[Adherent Perinephric Fat: a prognosis and influence of perioperative results of organ-sparing procedures in localized kidney parenchyma tumors].

The results of recently published articles on the etiology and pathogenesis of "Adherent Perinephric Fat" (APF) are presented in the review. The current possibilities for predicting the presence of APF based on clinical data and imaging methods are highlighted, as well as the to an influence of ARF on perioperative results of organ-sparing procedures using various surgical approaches in patients with localized kidney parenchyma tumors.

Comparative impact of standard approach, FDG PET and FDG dual-head coincidence gamma camera imaging in preoperative staging of patients with non-small-cell lung cancer.

We prospectively compared the impact of the standard approach, of fluorodeoxyglucose positron emission tomography (FDG PET) and of FDG dual-head coincidence gamma camera imaging (DHC) in preoperative staging of patients with non-small-cell lung cancer (NSCLC). In addition to traditional staging, 42 patients were studied with a PET system and a DHC system. The number of lesions detected on DHC and on PET were compared independently of the proof of a tumoural invasion. Then, for the sub-group of lesions with the proof of a tumoural invasion, the sensitivity of the different imaging modalities was compared. Finally, stagings were compared with final staging established by histopathological findings (n=28), additional imaging modalities (n=4), clinical and traditional imaging follow-up over at least 4 months. DHC detected 105 of the 145 lesions considered as pathological on PET (73%, P=0.01), with a concurrence of 89% (NS) in lesions larger than 1.5 cm, and only 17% (P=0.03) in those smaller or equal to 1 cm. Traditional staging detected 87 of the 114 verified tumoural lesions (76%), PET 110/114 (96%, P=0.01 vs traditional staging), DHC 88/114 (77%, NS vs traditional staging, P=0.01 vs PET). PET correctly predicted the N stage in 39/42 (93%) patients, DHC in 38/42 (90%), and computed tomography in 32/42 (76%). PET correctly predicted the M stage in 42/42 (100%) patients, DHC in 41/42 (98%), and traditional staging in 38/42 (90%). Identical NM staging was obtained with DHC and PET in 38/42 (90%) patients. Compared to traditional NM staging, PET correctly up-staged 9/42 (21%) patients and down-staged 3/42 (7%), with one additional false N up-staging. DHC correctly up-staged 7/42 (17%) patients and down-staged 3/42 (7%), with one additional false N down-staging. PET correctly reclassified 4/42 (9.5%) patients from resectable to unresectable and incorrectly reclassified one. DHC correctly reclassified 3/42 (7%) patients without false therapeutic reclassification. Although DHC detected fewer lesions than PET, DHC is a possible alternative to PET since the impact on staging was high as compared with traditional staging and was very similar to that of PET.

In vivo detection of striatal dopamine release during reward: a PET study with [(11)C]raclopride and a single dynamic scan approach.

A new simple method is proposed to detect, using PET and [(11)C]raclopride, changes in striatal extracellular dopamine concentration during a rewarded effortful task. This approach aimed to increase the sensitivity in detection of these effects. It requires a single-dynamic PET study and combines the classic kinetic compartmental model with the general linear model of SPM to provide statistical inference on changes in [(11)C]raclopride time-activity curve due to endogenous dopamine release during two short periods of activation. Kinetic simulations predicted that 100% dopamine increase during two 5-min periods starting at 30 and 60 min after the injection can be detected. Moreover the effects of dopamine release on the [(11)C]raclopride time-activity-curve are different from those induced by CBF increase. These simulated curves were used to construct the statistical linear model and to test voxel-by-voxel in healthy subjects the hypothesis that dopamine is released in the ventral striatum during periods of unexpected monetary gains, but not during periods of unexpected monetary loss. The experimental results are in line with the expected results although the amplitude of the effects due to dopamine release is moderate. The advantages and the limits of this method as well as the relevance of the results for dopamine involvement in reward processing are discussed.

Myocardial muscarinic receptor upregulation and normal response to isoproterenol in denervated hearts by familial amyloid polyneuropathy.

