Inhibition of carnitine-acyl transferase I by oxfenicine studied in vivo with [11C]-labeled fatty acids

METHODS: Anesthetized pigs were studied with [(11)C]-labeled fatty acids (FAs) with carbon chain length ranging from 8 to 16 carbon atoms, during control conditions and during inhibition of carnitine-palmitoyl transferase I (CPT I) with oxfenicine. The myocardial uptake of [(11)C]-FAs from blood was measured together with the relative distribution of [(11)C]-acyl-CoA between rapid mitochondrial oxidation and incorporation into slow turnover lipid pools in the heart. RESULTS: During baseline conditions, the fractional oxidative utilization of palmitate was almost as high as that of carnitine-independent short-chain FAs, unless the carnitine shuttle was inhibited by high levels of lactate. Inhibition of CPT I almost completely blocked the oxidative pathway for palmitic acid and reduced the fractional oxidative utilization, while the rate of oxidative metabolism of acyl-CoA was unaffected. CONCLUSIONS: [(11)C]-Labeled FAs allow rapid oxidation to be well separated from esterification into slow turnover lipid pools in the heart of anaesthetized pigs. The fractional oxidative utilization of [(11)C]-palmitate serves well to characterize, in vivo, the carnitine-dependent transfer of long-chain FAs.     

Impaired cerebral glucose metabolism and cognitive functioning predict deterioration in mild cognitive impairment

The objective of this study was to assess whether reduced glucose metabolism (rCMRGlu) and cognitive functioning could predict development of Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Twenty MCI patients underwent baseline and follow-up investigations of rCMRGlu, as measured by PET, and cognitive function measured by neuropsychological test assessments. Subjects were clinically followed up with an average interval of 36.5 months. Two groups were obtained after the second clinical assessment. Nine patients were diagnosed as AD and classified as progressive MCI (P-MCI), whereas 11 patients remained clinically stable and were classified as stable MCI (S-MCI). There were no differences in demographic variables or baseline MMSE between the two subgroups. Logistic regression indicated the two variables that most effectively predicted future development of AD were rCMRGlu from the left temporoparietal area and performance on the block design. These combined measures gave an optimal 90% correct classification rate, whereas only rCMRGlu or neuropsychology alone gave 75% and 65% correct classification, respectively. Measures of temporoparietal cerebral metabolism and visuospatial function may aid in predicting the evolution to AD for patients with MCI.     

Regional cerebral blood flow and oxygen metabolism during migraine with and without aura

Eleven cases of migraine with and without aura were investigated with positron emission tomography (PET). Regional cerebral blood flow (rCBF), oxygen metabolism (rCMRO₂) and oxygen extraction (rOER) were measured during baseline ( n =11), aura ( n = 6), headache ( n = 10) and after treatment with sumatriptan ( n = 4). Data were analysed using and ROI-based approach from 26 different anatomically defined regions, and also an exploratory approach whereby all subjects were normalized to a stereotactic brain atlas; t -maps were constructed by depicting significant changes between states. The exploratory approach revealed a region corresponding to the primary visual cortex with significant reductions in rCBF (23.1%) and rCMRO₂ (22.5%), but no change in rOER during the headache phase compared to baseline. These data suggest that cerebral ischemia was not the primary cause of the attacks in these cases.     

Glucose utilisation in the lungs of septic rats

Sequestration and degranulation of leucocytes in the pulmonary microcirculation is considered to be a key event in the development of acute respiratory distress syndrome in patients with sepsis. Glucose serves as the main source of energy in activated leucocytes. The aim of this study was to assess whether glucose utilisation in the lungs can be used as an indicator of pulmonary leucocyte accumulation in an experimental model of sepsis of intra-abdominal origin. Sepsis was induced in rats by abdominal implantation of a gelatine capsule containing bacteria and rat colonic contents. Empty gelatine capsules were implanted in control animals. Animals were studied 6 and 12 h after sepsis induction. Glucose utilisation was measured as the tissue uptake of fluorine-18-fluorodeoxyglucose (¹⁸FDG) 1 h after intravenous injection of the tracer. Micro-autoradiography was also performed after injection of tritiated deoxyglucose. We found increased uptake of ¹⁸FDG in the lungs of septic animals. The uptake also increased with time after sepsis induction. ¹⁸FDG uptake in circulating leucocytes was increased in septic animals compared with controls, and micro-autoradiography showed intense accumulation of deoxyglucose in leucocytes in the lungs of septic animals. We conclude that glucose utilisation is increased in the lungs of septic rats. Measurements of pulmonary glucose utilisation as an index of leucocyte metabolic activity may open new possibilities for studies of the pathophysiology of sepsis and for evaluation of therapeutic interventions. Received 15 February and in revised form 28 April 1999     

Do organic solvents induce changes in the dopaminergic system? Positron emission tomography studies of occupationally exposed subjects

Objectives: The objective of this study was to test the hypothesis that long-term occupational exposure to organic solvents may effect the levels and turnover of dopamine in man. Methods: A study was performed on 17 patients with neuropsychiatric symptoms due to occupational solvent exposure, and 11 healthy non-exposed male volunteers (controls). Positron emission tomography (PET) was used to assess striatal dopaminergic function, using l-[¹¹C]DOPA, [¹¹C]nomifensine and [¹¹C]raclopride as tracers. Results: The rate of dopamine synthesis was significantly increased among subjects with occupational exposure to organic solvents compared with non-exposed controls. After controlling for the difference in age between exposed and controls, the effect of solvent exposure became less apparent and was reduced from +32% (P = 0.009) to +25% (P = 0.07). There were no differences with regard to the binding of [¹¹C]nomifensine. Patients with and without the diagnosis of toxic encephalopathy did not differ with regard to their putaminal uptake of l-[¹¹C]DOPA, [¹¹C]nomifensine and [¹¹C]raclopride. Conclusion: The data support the hypothesis that long-term exposure to organic solvents may increase the rate of dopamine synthesis in the brain without affecting the number of presynaptic terminals or postsynaptic dopamine receptors. Received: 8 October 1996 / Accepted: 7 February 1997     

Error analysis of combined measurements of regional ventilation and V/Q ratio using positron emission tomography.

