated using methods that avoid contact with serum 2-5. We have studied the complement pathways involved in baculovirus inactivation in vitro and the systemic administration of baculovirus vectors in vivo, with the co-administration of the complement inhibitor, soluble complement inhibitor 1 (sCR1). RESULTS: EDTA increased baculovirus survival in human serum more than EGTA showing that both the alternative and classical pathways of complement are activated. Depleting serum of IgM increased survival, whereas reconstitution with pooled IgM restored activity against baculovirus, suggesting naturally occurring IgM antibodies with affinity for baculovirus may be partially responsible for complement activation. Intraportal administration of baculovirus led to hepatic expression when the complement inhibitor sCR1 (soluble complement receptor type 1) was co-administered by tail vein injection; however, liver histology showed hepatic necrosis. Without co-administration of sCR1, intraportal infusion of baculovirus was fatal within 24 h. Histology demonstrated massive hepatic necrosis. Yolk sac vein injection of baculovirus was associated with fetal death. CONCLUSIONS: Transgene expression was demonstrated following intraportal infusion of recombinant baculovirus vectors in combination with sCR1; however, our experiments suggest a significant associated toxicity.

Animals↗
PubMed2005

Proton and phosphorus-31 nuclear magnetic resonance spectroscopy of human bile in hepatopancreaticobiliary cancer.

OBJECTIVE: Hepatopancreaticobiliary cancers can be difficult to diagnose. Nuclear magnetic resonance (NMR) spectroscopy provides non-invasive information on phospholipid metabolism, and previous studies of liver tissue have highlighted changes in phospholipids in malignancy. We hypothesised that in-vitro NMR spectroscopy of human bile may provide independent diagnostic indices in cancer management through an assessment of the phospholipid content. DESIGN AND METHODS: Bile samples from 24 patients were collected at endoscopic retrograde cholangiopancreatography and from one subject at cholecystectomy. Thirteen patients had cancer: pancreatic carcinoma (eight), cholangiocarcinoma (three) and metastatic liver disease (two). The remaining 12 patients had non-malignant pathology. In-vitro proton (H) and phosphorus-31 (P) NMR spectra were obtained from all samples using an 11.7 Tesla NMR spectroscopy system. RESULTS: Complementary information was obtained from the H and P NMR spectra. Signals were assigned to phosphatidylcholine in both H and P NMR spectra. Phosphatidylcholine levels were significantly reduced in the bile from cancer patients when compared with bile from non-cancer patients (P=0.007). CONCLUSION: These preliminary studies suggest that H and P NMR spectroscopy of bile may be used to detect differences in phospholipid content between cancer and non-cancer patients. This may have implications for the development of novel diagnostic strategies in hepatopancreaticobiliary cancers. Further larger-scale studies are warranted.

Adult↗
PubMed2005

A review of cognitive impairment and cerebral metabolite abnormalities in patients with hepatitis C infection.

Numerous studies have reported associations between chronic hepatitis C virus (HCV) infection and fatigue, depression and impairments in health-related quality of life, which are independent of the severity of liver disease. Although there are a large number of potential explanations for these symptoms, including a history of substance abuse and associated personality types, or the effect of the diagnosis of HCV infection itself, there has been recent interest in the possibility of a biological effect of HCV infection on cerebral function. There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be wholly attributed to substance abuse, co-existent depression or hepatic encephalopathy. Impairments are predominantly in the domains of attention, concentration and information processing speed. Furthermore, in-vivo cerebral magnetic resonance spectroscopy studies in patients with hepatitis C and normal liver function have reported elevations in cerebral choline-containing compounds and reductions in N-acetyl aspartate, suggesting that a biological mechanism may underlie the cognitive findings. The recent detection of HCV genetic sequences in post-mortem brain tissue raises the intriguing possibility that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment.

Brain↗
PubMed2005

In vivo and in vitro nuclear magnetic resonance spectroscopy as a tool for investigating hepatobiliary disease: a review of H and P MRS applications.

Nuclear magnetic resonance (NMR) spectroscopy is a non-invasive technique, which allows the study of cellular biochemistry and metabolism. It is a diverse research tool, widely used by biochemists to investigate pathophysiological processes in vitro and, more recently, by physicians to determine disease abnormalities in vivo. This article reviews the basics of the NMR phenomenon and summarises previous research on the hepatobiliary system using both laboratory-based and clinical methodologies. The role of proton and phosphorus-31 ((31)P) NMR spectroscopy in the study of malignant and non-malignant liver disease and studies of bile composition are discussed. In vivo techniques (magnetic resonance spectroscopy, MRS) can be performed as an adjunct to standard MR examination of the liver. Although still primarily a research tool, the in vivo technique provides non-invasive biochemical information on disease severity and holds promise in its use to gauge response to treatment regimens.

Biliary Tract Diseases↗
PubMed2005

p53 Mutations in human cholangiocarcinoma: a review.

