Protonation of aqueous alanine by photoionization of water.

Hydronium ions produced by photolysis of water are used to study the protonation dynamics of alanine zwitterions in water. The measurements are done by UV-VIS and UV-IR femtosecond transient absorption spectroscopy on alanine in H2O and D2O. It is estimated that the reaction rate constant for the deuteration of alanine zwitterions is 4 × 1010 M-1 s-1, while the reverse process has a rate constant of 2 × 108 s-1. In addition to hydronium ions the photolysis of water yields hydrogen atoms and hydrated electrons together with hydroxyl radicals and hydroxyl ions. However, no other products resulting from reactions between aqueous alanine and the photolysis products of water are positively identified during the first 530 ps after the photolysis. Potential secondary reactions that are not observed experimentally are discussed and an upper limit is set for their yield where possible.

PET imaging of patients with non-small cell lung cancer employing an EGF receptor targeting drug as tracer.

BACKGROUND: We have previously developed (11)C-erlotinib as a new positron emission tomography (PET) tracer and shown that it accumulates in epidermal growth factor receptor (EGFR)-positive lung cancer xenografts in mice. Here, we present a study in patients with non-small cell lung cancer (NSCLC) investigating the feasibility of (11)C-erlotinib PET as a potential method for the identification of lung tumours accumulating erlotinib. METHODS: Thirteen patients with NSCLC destined for erlotinib treatment were examined by contrast-enhanced computed tomography (CT), (11)C-erlotinib PET/low-dose CT and (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/low-dose CT before start of the erlotinib treatment. After 12 weeks treatment, they were examined by (18)F-FDG PET/contrast-enhanced CT for the assessment of clinical response. RESULTS: Of the 13 patients included, 4 accumulated (11)C-erlotinib in one or more of their lung tumours or lymph-node metastases. Moreover, (11)C-erlotinib PET/CT identified lesions that were not visible on (18)F-FDG PET/CT. Of the four patients with accumulation of (11)C-erlotinib, one died before follow-up, whereas the other three showed a positive response to erlotinib treatment. Three of the nine patients with no accumulation died before follow-up, four showed progressive disease while two had stable disease after 12 weeks of treatment. CONCLUSION: Our data show a potential for (11)C-erlotinib PET/CT for visualizing NSCLC lung tumours, including lymph nodes not identified by (18)F-FDG PET/CT. Large clinical studies are now needed to explore to which extent pre-treatment (11)C-erlotinib PET/CT can predict erlotinib treatment response.

Forearm and leg amino acid metabolism in the basal state and during combined insulin and amino acid stimulation after a 3-day fast.

AIM: Fasting is characterized by a progressive loss of protein, but data on protein kinetics are unclear and few have studied the effects of re-feeding. The present study was designed to test the hypothesis that a combined infusion of insulin and amino acids after fasting would induce compensatory increases in protein synthesis and reductions in protein breakdown at the whole body level and in muscle. METHODS: We included 10 healthy male volunteers and studied them twice: (1) in the post-absorptive state and (2) after 72 h of fasting. Amino acid kinetics was measured using labelled phenylalanine and tyrosine, whole body energy expenditure was assessed and urea nitrogen synthesis rates were calculated. RESULTS: After fasting we observed an increase in arterial blood concentration of branched chain amino acids and a decrease in gluconeogenic amino acids (P < 0.05). Isotopically determined whole body, forearm and leg phenylalanine fluxes were unaltered apart from a 30% decrease in phenylalanine-to-tyrosine conversion (2.0 vs. 1.4 mumol kg(-1) h(-1), P < 0.01). During infusion of insulin and amino acids, amino acid concentrations increased. CONCLUSION: Our data indicate that after a 72-h fast basal and insulin/amino acid-stimulated regional phenylalanine fluxes in leg and forearm muscle are unaltered. During fasting concentrations of gluconeogenic amino acids decrease and hepatic and/or renal phenylalanine-to-tyrosine conversion decreases. Thus, as opposed to glucose and lipid metabolism, fasting does not induce insulin resistance as regards amino acid metabolism.