BACKGROUND: Patients with familial amyloid polyneuropathy, a rare hereditary form of amyloidosis, have progressive autonomic neuropathy. The disease usually does not induce heart failure but is associated with sudden death, conduction disturbances, and an increased risk of complications during anesthesia. Although cardiac sympathetic denervation has been clearly demonstrated, the postsynaptic status of the cardiac autonomic nervous system remains unelucidated. METHODS AND RESULTS: Twenty-one patients were studied (age, 39+/-11 years; normal coronary arteries; left ventricular ejection fraction 68+/-9%). To evaluate the density and affinity constants of myocardial muscarinic receptors, PET with (11)C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, was used. Cardiac beta-receptor functional efficiency was studied by the heart rate (HR) response to intravenous infusion of isoproterenol (5 minutes after 2 mg of atropine, 5, 10, and 15 ng/kg per minute during 5 minutes per step). The mean muscarinic receptor density was higher in patients than in control subjects (B'(max), 35.5+/-8.9 versus 26.1+/-6.7 pmol/mL, P=0.003), without change in receptor affinity. The increase in HR after injection of atropine as well as of MQNB was lower in patients compared with control subjects despite a similar basal HR (DeltaHR after atropine, 11+/-21% versus 62+/-17%; P<0.001), consistent with parasympathetic denervation. Incremental infusion of isoproterenol induced a similar increase in HR in patients and control subjects. CONCLUSIONS: Cardiac autonomic denervation in familial amyloid polyneuropathy results in an upregulation of myocardial muscarinic receptors but without change in cardiac beta-receptor responsiveness to catecholamines.

Validation of myocardial perfusion reserve measurements using regularized factor images of H(2)(15)O dynamic PET scans.

UNLABELLED: The use of H(2)(15)O PET scans for the measurement of myocardial perfusion reserve (MPR) has been validated in both animal models and humans. Nevertheless, this protocol requires cumbersome acquisitions such as C(15)O inhalation or (18)F-FDG injection to obtain images suitable for determining myocardial regions of interest. Regularized factor analysis is an alternative method proposed to define myocardial contours directly from H(2)(15)O studies without any C(15)O or FDG scan. The study validates this method by comparing the MPR obtained by the regularized factor analysis with the coronary flow reserve (CFR) obtained by intracoronary Doppler as well as with the MPR obtained by an FDG acquisition. METHODS: Ten healthy volunteers and 10 patients with ischemic cardiopathy or idiopathic dilated cardiomyopathy were investigated. The CFR of patients was measured sonographically using a Doppler catheter tip placed into the proximal left anterior descending artery. The mean velocity was recorded at baseline and after dipyridamole administration. All subjects underwent PET imaging, including 2 H(2)(15)O myocardial perfusion studies at baseline and after dipyridamole infusion, followed by an FDG acquisition. Dynamic H(2)(15)O scans were processed by regularized factor analysis. Left ventricular cavity and anteroseptal myocardial regions of interest were drawn independently on regularized factor images and on FDG images. Myocardial blood flow (MBF) and MPR were estimated by fitting the H(2)(15)O time-activity curves with a compartmental model. RESULTS: In patients, no significant difference was observed among the 3 methods of measurement-Doppler CFR, 1.73 +/- 0.57; regularized factor analysis MPR, 1.71 +/- 0.68; FDG MPR, 1.83 +/- 0.49-using a Friedman 2-way ANOVA by ranks. MPR measured with the regularized factor images correlated significantly with CFR (y = 1.17x - 0.30; r = 0.97). In the global population, the regularized factor analysis MPR and FDG MPR correlated strongly (y = 0.99x; r = 0.93). Interoperator repeatability on regularized factor images was 0.126 mL/min/g for rest MBF, 0.38 mL/min/g for stress MBF, and 0.34 for MPR (19% of mean MPR). CONCLUSION: Regularized factor analysis provides well-defined myocardial images from H(2)(15)O dynamic scans, permitting an accurate and simple measurement of MPR. The method reduces exposure to radiation and examination time and lowers the cost of MPR protocols using a PET scanner.

Parametric images of the extrastriatal D2 receptor density obtained using a high-affinity ligand (FLB 457) and a double-saturation method.

