Aerobic exercise training improves the role of high-density lipoprotein antioxidant and reduces plasma lipid peroxidation in type 2 diabetes mellitus.

In this study, we analyzed the effect of aerobic exercise training (AET) and of a single bout of exercise on plasma oxidative stress and on antioxidant defenses in type 2 diabetes mellitus (DM) and in healthy control subjects (C). DM and C did not differ regarding triglycerides, high-density lipoprotein cholesterol (HDL-c), insulin, and HOMA index at baseline and after AET. To measure the lag time for low-density lipoprotein (LDL) oxidation (LAG) and the maximal rate of conjugated diene formation (MCD), participants' plasma HDL(2) and HDL(3) were incubated with LDL from pooled healthy donors' plasma. In the presence of HDL(3), both LAG and MCD were similar in C and DM, but only in DM did AET improve LAG and reduce MCD. In the presence of HDL(2), the lower baseline LAG in DM equaled C after AET. MCD was unchanged in DM after AET, but was lower than C only after AET. Furthermore, after AET plasma thiobarbituric acid-reactive substances were reduced only in DM subjects. Despite not modifying the total plasma antioxidant status and serum paraoxonase-1 activity in both groups, AET lowered the plasma lipid peroxides, corrected the HDL(2), and improved the HDL(3) antioxidant efficiency in DM independent of the changes in blood glucose, insulin, and plasma HDL concentration and composition.

Effect of fat distribution on the pharmacokinetics of cortisol in obesity.

OBJECTIVE: Patients with predominantly upper body obesity are at greater risk for developing diabetes mellitus, hyperlipidemia, hypertension, and cardiovascular disease. Little is known about the mechanisms involved in the regulation of regional body distribution. It has been accepted that the accumulation of fat into adipose tissue depends on regional metabolic regulation of adipocytes and that glucocorticoids play a role in this mechanism. The aim of the present study is to investigate how the pharmacokinetics of cortisol correlate to intraabdominal and subcutaneous fat distribution in obese patients. METHODS: A group of 24 obese patients (13 males and 11 females) were submitted to a CT scan for intraabdominal and subcutaneous fat area evaluation. A 30-min cortisol infusion (0.25 mg/kg) was administered and plasma cortisol was measured over 6 hours. RESULTS: Patients with larger intraabdominal fat areas were found to have a higher cortisol clearance than those with lower intraabdominal fat areas. Cortisol clearance (both, absolute and body-weight corrected) showed a statistically significant correlation with intraabdominal fat area, either expressed by waist-hip ratio or obtained by computerized tomography. CONCLUSIONS: These findings indicate a more effective clearance capability for cortisol in patients with central obesity resulting in lowered cortisol plasma levels despite an increased cortisol secretion observed in this patient group.

Plasma cholesteryl ester transfer protein concentration, high-density lipoprotein cholesterol esterification and transfer rates to lighter density lipoproteins in the fasting state and after a test meal are similar in Type II diabetics and normal controls.

Rates of ester formation from [3H]cholesterol and of [3H]cholesteryl ester transfer from the HDL-containing plasma fraction to lipoproteins of lighter densities (apo B-containing LP) and plasma cholesteryl ester transfer protein concentration (CETP) were measured in normotriglyceridemic Type II diabetics (n = 11) and normal controls (n = 10) both in the fasting state and 4 h after a standard milk-shake test meal (50g of fat/m of body surface). The percent of [3H]cholesteryl ester synthesis was measured in a plasma [3H]cholesterol-HDL containing preparation incubated for 30 min and the [3H]cholesteryl ester transfer was measured upon precipitation of apo B-containing lipoproteins with dextran sulphate/MgCl2 following a 2 h period of plasma incubation with [3H]cholesteryl ester-HDL. The test meal significantly increased the plasma triglyceride concentration and to a similar extent in diabetics and in normal controls. Both a HDL-[3H]cholesteryl ester synthesis and transfer rates were equally stimulated in diabetics and in controls. When data were expressed by the concentration of plasma triglycerides, cholesteryl ester formation and transfer rates were similar in the alimentary and fasting periods, and when expressed per apo B concentration, cholesteryl ester transfer rates rose during the alimentary period in both diabetics and controls indicating that there was a net gain of cholesteryl ester per apo B lipoprotein. Plasma CETP mass, and neutral lipid transfer activity were similar in diabetics and normal controls demonstrating that the reverse transport of cholesterol through the apo B lipoprotein pathway is not altered in normotriglyceridemic Type II diabetics.