We measured the regional pulmonary ventilation/perfusion ratio with intravenous 13N in saline solution, using positron emission tomography, in eight normal healthy volunteers, 10 patients with asthma and 10 patients with chronic obstructive pulmonary disease. Regional pulmonary ventilation was also measured with 19Ne, and this information was used to (i) correct ventilation/perfusion ratios obtained with 13N in regions with impaired ventilation and (ii) calculate regional perfusion, Q. In this paper we analyse the errors inherent in these measurements. Dead space ventilation and focal inhomogeneities in ventilation and/or blood flow will affect the transport of both 19Ne and 13N, but in different ways. Combining the two methods, values of blood flow obtained tend to overestimate Q in normal supine subjects by some 6% in the non-dependent part of the lung and to underestimate Q by a similar amount in the dependent part. In patients with air flow obstruction, blood flow is underestimated in regions with low ventilation/perfusion ratios and overestimated in regions with high ventilation/perfusion ratios. In the groups of patients studied, errors may reach a level of 10-20%. The limitations of the method in regions with extensive gas flow and/or blood flow heterogeneities are discussed on a theoretical basis and in some extreme conditions blood flow may be overestimated by a factor of two to three.     

Glucose utilisation in the lungs of septic rats.

Sequestration and degranulation of leucocytes in the pulmonary microcirculation is considered to be a key event in the development of acute respiratory distress syndrome in patients with sepsis. Glucose serves as the main source of energy in activated leucocytes. The aim of this study was to assess whether glucose utilisation in the lungs can be used as an indicator of pulmonary leucocyte accumulation in an experimental model of sepsis of intra-abdominal origin. Sepsis was induced in rats by abdominal implantation of a gelatine capsule containing bacteria and rat colonic contents. Empty gelatine capsules were implanted in control animals. Animals were studied 6 and 12 h after sepsis induction. Glucose utilisation was measured as the tissue uptake of fluorine-18-fluorodeoxyglucose ((18)FDG) 1 h after intravenous injection of the tracer. Micro-autoradiography was also performed after injection of tritiated deoxyglucose. We found increased uptake of (18)FDG in the lungs of septic animals. The uptake also increased with time after sepsis induction. (18)FDG uptake in circulating leucocytes was increased in septic animals compared with controls, and micro-autoradiography showed intense accumulation of deoxyglucose in leucocytes in the lungs of septic animals. We conclude that glucose utilisation is increased in the lungs of septic rats. Measurements of pulmonary glucose utilisation as an index of leucocyte metabolic activity may open new possibilities for studies of the pathophysiology of sepsis and for evaluation of therapeutic interventions.     

Regional V˙A/Q˙ ratios in man using 133Xe and single photon emission computed tomography (SPECT) corrected for attenuation

We describe a technique to obtain non-invasively regional pulmonary ventilation–perfusion ratios (V˙_A/Q˙) using single photon emission computed tomography (SPECT) and continuous infusion of ¹³³Xe. Single photon transmission tomography was used for attenuation correction, for delineation of the lungs and for V˙_A/Q˙ calculations. Data are presented for six normal subjects and compared to those for two patients with moderate chronic obstructive pulmonary disease (COPD). The mean V˙_A/Q˙ for the whole lung of the normal subjects ranged from 0·49 to 0·65, group mean 0·56 ± 0·07 (1 SD), and there was no significant difference between the right and left lung. The consistently too low V˙_A/Q˙ values are related to the inability to measure regional blood volume and the low resolution of the scintillation camera, giving an under-estimation of tracer input. For the normal subjects, the dispersion of V˙_A/Q˙, as defined by the standard deviation of the individual distribution functions, ranged from 0·12 to 0·19. One of the patients was characterized by a low mean V˙_A/Q˙ of 0·35, and the other patient had a wide dispersion (SD) of V˙_A/Q˙ of 0·37. In the normal subjects, a consistent V˙_A/Q˙ gradient was found only in the ventrodorsal direction. ¹³³Xe and SPECT can be used to obtain meaningful biological information regarding ventilation/perfusion relationships of potential clinical value.     

Contribution of the positron camera to studies of regional lung structure and function

Positron emission tomography is a major technological advance in the characterisation of structure-function relationships within and between regions in normal and abnormal lungs (Hughes et al. 1985). The measurements are noninvasive and relatively exact since the geometric conditions are precisely defined. Regional expansion, flow (ventilation, perfusion), oxygen concentration (from \({{\dot V_{\text{A}} } \mathord{\left/ {\vphantom {{\dot V_{\text{A}} } {\dot Q}}} \right. \kern-\nulldelimiterspace} {\dot Q}}\)) and glucose metabolism can be measured in absolute terms per cubic centimetre of thorax or per gram of extravascular lung. Examples of structure-function relationships in normal subjects, emphysema, bronchitis and sarcoidosis are briefly presented.