The potential of positron emission tomography for the quantitative estimation of receptor concentration in extrastriatal regions has been limited in the past because of the low density of the D2 receptor sites in these regions and the insufficient affinity of the most widely used radioligands for dopamine receptors. The new method described in this paper permits the estimate of the D2 receptor concentration in the extrastriatal regions using a two-injection protocol and FLB 457, a ligand with a high affinity (20 pmol/L in vitro ) with D2 dopamine receptors. This approach is not valid for the striatal regions because some hypotheses cannot be verified (because of the high receptor concentration in these regions). The experimental protocol includes two injections with ligand doses designed to significantly occupy the extrastriatal receptor sites (approximately 90%), while leaving less than 60% of the receptor sites occupied by the ligand in the striatal regions. The results obtained using this double-saturation method are in line with the concentration estimates previously obtained using the multiinjection approach. The receptor concentration is 2.9 +/- 0.5 pmol/mL in the thalamus, 1.0 +/- 0.2 pmol/mL in the temporal cortex, and 0.35 +/- 0.13 pmol/mL in the occipital cortex. This study provides new arguments supporting the presence of a small receptor-site concentration in the cerebellum, estimated at 0.35 +/- 0.16 pmol/mL The simplicity of the calculation used to estimate the receptor concentration lends itself easily to parametric imaging. The receptor concentration is estimated pixel by pixel, without filtering. This method permits estimation of the extrastriatal D2 receptor concentration using an experimental protocol that can easily be used in patient studies (i.e., single experiment, no blood sampling, short experiment duration).

Clinical impact of (18)F-FDG PET in thyroid carcinoma patients with elevated thyroglobulin levels and negative (131)I scanning results after therapy.

UNLABELLED: 18F-FDG PET has been shown to effectively detect differentiated thyroid carcinoma (DTC) metastases with impaired iodine-trapping ability. This article evaluates the potential contribution of FDG PET in the follow-up of patients with differentiated thyroid carcinoma, elevated thyroglobulin (Tg) levels, and negative whole-body scan results obtained after high doses of (131)I. METHODS: We prospectively assessed the ability of FDG to detect metastases in 37 DTC patients who had undergone total thyroidectomy and radioactive ablation and presented with persistent disease, as assessed from elevated Tg levels and negative results of whole-body scans performed after therapeutic doses of (131)I. Additional conventional imaging procedures were performed to detect residual disease, and the patients were divided into 2 groups: group 1, with positive conventional imaging findings (n = 10), and group 2, with negative conventional imaging findings (n = 27). RESULTS: FDG PET showed positive findings in 28 patients and accurately localized tumor sites in 89% of them. In group 1, FDG PET confirmed 17 of 18 previously known tumor sites and detected 11 additional sites. In group 2, FDG PET findings were positive in 19 of 27 patients with no previously detected metastases. PET was effective for both low- and high-stage tumors. The FDG data led to a change in the clinical management of 29 of 37 patients with further surgical resection in 23 patients, 14 of whom achieved disease-free status, and external radiation therapy in 4 patients. CONCLUSION: FDG PET is able to detect metastases undetected by (131)I posttherapy whole-body scanning in patients with elevated Tg levels. It should be proposed as a first-line investigation in patients with persistent disease but negative findings on (131)I whole-body scans after treatment.

Impaired cardiac adrenergic innervation assessed by MIBG imaging as a predictor of treatment response in childhood dilated cardiomyopathy.

OBJECTIVE: To evaluate the prognostic value of metaiodobenzylguanidine (MIBG) imaging in childhood cardiomyopathy. DESIGN: Prospective cohort study. SETTING: Tertiary referral centre. PATIENTS: 40 children (21 boys, 19 girls; mean (SD) age, 7.0 (5.6) years) with heart failure resulting from idiopathic dilated cardiomyopathy (n = 23) or various other disorders (n = 17). METHODS: At the initial examination, cardiac (123)I-MIBG uptake and release, circulating noradrenaline (norepinephrine) concentration, x ray cardiothoracic ratio, and echocardiographic variables were recorded. Cardiac MIBG uptake was obtained by measuring the heart to mediastinum activity ratio on the planar image obtained four hours after MIBG injection. MIBG washout rate was evaluated using relative decrease in cardiac activity measured at 20 minutes and four hours. Patients were treated with angiotensin converting enzyme inhibitors, diuretics, and digitalis, and were followed up for 12 (10) months. Fifteen patients did not respond to medical treatment (12 heart transplants; three deaths), and 25 did respond (improved or stable). RESULTS: Cardiac MIBG uptake was positively correlated with x ray cardiothoracic index (r = 0.55, p = 0.0008) and echocardiographic left ventricular fractional shortening (r = 0.68, p < 0.0001). Among all the clinical and laboratory variables tested, multivariate discriminant analysis showed that the only independent predictor of an unfavourable outcome was a low MIBG uptake (p < 0.001). Survival curves had a mean threshold value of 1.54 for MIBG uptake. CONCLUSIONS: Impaired cardiac adrenergic innervation is strongly related to adverse outcome in children with dilated cardiomyopathy, independently of the aetiology. MIBG imaging may help to stratify risk in such patients.