Plasma cholesteryl ester synthesis, cholesteryl ester transfer protein concentration and activity in hypercholesterolemic women: effects of the degree of saturation of dietary fatty acids in the fasting and postprandial states.

Hypercholesterolemic women (n = 19) sequentially maintained on a long-term saturated (SAT) or a polyunsaturated (PUFA) fatty acid-rich diet, respectively, were studied in the fasting state and after a meal rich in SAT or PUFA. When apo B-containing lipoprotein was excluded from plasma the in vitro HDL-14C-cholesterol esterification rate was identical for the saturated (SAT) and polyunsaturated (PUFA) fatty acid diets, and did not increase during the postprandial period. Rates of transfer of 14C-cholesteryl ester to apo B-containing lipoproteins from HDL were also similar for both diets in the fasting state and increased to the same extent in the postprandial period in parallel with the rise in plasma triglycerides. When transfer data were related to the plasma concentration of apo B, the gain of cholesteryl ester by the triglyceride-containing particles (VLDL + LDL) also increased in the postprandial period to a similar extent for both diets. Cholesteryl ester transfer protein (CETP) concentration measured by radioimmunoassay was similar during both experimental diets, although greater in the postprandial period for the PUFA diet. The rate limiting factor for CETP-mediated transfer of HDL-derived cholesteryl ester (CE) was the plasma triglyceride concentration, that is, the content of triglycerides per lipoprotein particle and the quantity of TG-containing particles (VLDL + LDL). In contrast, the fatty acid composition of these particles had less effect on CETP-mediated CE transfer.

A positron emission tomography [18F]deoxyglucose study of developmental stuttering.

Positron emission tomography using [18F]deoxyglucose (FDG) as a marker of regional brain metabolism was used to investigate the neural substrate of stuttering. Four patients with severe developmental stuttering were studied while reading aloud to another person (stuttering condition) and while reading aloud in unison with someone else (non-stuttering condition). The patients were also compared with four normal controls reading aloud by themselves. In the stuttering condition, significant decreases in regional glucose metabolism in Broca's area, Wernicke's area and frontal pole were seen compared with themselves while not stuttering. These differences were also seen in stuttering condition compared with normal controls. Significantly lower left caudate metabolism was seen in patients during both stuttering and non-stuttering conditions compared with normal controls. A circuit for stuttering is proposed based on these findings.

Selective reductions in prefrontal glucose metabolism in murderers.

This study tests the hypothesis that seriously violent offenders pleading not guilty by reason of insanity or incompetent to stand trial are characterized by prefrontal dysfunction. This hypothesis was tested in a group of 22 subjects accused of murder and 22 age-matched and gender-matched controls by measuring local cerebral uptake of glucose using positron emission tomography during the continuous performance task. Murderers had significantly lower glucose metabolism in both lateral and medial prefrontal cortex relative to controls. No group differences were observed for posterior frontal, temporal, and parietal glucose metabolism, indicating regional specificity for the prefrontal deficit. Group differences were not found to be a function of raised levels of left-handedness, schizophrenia, ethnic minority status, head injury, or motivation deficits in the murder group. These preliminary results suggest that deficits localized to the prefrontal cortex may be related to violence in a selected group of offenders, although further studies are needed to establish the generalizability of these findings to violent offenders in the community.

Clozapine effects on glucose metabolic rate in striatum and frontal cortex.