FDG-PET improves management of patients with colorectal liver metastases allocated for local treatment: a consecutive prospective study.

BACKGROUND AND AIM: Colorectal cancer is a common cancer in the Nordic countries and 50% of the patients develop liver metastases. Liver resection may result in long term survival. Proper staging is therefore essential and CT is the standard imaging modality. We examined whether additional FDG-PET improves therapeutic management of patients with colorectal liver metastases. PATIENTS AND METHODS: Fifty-four consecutive patients were enrolled. Each patient had a treatment plan made based on our standard evaluation. The patients then had a PET scan and the treatment plan was re-evaluated, taking these results into account. RESULTS: In 76% of the cases, PET did not change the treatment plan due to complete concordance with CT. In another 19% of the cases, the plan was altered due to finding of more liver lesions by PET than by CT (four patients), fewer or no liver lesions (three patients), and extrahepatic lesions not visible on CT (three patients). In 5% of the cases, non-concordance between PET and CT did not change the therapeutic plan. CONCLUSION: Pre-treatment FDG-PET, used supplementary to CT, improved the treatment plan in one fifth of the patients with colorectal liver metastases.

Effects of a 3-day fast on regional lipid and glucose metabolism in human skeletal muscle and adipose tissue.

AIM: Fasting is characterized by increased whole body lipolysis and lipid oxidation, decreased glucose oxidation and insulin resistance. To identify the regional sources and underlying mechanisms, we studied 10 healthy male volunteers post-absorptively and after 72 h of fasting. METHODS: Each study comprised a 3-h basal period and a 3-h hyperinsulinaemic euglycaemic clamp and we used a combination of leg and forearm arteriovenous techniques, upper and lower body microdialysis and glucose and palmitate tracers. RESULTS: In the basal state, plasma levels, fluxes and oxidation rates of free fatty acids all roughly doubled after fasting. Palmitate fluxes across the forearm and leg also increased by two to threefold and interstitial leg muscle glycerol concentrations doubled. Subcutaneous femoral glycerol concentrations and blood flows were unaltered, but abdominal subcutaneous blood flow increased by 50% in the presence of unchanged glycerol concentrations, indicating stimulated abdominal lipolysis. During the clamp, we observed whole body insulin resistance and glucose uptake across the leg and forearm decreased by 60%. CONCLUSION: Our data show that fasting induces insulin resistance in upper and lower body muscles and suggest that increased lipolysis, is primarily due to the activation of lipolysis in muscle-associated fat (in the leg) and in upper body subcutaneous fat, whereas peripheral subcutaneous fat is spared.

A 158 fs 5.3 nJ fiber-laser system at 1 microm using photonic bandgap fibers for dispersion control and pulse compression.

We demonstrate a 158 fs 5.3 nJ mode-locked laser system based on a fiber oscillator, fiber amplifier and fiber compressor. Dispersion compensation in the fiber oscillator was obtained with a solid-core photonic bandgap (SC-PBG) fiber spliced to standard fibers, and external compression is obtained with a hollow-core photonic bandgap (HC-PBG) fiber.

Budd-Chiari and inferior caval vein syndromes due to membranous obstruction of the liver veins: successful treatment with angioplasty and transcaval transjugular intrahepatic porto-systemic shunt.

The case is presented of a 25-year-old Caucasian patient with Budd-Chiari syndrome due to membranous obstruction of the liver veins and inferior caval vein syndrome as a result of secondary hyperplasia of the caudate lobe of the liver, obstructing the caval vein. Diagnosis was established by intravascular pressure measurements, ultrasound examinations and caval and liver vein angiograms. Treatment consisting of stent placement in the outlet of a hepatic vein and subsequent transjugular intrahepatic porto-systemic shunt (TIPS) insertion via the caval vein was successful. After 34 months of follow-up the stents remain open and the patient is symptom free. This successful combination of stent placement and TIPS has not been described before. The case report is followed by a review of the literature on the use of angioplasty in short hepatic vein stenosis and TIPS in Budd-Chiari syndrome. It is concluded that angioplasty and TIPS are safe and efficient procedures to reduce liver engorgement and complications of portal hypertension in selected patients with Budd-Chiari syndrome.

