IGF-I and the aging mammalian brain.

Insulin-like growth factors (IGFs) are important modulators of organismal life-span all along phylogeny. These growth factors are widely viewed as detrimental for long life by reducing tissue resistance to oxidative stress. However, IGF-I has been consistently shown to be a potent neuroprotective factor in mammals, and as such, a deterrent of brain aging. Conversely, recent data suggest that IGF-I may contribute to amyloid neurodegeneration underlying Alzheimer's disease. These opposing observations underline an incomplete understanding of the significance of this ancestral hormone pathway in relation to brain aging. It is possible that these opposite results are the consequence of using different experimental approaches. Thus, brain amyloid injury is reduced in mutant mice partially defective in IGF-I receptor function, whereas IGF-I is neuroprotective when administered to animal models of neurodegenerative disease or normal brain aging. This approach-dependent effect of IGF-I highlights a fundamental gap in our knowledge of the relationship between peripheral and brain IGF-I function and the actual biological impact of experimental modulation of brain IGF-I function. We suggest to directly address brain IGF-I function in the varying experimental approaches used to confirm that changes have taken place in the desired way.

Independent alterations in the central and peripheral somatosensory pathways in rat diabetic neuropathy.

Peripheral and central diabetic neuropathies were studied in streptozotocin-diabetic rats, using behavioral, biochemical and electrophysiological techniques. Diabetic rats showed thermal hypoalgesia and decreasing motor nerve conduction velocity at 4 and 8 weeks of diabetes. In addition, amplitude of the evoked potential recorded in primary somatosensory cortex after stimulation of the sciatic nerve was markedly reduced at 8 weeks of diabetes. This decrease was accompanied by decreases in GluR2/3 AMPA receptor subunits. These changes seem to be specific to the somatosensory system and to originate in higher centers since they were not present in the hippocampus and were not observed at the level of gracilis nucleus. Insulin-like growth factor I (IGF-I) treatment reversed the reduced thermal sensitivity and peripheral nerve conduction velocity but did not reverse changes in the CNS, suggesting that once initiated, both anomalies may develop independently in this model of diabetic neuropathy. In conclusion, the results indicate that diabetes induces a wide spectrum of alterations in the central somatosensory system that are independent of the decreases in peripheral sensory transmission that could be responsible for the disturbances in somatosensory perception observed in diabetes.

Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects.

Increasing evidence indicates that circulating insulin-like growth factor I (IGF-I) acts as a peripheral neuroactive signal participating not only in protection against injury but also in normal brain function. Epidemiological studies in humans as well as recent evidence in experimental animals suggest that blood-borne IGF-I may be involved in cognitive performance. In agreement with observations in humans, we found that mice with low-serum IGF-I levels due to liver-specific targeted disruption of the IGF-I gene presented cognitive deficits, as evidenced by impaired performance in a hippocampal-dependent spatial-recognition task. Mice with serum IGF-I deficiency also have disrupted long-term potentiation (LTP) in the hippocampus, but not in cortex. Impaired hippocampal LTP was associated with a reduction in the density of glutamatergic boutons that led to an imbalance in the glutamatergic/GABAergic synapse ratio in this brain area. Behavioral and synaptic deficits were ameliorated in serum IGF-I-deficient mice by prolonged systemic administration of IGF-I that normalized the density of glutamatergic boutons in the hippocampus. Altogether these results indicate that liver-derived circulating IGF-I affects crucial aspects of mature brain function; that is, learning and synaptic plasticity, through its trophic effects on central glutamatergic synapses. Declining levels of serum IGF-I during aging may therefore contribute to age-associated cognitive loss.

Nifedipine-mediated mobilization of intracellular calcium stores increases spontaneous neurotransmitter release at neonatal rat motor nerve terminals.