Absolute quantification by positron emission tomography of the endogenous ligand.

The results of several recent papers have shown a significant influence of the endogenous neurotransmitters on the exogenous ligand kinetics measured by positron emission tomography. For example, several groups found that the percentage of D2 receptor sites occupied by the endogenous dopamine ranged from 25% to 40% at basal level. An obvious consequence of this significant occupancy is that the ligand-receptor model parameters, usually estimated by a model that does not take into account the endogenous ligand (EL) kinetics, can be significantly biased. In the current work, the authors studied the biases obtained by using the multiinjection approach. The results showed that in the classical ligand-receptor model, the receptor concentration is correctly estimated and that only the apparent affinity is biased by not taking the EL into account. At present, all absolute quantifications of the EL have been obtained through pharmacologic manipulation of the endogenous transmitter concentration, which is often too invasive a method to be used in patients. A theoretical reasoning showed that a noninvasive approach is necessarily based on both the apparent affinity measurement and on a multiregion approach. The correlation between the receptor concentration and the apparent affinity, previously observed with some ligands, verifies these two conditions; thus, the authors suggest that this correlation could be the result of the EL effect. To test this assumption experimentally, the effect of reserpine-induced dopamine depletion on the interactions between the D2 receptor sites and the FLB 457 is studied. With untreated baboons, the apparent FLB 457 affinity was smaller in the receptor-rich regions (striatum) than in the receptor-poor regions. This discrepancy disappeared after dopamine depletion, strongly suggesting that this affinity difference was related to the EL effect. Therefore, the purpose of the current study was to test the ability to quantify the EL based on the observed correlation between the receptor concentration and the apparent affinity. This approach offers a method for estimating the percentage of receptor sites occupied by the EL and, if its affinity is known, the free EL concentration. From the data obtained using FLB 457 with baboons, the authors found that approximately 53% of the D2 receptor sites are occupied by dopamine in the striatum and that the free dopamine concentration is approximately 120 nmol/L at basal level. This approach is transferable to patients, because the experimental data are obtained without pharmacologically induced modification of the EL.

Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK1195.

Using quantitative PET, the authors studied the binding of [11C]PK11195, a marker of activated microglia, in the thalamus of patients with chronic middle cerebral artery infarcts. All patients showed increased [11C]PK11195 binding in the ipsilateral thalamus, indicating the activation of microglia in degenerating projection areas remote from the primary lesion. A persistent increase in [11C]PK11195 binding suggests active, long-term thalamic microstructural changes after corticothalamic connection damage.

[Fluorodeoxyglucose (FDO) positron emission tomography (PET) in testicular germ cell tumors in adults: preliminary French clinical evaluation, development of the technique and its clinical applications]. / Tomographie à émission de positons (T.E.P.) au fluorodéoxyglucose (F.D.G.) dans les tumeurs germinales testiculaires de l'adulte: première évaluation clinique française, mise au point sur la technique et ses applications cliniques.

OBJECTIVES: Metabolic positron emission tomography (PET) is a new imaging modality for the detection of tumours, which uses fluorodeoxyglucose (FDG) to demonstrate increased carbohydrate metabolism of malignant cells. The management of testicular germ cell tumours in adults raises three clinical problems poorly resolved by conventional imaging techniques: identification of suspected recurrences in a context of elevated circulating serum markers, initial staging assessment after orchidectomy, evaluation of the response to treatment. MATERIAL AND METHODS: The authors report the data obtained in 16 patients (6 cases of seminoma and 10 cases of non seminomatous germ cell tumour [NSGCT]), investigated in the Frédéric-Joliot Department using a dedicated PET camera, 60 minutes after intravenous injection of 270 MBq of FDG. RESULTS: In 9 cases of assessment of elevated serum markers with no tumour identified by conventional examinations, PET demonstrated images likely to correspond to tumour sites in 7 patients (5 true-positives [TP] and 2 false-positives [FP] due to postoperative inflammatory changes). PET was negative in 2 out of 9 patients, in whom subsequent follow-up showed spontaneous but delayed return to normal of tumour markers. In 3 of the 4 cases of initial staging of the disease, PET excluded an extension suspected by conventional imaging and the 4th case was a FP for PET. In 3 cases of evaluation of the response to treatment, PET concluded on the absence of viable residual tumour mass, with a false-negative result in one case. CONCLUSIONS: These results are in line with those reported in the literature, which emphasize the diagnostic difficulties encountered in this disease. The significant contribution of FDG-PET should be confirmed by larger series of patients investigated by this new modality.