Combined liver vein and spleen pulp pressure measurements in patients with portal or splenic vein thrombosis.

BACKGROUND: Patients with thrombosis of the portal or splenic vein may develop portal hypertension with bleeding from oesophageal or gastric varices. The relevant portal pressure cannot be measured by liver vein catheterization or transhepatic puncture of the portal vein because the obstruction is peripheral to the accessible part of the portal system. METHODS: Liver vein catheterization was combined with percutaneous splenic pressure measurement in 10 patients with portal or splenic vein thrombosis and no cirrhosis, and 10 cirrhotic patients without thrombosis. The splenic pressure was measured by percutaneous puncture below the curvature of the ribs with an angle of the needle to skin of 30 degrees in order to minimize the risk of cutting the spleen if the patient took a deep breath. RESULTS: None of the patients in whom the described procedure was followed had complications. Pressure measurements in the spleen pulp and splenic vein were concordant. The pressure gradient across the portal venous system (splenic-to-wedged hepatic vein pressure) was -1.3 to 8.5 mmHg (median, 2.8 mmHg) in cirrhosis patients and 0-44 mmHg (median, 18 mmHg) in thrombosis patients, the variation reflecting various degrees of obstruction to flow in the portal venous system. Peripheral portal pressure (splenic-to-free liver vein pressure gradient) was 1.1-28 mmHg (median, 17 mmHg) in cirrhotic patients and 11-52 mmHg (median, 23 mmHg) in thrombosis patients. CONCLUSIONS: Liver vein catheterization combined with percutaneous splenic pressure measurement is feasible in quantifying pressure gradient across a thrombosis of the portal/splenic vein and in quantifying portal pressure peripheral to this kind of thrombosis.

Intrahepatic heterogeneity of hepatic venous pressure gradient in human cirrhosis.

BACKGROUND: The hepatic venous pressure gradient (HVPG) is used to evaluate portal hypertension. METHODS: We measured HVPG in two separate liver veins in 169 liver vein catheterizations in 102 cirrhosis patients and in 27 patients with no liver disease (controls). RESULTS: In the controls, the two measurements differed by 0.0 +/- 1.8 mmHg (mean +/- s, n = 27), upper 95% confidence limit 3.6 mmHg (mean + 2 s). HVPG ranged from -0.1 to 8.3 mmHg, upper 95% confidence limit 6.7 mmHg. In cirrhosis, the two measurements agreed within +/- 3.6 mmHg in 39%. In 61%, the measurements differed by 4-34 mmHg. In 35%, fluoroscopy demonstrated hepatic vein-to-hepatic-vein shunting in veins with low HVPG values. In some patients with HVPG measurements above 30 mmHg, Doppler ultrasound examination showed arterialization of the hepatic vasculature. DISCUSSION: Our results demonstrate a hitherto unrecognized notable heterogeneity of the intrahepatic vasculature and HVPG measurements in cirrhosis. The presumption of interposition of non-flowing blood between the catheter tip and the portal system for the measurement of HVPG may thus be violated in about one-third of the cirrhosis cases because of abnormal outlet into hepatic venous shunts and in a minor fraction because of abnormal arterial inlet. In 26%, one measurement was below 12 mmHg, the other measurement above. If the HVPG had been measured in only one liver vein, 13% of the cases would have been classified in a lower risk group than appropriate according to the 12 mmHg concept of risk of bleeding from oesophageal varices.

Positron emission tomography of hepatic first-pass metabolism of ammonia in pig.

Hepatic first-pass metabolism plays a key role in metabolic regulation and drug metabolism. Metabolic processes can be quantified in vivo by positron emission tomography scanning (PET). We wished to develop a PET technique to measure hepatic first-pass metabolism of ammonia. Seven anaesthetised pigs were given positron-labelled ammonia, (13)NH(3), into the portal vein and into the vena cava as successive 2-min infusions followed by 22-min dynamic liver scanning. Vena cava infusion data were used to account for recirculation of tracer and metabolites following the portal vein infusion. The scan data were analysed by a model of sinusoidal zonation of ammonia metabolism with periportal urea formation and perivenous formation of glutamine. The hepatic extraction fraction of (13)NH(3) was 0.73+/-0.16 (mean+/-SD, n=7 pigs). Values of clearance of ammonia to urea and to glutamine were obtained, as were rate constants for washout of these two metabolites. Overall, the modelling showed half of the ammonia uptake to be converted to urea and half to glutamine. The washout rate constant for glutamine was about one-tenth of that for urea. We conclude that hepatic first-pass metabolism of ammonia was successfully assessed by PET.