Eighteen patients with schizophrenia had cerebral metabolic rates assessed with positron emission tomography during a double-blind, placebo-controlled crossover study of clozapine treatment. Relative metabolic rates were increased in the basal ganglia, especially on the right side. In the frontal lobe, metabolic rates were lowered, more on the left than on the right. The anterior nuclei of the thalamus also showed lower metabolic rates after clozapine. We have previously observed patients with schizophrenia to have low metabolic rates in the basal ganglia and to lack the normal right > left asymmetry; in this study, clozapine normalized striatal activity. In the frontal lobe, asymmetry was normalized, but hypofrontal function was, if anything, exaggerated. This effect in the frontal lobe was not observed with haloperidol in earlier studies. The cortical effects of clozapine may be related to its unique clinical properties and suggest important differences between typical and atypical antipsychotic drugs.

Selected cases of poor outcome following a minor brain trauma: comparing neuropsychological and positron emission tomography assessment.

Neuropsychological residua are common particularly in the early stages following a minor traumatic brain injury (TBI), however, a minority of individuals complain of persistent deficits following months or years post-accident. Nine such cases are presented with little or no evidence of brain damage demonstrated according to non-functional neuroimaging (for example CT, MRI), yet their neuropsychological examinations were positive. Since the introduction of positron emission tomography (PET), which captures a functional approach, the question arose as to what extent the two techniques (i.e. PET and neuropsychological examination) are interrelated. All nine minor TBI cases revealed a corroboration between the positive neuropsychological findings confirmed on the PET. The PET procedure documented neuropathology which frequently was pronounced in the frontal and anteriotemporo-frontal regions. Moreover, no significant differences were evident between those five cases with reported loss of consciousness vs. those four cases without.

Simultaneous measurements of chylomicron lipolysis and remnant removal using a doubly labeled artificial lipid emulsion: studies in normolipidemic and hyperlipidemic subjects.

An artificial chylomicron-like lipid emulsion doubly labeled with tri[(N)3H]oleoylglycerol ([3H]TO) and cholesteryl [1-14C]oleate ([14C]CO) was infused intravenously into human subjects with the purpose of simultaneously measuring the plasma disappearance rates (residence time, RT) of [14C]CO, which represents solely the splanchnic organ uptake of the remnant chylomicron core, and of [3H]TO, which combines the remnant disappearance with the shedding off of chylomicron triglycerides by the action of lipoprotein lipase. Thus, the fraction of the particle triglyceride content that is removed before the remnant is taken up is expressed as a delipidation index (DI = 1 - RT of [3H]TO/RT of [14C]CO. The present procedure has an advantage over the use of chylomicrons labeled with retinyl ester or radioactive triglycerides alone that represent, respectively, the chylomicron remnant or the whole particle metabolism only. When normal subjects as well as primary hyperlipidemic subjects were studied, the plasma triglyceride concentration was directly related to [14C]CO RT and [3H]TO RT, but inversely related to the delipidation index. There may be different patterns of relations between these parameters of chylomicron metabolism in primary and in secondary hyperlipidemias, as well as under the action of drugs that influence the metabolism of lipoproteins.

Cortical-striatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients.

OBJECTIVE: The cortical-striatal-thalamic circuit modulates cognitive processing and thus may be involved in the cognitive dysfunction in schizophrenia. The imaging of metabolic rate in the structures making up this circuit could reveal the correlates of schizophrenia and its main symptoms. METHOD: Seventy male schizophrenic patients underwent [18F]-fluorodeoxyglucose positron emission tomography after a period of at least 4 weeks during which they had not received neuroleptic medication and were compared to 30 age-matched male normal comparison subjects. RESULTS: Analyses revealed decreased metabolism in medial frontal cortex, cingulate gyrus, medial temporal lobe, corpus callosum, and ventral caudate and increased metabolism in the left lateral temporal and occipital cortices in the schizophrenic cohort. Consistent with previous studies, the schizophrenic group had lower hypofrontality scores (ratios of lateral frontal to occipital metabolism) than did comparison subjects. The lateral frontal cortical metabolism of schizophrenic patients did not differ from that of comparison subjects, while occipital cortical metabolism was high, suggesting that lateral hypofrontality is due to abnormalities in occipital rather than lateral frontal activity. Hypofrontality was more prominent in medial than lateral frontal cortex. Brief Psychiatric Rating Scale (BPRS) scores, obtained for each schizophrenic patient on the scan day, were correlated with regional brain glucose metabolic rate. Medial frontal cortical and thalamic activity correlated negatively with total BPRS score and with positive and negative symptom scores. Lateral frontal cortical metabolism and hypofrontality scores did not significantly correlate with negative symptoms. Analyses of variance demonstrated a reduced right greater than left asymmetry in the schizophrenic patients for the lateral cortex as a whole, with simple interactions showing this effect specifically in temporal and frontal cortical regions. CONCLUSIONS: Low metabolic rates were confirmed in medial frontal cortical regions as well as in the basal ganglia, consistent with the importance of the cortical-striatal-thalamic pathways in schizophrenia. Loss of normal lateralization patterns was also observed on an exploratory basis. Correlations with negative symptoms and group differences were more prominent in medial than lateral frontal cortex, suggesting that medial regions may be more important in schizophrenic pathology.