Prognostic value of MIBG imaging in idiopathic dilated cardiomyopathy.

UNLABELLED: Alterations of cardiac sympathetic innervation are likely to contribute to fatal outcomes in patients with heart failure. These alterations can be evaluated noninvasively by 123I-metaiodoben-zylguanidine (MIBG) imaging. METHODS: The hypothesis that impaired cardiac sympathetic innervation, as assessed using MIBG imaging, is related to adverse outcomes was tested in 112 patients with heart failure resulting from idiopathic cardiomyopathy. Main inclusion criteria were New York Heart Association classes II-IV and radionuclide left ventricular ejection fraction (LVEF) < 40%. Patients were assessed for cardiac MIBG uptake, circulating norepinephrine concentration, LVEF, peak Vo2, x-ray cardiothoracic ratio, M-mode echographic end-diastolic diameter and right-sided heart catheterization parameters. RESULTS: During a mean follow-up of 27 +/- 20 mo, 19 patients had transplants, 25 died of cardiac death (8 sudden deaths), 2 died of noncardiac death and 66 survived without transplantation. The only independent predictors for mortality were low MIBG uptake (P < 0.001) and LVEF (P = 0.02) when using multivariate discriminant analysis. Moreover, MIBG uptake (P < 0.001) and circulating norepinephrine concentration (P = 0.001) were the only independent predictors for life duration when using multivariate life table analysis. CONCLUSION: Impaired cardiac adrenergic innervation as assessed by MIBG imaging is strongly related to mortality. MIBG imaging may help risk stratify patients with heart failure resulting from idiopathic dilated cardiomyopathy.

Quantitation of extrastriatal D2 receptors using a very high-affinity ligand (FLB 457) and the multi-injection approach.

The multi-injection approach has been used to study in baboon the in vivo interactions between the D2 receptor sites and FLB 457, a ligand with a very high affinity for these receptors. The model structure was composed of four compartments (plasma, free ligand, and specifically and unspecifically bound ligands) and seven parameters (including the D2 receptor site density). The arterial plasma concentration, after correction for metabolites, was used as the input function. The experimental protocol, which consisted of three injections of labeled and/or unlabeled ligand, allowed the evaluation of all model parameters from a single positron emission tomography experiment. In particular, the concentration of receptor sites available for binding (B'max) and the apparent in vivo FLB 457 affinity were estimated in seven brain regions, including the cerebellum and several cortex regions, in which these parameters are estimated in vivo for the first time (B'max is estimated to be 4.0+/-1.3 pmol/mL in the thalamus and from 0.32 to 1.90 pmol/mL in the cortex). A low receptor density was found in the cerebellum (B'max = 0.39+/-0.17 pmol/mL), whereas the cerebellum is usually used as a reference region assumed to be devoid of D2 receptor sites. In spite of this very small concentration (1% of the striatal concentration), and because of the high affinity of the ligand, we demonstrated that after a tracer injection, most of the PET-measured radioactivity in the cerebellum results from the labeled ligand bound to receptor sites. The estimation of all the model parameters allowed simulations that led to a precise knowledge of the FLB 457 kinetics in all brain regions and gave the possibility of testing the equilibrium hypotheses and estimating the biases introduced by the usual simplified approaches.

Sympathetic nerve alterations assessed with 123I-MIBG in the failing human heart.