Metabolites of (18)F-FDG and 3-O-(11)C-methylglucose in pig liver.

UNLABELLED: PET uses (18)F-FDG widely to estimate glucose metabolism in vivo. Dynamic PET data are evaluated by kinetic models of the metabolic pathways. Knowledge of the metabolites of FDG is of critical importance for the interpretation of kinetic PET studies. The purpose of this study was to determine the metabolic pathways of FDG and 3-O-(11)C-methylglucose (MG) in liver tissue in vivo. It is usually assumed that MG is not metabolized and FDG is converted to (18)F-FDG-6-phosphate (FDG-6-P). METHODS: The study was performed on 6 anesthetized 40-kg pigs that were given the 2 tracers intravenously. The content of metabolites was determined in successive liver tissue biopsies. Freeze-clamped liver tissue samples were subjected to extraction by acetonitrile at -5 degrees C to -10 degrees C, and extracts were analyzed by radio-high-performance liquid chromatography (radio-HPLC). The findings were identified by means of radio-HLPC measurements of the products of in vitro enzymatic reactions. RESULTS: The applied extraction technique provided almost quantitative recovery of the radioactivity from tissue. After MG injection, only MG was detectable in the liver tissue; no labeled metabolites were found. After FDG injection, 2 metabolites were identified, FDG-6-P and 2-(18)F-fluoro-2-deoxy-6-phosphogluconate (FD-6-PG1). The tissue content of FDG increased rapidly, and, after 5 min, only FDG was identified; hereafter, the fraction of FDG decreased to approximately 40% of the tissue radioactivity after 180 min. After 20 min, FDG-6-P was found in each of the pigs and it increased throughout the measurement period of 180 min, with a somewhat slower rise at late time points. FD-6-PG1 began to appear in the liver tissue after 45 min and increased throughout the 180-min experiment, with the increase somewhat slower than that of FDG-6-P. After 180 min, approximately 40% of the metabolites was attributed to FD-6-PG1. The content of other metabolites was <2%, even after 180 min. CONCLUSION: After the FDG injection, not only FDG-6-P but also FD-6-PG1 were formed in the liver. Any possible incorporation of FDG into glycogen was of minor importance.

Liver kinetics of glucose analogs measured in pigs by PET: importance of dual-input blood sampling.

UNLABELLED: Metabolic processes studied by PET are quantified traditionally using compartmental models, which relate the time course of the tracer concentration in tissue to that in arterial blood. For liver studies, the use of arterial input may, however, cause systematic errors to the estimated kinetic parameters, because of ignorance of the dual blood supply from the hepatic artery and the portal vein to the liver. METHODS: Six pigs underwent PET after [15O]carbon monoxide inhalation, 3-O-[11C]methylglucose (MG) injection, and [18F]FDG injection. For the glucose scans, PET data were acquired for 90 min. Hepatic arterial and portal venous blood samples and flows were measured during the scan. The dual-input function was calculated as the flow-weighted input. RESULTS: For both MG and FDG, the compartmental analysis using arterial input led to systematic underestimation of the rate constants for rapid blood-tissue exchange. Furthermore, the arterial input led to absurdly low estimates for the extracellular volume compared with the independently measured hepatic blood volume of 0.25 +/- 0.01 mL/mL (milliliter blood per milliliter liver tissue). In contrast, the use of a dual-input function provided parameter estimates that were in agreement with liver physiology. Using the dual-input function, the clearances into the liver cells (K1 = 1.11 +/- 0.11 mL/min/mL for MG; K1 = 1.07 +/- 0.19 mL/min/mL for FDG) were comparable with the liver blood flow (F = 1.02 +/- 0.05 mL/min/mL). As required physiologically, the extracellular volumes estimated using the dual-input function were larger than the hepatic blood volume. The linear Gjedde-Patlak analysis produced parameter estimates that were unaffected by the choice of input function, because this analysis was confined to time scales for which the arterial-input and dual-input functions were very similar. CONCLUSION: Compartmental analysis of MG and FDG kinetics using dynamic PET data requires measurements of dual-input activity concentrations. Using the dual-input function, physiologically reasonable parameter estimates of K1, k2, and Vp were obtained, whereas the use of conventional arterial sampling underestimated these parameters compared with independent measurements of hepatic flow and hepatic blood volume. In contrast, the linear Gjedde-Patlak analysis, being less informative but more robust, gave similar parameter estimates (K, V) with both input functions.