Magnetic resonance and positron emission tomography imaging of the corpus callosum: size, shape and metabolic rate in unipolar depression.

Magnetic resonance imaging (MRI) and positron emission tomography (PET) with fluorodeoxyglucose were used to study the size and shape of the corpus callosum in 20 patients with unipolar depressive disorder and 16 normal controls. An automated algorithm outlined the corpus callosum and divided it into quarters. The anterior and posterior quarters of the corpus callosum were larger in depressed patients than in controls, findings similar to most earlier MRI studies of the corpus callosum in schizophrenics. The patient-normal difference was more marked in females than in males. PET glucose metabolic values were higher in patients with thinner or smaller callosums. The presence of marked sex differences makes future larger studies controlling body size and age important.

Cerebral metabolic change after treatment in biotinidase deficiency.

A 13.5-year-old boy with biotinidase deficiency was studied 8 days before and 5 months after biotin treatment by positron emission tomography (PET) and computerized electroencephalographic topography (CET). With biotin treatment there was a marked improvement in the presenting symptom of loss of visual acuity and a more modest recovery in spastic quadraparesis. By PET scanning, the relative metabolic rate for glucose was more than 2 standard deviations lower in the temporal and occipital cortices than in adult or age-matched controls. With biotin treatment, these values rose to normal limits for both control groups. By CET, normalized EEG equivalent to the relative glucose metabolic rate showed asymmetric slowing in the left temporal and frontal regions before treatment, whereas none of the 32 leads exceeded normal limits of delta, theta, alpha or beta after treatment. These results suggest a strong correlation between clinical, metabolic and electrical measures of brain function as related to biotin treatment in biotinidase deficiency.

Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics.

We scanned 18 patients with schizophrenia who had never received neuroleptic medication and 20 age- and sex-matched controls by positron emission tomography with 18-F-fluorodeoxyglucose (fludeoxyglucose F 18) as a tracer of glucose metabolism. Subjects performed the Continuous Performance Test during 18-F-fluorodeoxyglucose uptake. Scan results were converted to metabolic rates, and computer algorithms were used to identify cortical regions. Previous reports of relative hypofrontality in schizophrenia were confirmed, indicating that this finding is not an artifact of previous treatment. Significantly reduced ratios of inferior and medial frontal regions to occipital cortex were found, together with diminished metabolism in the basal ganglia. This suggests the presence of a combined frontostriatal dysfunction in schizophrenia.

Striatal metabolic rate and clinical response to neuroleptics in schizophrenia.

A low metabolic rate in the caudate nucleus and putamen in schizophrenic patients while they were not receiving medication was found to predict a favorable clinical response to haloperidol. Twenty-five patients (21 men and four women) entered a double-blind crossover trial of haloperidol and placebo; to our knowledge, this is the first such trial with positron emission tomography to be reported. Patients received either placebo or medication for the first 5 weeks, and they received the other treatment for the second 5 weeks. Positron emission tomographic scans were obtained at weeks 5 and 10. Patients with low relative metabolic rates in the caudate nucleus and putamen while they were receiving placebo were more likely to show decreases in their Brief Psychiatric Rating Scale scores with haloperidol treatment than individuals with normal or high metabolic rates. Among responders, haloperidol treatment had a "normalizing" effect on metabolic activity in the striatum, with the metabolic rate while they were receiving haloperidol being higher than that while they were receiving placebo. Nonresponders were more likely to show a worsening of hypofrontality while they were receiving medication and an absence of change in the striatum.