UNLABELLED: Norepinephrine (NE) reuptake function is impaired in heart failure and this may participate in myocyte hyperstimulation by the neurotransmitter. This alteration can be assessed by 123I-metaiodobenzylguanidine (MIBG) scintigraphy. METHODS: To determine whether the impairment of neuronal NE reuptake was reversible after metoprolol therapy, we studied 18 patients (43+/-7 y) with idiopathic dilated cardiomyopathy who were stabilized at least for 3 mo with captopril and diuretics. Patients underwent, before and after 6 mo of therapy with metoprolol, measurements of radionuclide left ventricular ejection fraction (LVEF), maximal oxygen consumption and plasma NE concentration. The cardiac adrenergic innervation function was scintigraphically assessed with MIBG uptake and release measurements on the planar images obtained 20 min and 4 h after tracer injection. To evaluate whether metoprolol had a direct interaction with cardiac MIBG uptake and release, six normal subjects were studied before and after a 1-mo metoprolol intake. RESULTS: In controls, neither cardiac MIBG uptake and release nor circulating NE concentration changed after the 1-mo metoprolol intake. Conversely, after a 6-mo therapy with metoprolol, patients showed increased cardiac MIBG uptake (129%+/-10% versus 138%+/-17%; P = 0.009), unchanged cardiac MIBG release and decreased plasma NE concentration (0.930+/-412 versus 0.721+/-0.370 ng/mL; P = 0.02). In parallel, patients showed improved New York Heart Association class (2.44+/-0.51 versus 2.05+/-0.23; P = 0.004) and increased LVEF (20%+/-8% versus 27%+/-8%; P = 0.0005), whereas maximal oxygen uptake remained unchanged. CONCLUSION: Thus, a parallel improvement of myocardial NE reuptake and of hemodynamics was observed after a 6-mo metoprolol therapy, suggesting that such agents may be beneficial in heart failure by directly protecting the myocardium against excessive NE stimulation.

The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine.

BACKGROUND: Changes in serotonin (5-HT)2 receptor densities were reported in depression by postmortem studies and following treatment with tricyclic antidepressants in animal studies. Here, 5-HT2 receptors were studied in vivo in depressed patients. METHODS: Cortical 5-HT2 receptors were investigated prospectively using positron-emission tomography and [18F]-setoperone in 7 depressed patients, before and after at least 3 weeks of clomipramine (CMI), 150 mg daily. They were compared to 7 age-matched controls. RESULTS: There was no significant difference between the untreated patients and the controls, except in the frontal region, where the [18F]-setoperone specific binding was slightly lower in patients. After CMI treatment, depression scores significantly improved and [18F]-setoperone specific binding decreased in cortical regions, suggesting receptor occupancy and/or receptor regulation, by CMI; however, no clinical score correlated with the 5-HT2 receptor measurements either in the untreated or in the treated conditions. CONCLUSIONS: These data substantiate the view that tricyclic antidepressants such as clomipramine significantly interact with cortical 5-HT2 serotoninergic receptors in actual therapeutic situations.

[Fluorodeoxyglucose and bronchopulmonary cancer. Initial French results with positron emission tomography]. / Fluoro-déoxy-glucose et cancer bronchopulmonaire. Les premiers résultats français en caméra à positons.

Despite recent advances, the contribution of medical imaging techniques is limited, particularly in terms of tissue characterization, in the diagnosis of pulmonary nodules and search for extension of bronchogenic cancer. The metabolic properties of the glucose analog deoxyglucose labeled with 18F1 would allow metabolic imaging. Positron emission tomography (PET) provides clinicians with quality images with an interesting sensitivity. We report the results of a feasibility study conducted in our first 17 patients. We observed 14 true positives, 1 true negative and 1 false positive and 1 false negative in patients with a malignant primary lesion. We analyzed the causes of error. Ten disseminated localizations were identified. Possible developments in terms of therapeutic strategy are discussed. The agreement between our findings and data reported in the literature prompted us to develop a study protocol using 18-fluorodeoxyglucose PET in patients with bronchogenic cancer.

Frontal dysfunction in neurologically normal chronic alcoholic subjects: metabolic and neuropsychological findings.