The reported mortality from intrahepatic bile duct tumours is increasing markedly in industrialised countries, for reasons that remain unknown. Inactivation of the tumour suppressor gene p53, is the commonest genetic abnormality in human cancer and has been implicated in the genesis of cholangiocarcinoma in various immunohistochemical and molecular epidemiological investigations, including gene sequencing studies. The structure and function of p53 and its role in linking cancer to specific carcinogens by way of mutational signatures is reviewed. The findings of previous p53 studies and their relevance in human cholangiocarcinoma are summarised.

Bile Duct Neoplasms↗
PubMed2005

Can Doppler sonography grade the severity of hepatitis C-related liver disease?

OBJECTIVE: Many authors have claimed that Doppler sonography indexes are of value in grading and assessing diffuse liver disease. However, there is much controversy regarding the reliability and reproducibility of these techniques. We performed a prospective study to evaluate whether these methods can grade disease in a well-stratified cohort of patients with hepatitis C virus (HCV)-related liver disease. SUBJECTS AND METHODS: Sixty-five patients with biopsy-proven HCV-related liver disease were recruited, and Doppler sonography was performed by one operator. The patients were classified into one of the following three groups on the basis of the Ishak-modified histologic activity index (HAI) fibrosis (F) and necroinflammatory (NI) scores: mild hepatitis (F < or = 2 and NI < or = 3), moderate or severe hepatitis (3 < or = F < 6 or NI > or = 4), or cirrhosis (F = 6/6). We measured the following Doppler indexes: main hepatic artery peak velocity (Vmax) and resistive index, main portal vein peak velocity (Vmax), and maximal portal vein diameter and circumference that allowed calculation of the portal vein congestive index (portal vein area and portal vein velocity). The ratio of the hepatic artery velocity (Vmax) to the portal vein velocity (Vmax) was also calculated, and the phasicity (triphasic, biphasic, or monophasic) of the hepatic veins of each patient was recorded. We also measured the maximal spleen length longitudinally. RESULTS: A total of 65 patients with liver disease (mild hepatitis, n = 20; moderate or severe hepatitis, n = 25; cirrhosis, n = 20) with biopsy-proven HCV-related liver disease were studied. Optimal hepatic arterial traces were obtained in only 30 patients and portal vein circumference in 18 patients. No significant differences were observed in the Doppler indexes with increasing severity of liver disease. Five (29%) of 17 patients with mild hepatitis had an abnormal hepatic vein trace (i.e., biphasic or monophasic) compared with 11 (55%) of 20 patients with moderate or severe hepatitis and 12 (60%) of 20 patients with cirrhosis. The only index to show a significant intergroup difference was splenic length (analysis of variance, p < 0.001), but there was still overlap between the groups. CONCLUSION: Doppler-derived indexes, which have previously been recommended for the assessment of severity in chronic liver disease, are difficult to reproduce reliably and therefore have a limited clinical role in the noninvasive assessment of hepatic fibrosis or inflammation.

Cohort Studies↗
PubMed2004

Central nervous system involvement in hepatitis C virus infection.

Hepatic encephalopathy is the most obvious neurological consequence of chronic hepatitis C virus (HCV) infection. There are also case reports of HCV-associated cerebral vasculitis. This review is concerned with the possibility of an effect of HCV on cerebral dysfunction, occurring at an early stage of chronic infection, prior to the development of cirrhosis and unrelated to vasculitis. There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be attributed to substance abuse, coexistent depression, or hepatic encephalopathy. In vivo magnetic resonance spectroscopy and neurophysiological studies have suggested that a biological mechanism may underlie these cognitive findings. The recent detection of HCV genetic sequences in postmortem brain tissue raises the intriguing possibility that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment.

Cognition Disorders↗
PubMed2004

Autoregulatory role of interleukin-10 in hepatitis C patients treated with IFN-alpha.

Interferon-alpha2 (IFN-alpha2) is used as standard treatment of patients with chronic hepatitis C (cHCV), but little is known about the immunomodulatory effects of this cytokine in vivo. We have studied immunologic parameters in freshly isolated peripheral blood mononuclear cells (PBMC) of 26 patients with cHCV 12 h before and 12 h after the first s.c. injection of 5-6 MU IFN-alpha2. In PBMC obtained after IFN injection, a substantial increase in IL-10 production after antigen-specific and nonspecific stimulation was observed, whereas IFN-gamma production and proliferation were significantly diminished compared with PBMC obtained before IFN injection. Patients were stratified according to single nucleotide polymorphisms (SNPs) in the interleukin-10 (IL-10) promoter, which have been associated with the response to IFN therapy. Induction of IL-10 and suppression of IFN-gamma levels were more prominent in patients with genotype CC at position -592 (n = 15) compared with patients with genotype AA/AC (n = 11). In conclusion, our data indicate that IFN-alpha2 therapy can potently enhance IL-10 and suppress IFN-gamma production of PBMC, which is, at least partially, dependent on an SNP in the IL-10 promoter. This suggests an autoregulatory role of IL-10 in IFN therapy.

Adult↗