Liver transplantation in patients over 60 years of age.

Liver transplantation was previously only offered to patients under 60 years of age. We have analyzed the outcome after acceptance on the waiting list and after liver transplantation of patients over 60 years old. A total of 150 patients over 60 years old were listed for a first liver transplantation during 1990-1998. The annual number increased throughout the period. Primary biliary cirrhosis, primary sclerosing cholangitis, and acute hepatic failure were the most frequent diagnoses. A total of 119 patients received a first liver allograft. The patient 1-year survival was 75% and 3-year survival 62%, which was not significantly lower (P = 0.21) than that of the younger patients. When correcting for year of transplantation, the survival was, however, moderately but significantly lower than among the younger patients. Survival among those > 65 years (n = 38) did not differ from that of patients 60-65 years of age (n = 81). We conclude that an increasing number of patients over 60 years old can be listed for liver transplantation and receive a liver allograft with highly satisfying results.

Feasibility of detecting hypoxia in experimental mouse tumours with 18F-fluorinated tracers and positron emission tomography--a study evaluating [18F]Fluoro-2-deoxy-D-glucose.

The study was designed to investigate the binding of [18F]Fluoromisonidazole ([18F]FMISO) and [18F]Fluoro-2-deoxy-D-glucose ([18F]FDG) in a C3H mouse mammary carcinoma. Non-anaesthetized tumour-bearing animals breathing either normal air or carbogen (to reduce tumour hypoxia) were examined by PET after tracer injection. Tumours were identified by radioactive labelling and methods of defining regions of interest (ROI) in the tumours were investigated. Reference tissue was selected elsewhere in the mice and the ratio between mean radioactivity in tumour and reference tissue was compared. The results showed a correlation between the methods of identifying ROIs and a significantly lower tumour to reference tissue ratio for carbogen-treated mice compared with controls when using [18F]FMISO. Only one of the methods showed a significant difference in the tumour labelling between treatment groups using [18F]FDG. The study supports the contention that [18F]FMISO may be able to identify hypoxia in tumours, whereas a similar role for [18F]FDG is more doubtful.

Dynamic 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography of liver tumours without blood sampling.

Positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) is a useful diagnostic tool for the detection of tumours. Using dynamic FDG PET, net metabolic clearance of FDG, K, can be calculated by Gjedde-Patlak analysis of the time course of the radioactivity concentrations in tissue and arterial blood. We examined whether time-activity curves (TACs) based on arterial blood sampling could be replaced by TACs obtained from the descending aorta in dynamic PET scans of patients with liver tumours. The study was performed in two parts, using data from dynamic liver scans with arterial blood sampling in human subjects: First, data from four patients with no liver tumours and five patients with liver tumours were used as a training group. Volumes of interest were defined in the descending aorta (aorta VOIs) by four different methods. K values were calculated based on the corresponding TACs and compared with those based on TACs of the arterial blood sample radioactivity concentrations. The aorta VOI which gave K values that were in best agreement with the K values based on the arterial blood sample measurements was called the AORTA-VOI. Use of the AORTA-VOI was subsequently tested in a test group of 19 tumour patients by comparing the K values from the AORTA-VOI with the K values based on the arterial blood sample measurements. The AORTA-VOI consisted of the sum of small regions of interest (ROIs) drawn in the centre of the aorta (approximately six pixels of 2.4x2.4 mm per transaxial slice of 3.1 mm thickness) in as many transaxial slices as possible (30-40 slices). There were no statistically significant differences between the two sets of K values. The ratio of K values in tumour tissue to K values in reference tissue was 2.1-9.7:1 (mean, 5.4:1) based on the AORTA TACs, and 2.1-8.4:1 (mean, 4.6:1) based on blood sample TACs (P>0.3). We conclude that arterial blood sampling can be replaced by the present AORTA-VOI in the calculation of the net metabolic clearance of FDG in dynamic PET studies of liver tumours in human subjects.