Effects of clozapine and thiothixene on glucose metabolic rate in schizophrenia.

Twelve patients with schizophrenia received positron emission tomography scans with 18F-deoxyglucose before and after 4 to 6 weeks of treatment with clozapine or thiothixene. Both stereotaxic and magnetic resonance image template methods were used to position regions of interest for metabolic rate analysis. Clozapine increased and thiothixene decreased metabolic rates in the basal ganglia; these effects were most marked on the right side. Within the basal ganglia, a superior to inferior gradient in drug effect was found for thiothixene but not clozapine. This gradient resembled in some respects observations on regional differences in D2 receptors in human autoradiography. Baseline metabolic rates also predicted clinical medication response, with right inferior caudate metabolic rates differentiating clozapine and thiothixene responders. Larger sample studies are needed to replicate and extend these initial findings.

Regional glucose metabolic changes after learning a complex visuospatial/motor task: a positron emission tomographic study.

Regional cerebral glucose metabolic rate (GMR) quantified with positron emission tomography (PET) with 18-fluoro-2-deoxyglucose (FDG) was measured twice in 8 young men performing a complex visuospatial/motor task (the computer game Tetris), before and after practice. After 4-8 weeks of daily practice on Tetris, GMR in cortical surface regions decreased despite a more than 7-fold increase in performance. Subjects who improved their Tetris performance the most after practice showed the largest glucose metabolic decreases after practice in several areas. These results suggest that learning may result in decreased use of extraneous or inefficient brain areas. Changes in regional subcortical glucose metabolic rate with practice may reflect changes in cognitive strategy that are a part of the learning process.

PET and neurobehavioral evidence of tetrabromoethane encephalopathy.

Organic solvents have been implicated in a number of neuropsychiatric disturbances, though physical and neurological exams are frequently negative. An individual with acute tetrabromoethane exposure was evaluated with positron emission tomography (PET), topographical electroencephalogram (EEG), and neurobehavioral assessment. Results suggest widespread central nervous system (CNS) dysfunction consistent with a solvent-induced encephalopathy.

In vivo acoustic attenuation in liver: correlations with blood tests and histology.

Results of in vivo attenuation measurements in the liver have been obtained in 26 normal controls and in 51 patients with chronic diffuse liver disease. A modified real-time sector scanner was used for narrow-band amplitude attenuation examination. In the control group (people without apparent liver disease), a statistically significant correlation was found between acoustic attenuation in liver and two blood tests reflecting liver function: serum albumin (n = 24, r = 0.67, p = 0.002) and prothrombin time (n = 23, r = 0.63, p = 0.019). There was a statistically significant positive correlation between attenuation and fat for all biopsied patients (n = 51, r = 0.32, p = 0.023) and for patients with minimal fibrosis (n = 25, r = 0.45, p = 0.027). Although no correlation with fibrosis was found for all patients, in the group of patients with minimal fat there was a correlation with portal fibrosis (n = 33, r = 0.37, p = 0.035). This double blind prospective study shows that in the liver: (1) attenuation estimates appear correlated with clinical parameters (blood tests) in normal volunteers, and (2) large changes in fat affect narrow-band acoustic attenuation estimates to a greater degree than severe portal fibrosis in patients with chronic diffuse liver disease. Further research is needed before these estimates can become a clinical tool.

Noninvasive evaluation of hepatic fibrosis using frequency demodulation of ultrasound signals.

A new ultrasound image can be produced by frequency demodulation (FM) of the conventional ultrasound signal. This new FM image appeared to produce a more accurate representation of the fine structure of the liver. The individual features of the FM image were correlated with hepatic portal fibrosis and cirrhosis on liver biopsy in 34 patients with minimal hepatic fat and sinusoidal collagen. An overall ultrasound score correlated with portal fibrosis (r = 0.788; P less than 0.001). We conclude that the FM image may be helpful in measuring and following the progression of hepatic fibrosis in patients with chronic liver disease.