BACKGROUND: Neuropsychological and imaging studies suggest that frontal dysfunction may occur in apparently normal chronic alcoholic subjects. METHODS: To investigate this issue further, we performed neuropsychological and fluorodeoxy-glucose-PET studies in 17 chronic alcoholics without patent neurological and psychiatric complications. RESULTS: Metabolic abnormalities were found in the mediofrontal and in the left dorsolateral prefrontal cortex, but not in the orbitofrontal cortex. Neuropsychological testing revealed significantly reduced verbal fluency and impaired performance on the Stroop test. The mediofrontal hypometabolism correlated with the reduction in verbal fluency and the time necessary to perform the interference condition of the Stroop test. The left dorsolateral prefrontal hypometabolism correlated with the number of errors on the Stroop test. CONCLUSION: These data indicate that circumscribed frontal dysfunctions may occur in chronic alcoholic subjects before clinically obvious neurological complications, and may account for some of the alcohol-related neuropsychological and behavioural impairments.

Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats.

Chronic hypoxia induces an overall sympathetic hyperactivation associated with a myocardial beta-receptor desensitization. The mechanisms involved in this desensitization were evaluated in 32 male Wistar rats kept in a hypobaric pressure chamber (PO2 = 40 Torr, atmospheric pressure = 450 Torr) for 5 days. In hypoxic compared with normoxic conditions, plasma norepinephrine (NE) levels were higher (2.1 +/- 0.7 vs. 0.6 +/- 0.2 ng/ml) with no difference in the plasma epinephrine levels (2.2 +/- 0.7 vs. 1.8 +/- 0.3 ng/ml). In hypoxia neuronal NE uptake measured by [3H]NE was decreased by 32% in the right ventricle (RV) and by 35% in the left ventricle (LV), and [3H]mazindol in vitro binding showed a decrease in uptake-1 carrier protein density by 38% in the RV and by 41% in the LV. In vitro binding assays with [3H]CGP-12177 indicate beta-adrenoceptor density reduced by 40% in the RV and by 32% in the LV, and this was due to reduced beta1-subtype fraction (competition binding experiments with practolol). Hypoxia reduced the production of cAMP induced by isoproterenol (36% decrease in the RV and 41% decrease in the LV), 5'-guanylylimododiphosphate (40% decrease in the RV and 42% decrease in the LV), and forskolin (39% decrease in the RV and 41% decrease in the LV) but did not alter the effect of MnCl2 and NaF. Quantitation of inhibitory G-protein alpha-subunit by immunochemical analysis showed a 46% increase in the cardiac-specific isoform Gialpha2 in hypoxic hearts. The present data demonstrate that in rats 5-day hypoxia leads to changes in pre- and postsynaptic myocardial adrenergic function. The myocardial desensitization associated with both a reduction in externalized beta1-adrenoceptor and an increase in inhibitory G-protein subunit may be caused by increased synaptic NE levels due to impaired uptake-1 system.

Impaired cerebral glucose metabolism in myotonic dystrophy: a triplet-size dependent phenomenon.

Myotonic dystrophy (DM) is caused by an expansion of a CTG triplet repeat sequence in the 3'-noncoding region of a protein kinase gene, yet the mechanism by which the triplet repeat expansion causes disease remains unknown. Impaired glucose penetration into brain tissues has been described in DM patients and is a phenomenon that remains unexplained. The present study shows that altered brain glucose metabolism is triplet repeat dependent. We studied brain glucose metabolism (CMRGlu, mumol/100 g/min) by the use of positron emission tomography and 18F-fluoro-2-deoxy-D-glucose in 11 ambulatory non-obese DM patients and in 11 age and sex matched healthy subjects. All subjects underwent a glucose tolerance test with plasma insulin determinations. The expansion of CTG triplet repeats was analyzed in patients with the probe cDNA25 after EcoRI digestion. As compared to controls, in DM patients, the CMRGlu was significantly decreased (26.26 +/- 5.05 vs. 33.43 +/- 2.18, mumol/100 g/min, P = 0.004), and after oral glucose loading, plasma insulin levels were significantly higher and plasma glucose levels remained unchanged (respectively, F = 11.21, P = 0.004 and F = 0.20, P = 0.66). Subsequently, the glucose/insulin ratio was significantly lower in DM patients (F = 6.25, P = 0.02). The length of the expansion of the CTG repeats correlated negatively with the CMRGlu (r2 = 0.63, P = 0.003) and positively with the area under the curve for insulin changes over time after oral glucose (r2 = 0.49, P = 0.016). We conclude that, in DM patients, the brain metabolism of glucose is impaired in a repeat dependent manner.