Interpretation of simultaneous measurements of hepatic extraction fractions of indocyanine green and sorbitol: evidence of hepatic shunts and capillarization?

Sorbitol and indocyanine green (ICG) have high hepatic extraction fractions (E(sorb) and E(ICG)) in normal subjects. A curved relationship has been observed between E(sorb) and E(ICG) in liver disease. According to one interpretation, the decrease of E(sorb) is a result of intrahepatic shunting and 1 - E(sorb) is the fraction of shunted flow (the shunt hypothesis). Under the further assumption that capillarization of functioning sinusoids prevents hepatic uptake of plasma protein-bound ICG and allows uptake of water-soluble sorbitol, the difference E(sorb) - E(ICG) has been suggested as a measure of capillarization. We propose an alternative hypothesis: that the sinusoidal permeability-surface area products for sorbitol and ICG are reduced in proportion by liver disease (proportional reduction hypothesis). Based on the sinusoidal perfusion model, predictions were produced from both hypotheses for the relation between E(sorb) and E(ICG) and the additional effects of capillarization were described. By use of liver vein catheterization, E(sorb) and E(ICG) were simultaneously measured during continuous infusions in 53 human subjects with varying degrees of liver disease. The data were in better agreement with the predictions of the proportional reduction hypothesis than with the shunt hypothesis. Even though both intrahepatic portosystemic shunts and sinusoidal capillarization are known to occur in cirrhosis and also may have influenced our data, they appeared to be of minor importance from a kinetic point of view. These findings favor the proportional reduction hypothesis and do not support the use of systemic nonrenal clearance of sorbitol as a measure of "functional liver blood flow."

[Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography]. / Detektion af kolangiokarcinom ved primaer skleroserende cholangitis ved hjaelp af positron-emissionstomografi.

Primary sclerosing cholangitis (PSC) predisposes to cholangiocarcinoma (CC). PET scanning can assess metabolism in vivo. The glucose analogue [18 F]fluoro-2-deoxy-D-glucose (FDG) accumulates in malignant tumours because of high glucose metabolism. PET scanning of the liver was performed after intravenous FDG in nine patients with PSC, six with PSC + CC, and five controls. "Hot spots" with radioactivity accumulation were seen in each PSC + CC patient, but not in the two other groups. Values of net metabolic clearance of FDG, K (ml min-1 100 ml-1 tissue), was in CC hot spots 1.59 to 4.17 (median, 2.34; n = 6); in reference liver tissues of these patients 0.40 to 0.69 (0.49); in PSC 0.23 to 0.53 (0.36); in controls 0.20 to 0.34 (0.31). The difference between K in CC hot spots and the other groups was statistically significant (P < 0.001). FDG-PET may detect small CC tumours and be useful in therapeutic management of PSC.

Far-infrared properties of DAST.

Using terahertz time-domain spectroscopy, we have measured the index of refraction and the absorption coefficient of the organic ionic salt 4-N, N-dimethylamino-4?-N?-methyl-stilbazolium tosylate (DAST). This promising organic electro-optic material exhibits strong absorption and dispersion for frequencies above 1 THz at both room temperature and 83 K. No reduction in the absorption strength is observed when DAST is cooled, suggesting a single-phonon origin of the resonances. A simple vibration of the anion and cation of the salt is suggested as the origin of the exceptionally strong far-infrared absorption and the high-frequency electro-optic properties of DAST.