The modulation of spontaneous release of acetylcholine by specific Ca2+ channel blockers was studied at neonatal rat neuromuscular junction. During early postnatal periods (0-4 days), blockers of N- and P/Q-type Ca2+ channels did not affect miniature endplate potential (MEPP) frequency. Unexpectedly, treatment with the L-type Ca2+ channel antagonist nifedipine, although not when treated with isradipine, nitrendipine, or calciseptine, resulted in strong increase in MEPP frequency. The potentiation effect of nifedipine was dose-dependent with a 56-fold maximum effect with 15 microM. The effect decreased during the first two postnatal weeks and disappeared by the third. The effect of nifedipine was not dependent on extracellular Ca2+ and was not altered by the presence of other Ca2+ channel blockers. In contrast, it was abolished by depleting intracellular Ca2+ stores with 2 microM thapsigargin and was partially inhibited by 10 microM ryanodine. In conclusion, we report a new ryanodine receptor-mediated effect of nifedipine on neonatal neuromuscular junction that may indicate the developmental expression of a specific receptor channel that interacts with intracellular Ca2+ stores. This effect of nifedipine should also be considered when using this drug as either a therapeutic or a research tool.

Comparison of exercise, dipyridamole, adenosine, and dobutamine stress with the use of Tc-99m tetrofosmin tomographic imaging.

PURPOSE: The purpose of this study was to compare defect extent and severity and myocardial uptake with exercise and pharmacologic stress with technetium-99m (Tc-99m) tetrofosmin tomographic myocardial perfusion imaging. BACKGROUND: Detection of stress-induced myocardial perfusion defects depends on both a disparity in blood flow between normal and stenotic vessels and the extraction fraction and linearity of myocardial uptake of the tracer. There are limited clinical data for exercise or pharmacologic stress with Tc-99m tetrofosmin tomographic myocardial perfusion imaging. METHODS: Thirty-one patients with coronary artery disease and 7 with a < 5% likelihood of coronary artery disease underwent on separate days Tc-99m tetrofosmin single-photon emission computed tomographic imaging at rest and after exercise, dipyridamole, adenosine, and dobutamine stress. Images were interpreted by a blinded consensus of 3 experienced readers with a 17-segment model and 5-point scoring system. RESULTS: Compared with exercise, the summed stress score was smaller with dipyridamole (P < .01), and the reversibility score was smaller with both dipyridamole (P < .01) and dobutamine (P < .05), whereas the number of abnormal and reversible segments was less with both dipyridamole (P < .01 and P < .001, respectively) and dobutamine (both P < .05). No significant differences were found in the summed stress or reversibility scores and the number of abnormal or reversible segments between exercise and adenosine. CONCLUSIONS: Compared with exercise, defect extent, severity, and reversibility are less with dipyridamole and dobutamine with Tc-99m tetrofosmin single photon emission computed tomographic imaging.

Effect of time on liver clearance of technetium-99m-tetrofosmin in patients with acute chest pain: when should imaging begin?

OBJECTIVE: Due to stable myocardial retention and technetium imaging characteristics, 99mTc-tetrofosmin has been considered potentially useful for acute chest pain imaging. Tetrofosmin also has favorable biokinetics with reported rapid liver clearance, 5 min poststress and 30-45 min post-rest injection. Since comparable data are not available, the effect of time on liver clearance was evaluated in patients with acute chest pain. METHODS: One hundred six patients received an intravenous injection of 25-30 mCi 99mTc-tetrofosmin to evaluate acute chest pain. SPECT imaging was performed 15-120 min after injection of the tracer. Patient images were grouped according to the time of acquisition after acute injection: 15-30 min, 31-45 min, 46-60 min, 61-90 min and > 90 min. Quantitative analysis was performed of a similar anterior projection for each patient consisting of 6 X 6-pixel region of interest over the myocardium and adjacent liver. Average counts per pixel were determined and a heart/liver (H/Li) ratio was calculated. RESULTS: The mean H/Li ratio was < 1.0 for patient images acquired 15-45 min after injection, and > 1.0 for patient images acquired after 45 min. The difference was statistically significant (p < 0.05). CONCLUSION: Quantitative analysis suggests that the optimal imaging time should be at least 45 min after the injection of 99mTc-tetrofosmin to allow adequate liver clearance before image acquisition of acute chest pain syndromes.

[Bronchiolitis obliterans with organizing pneumonia associated with idiopathic thrombocytopenic purpura]. / Bronquiolitis obliterante con neumonía organizada asociada a púrpura trombocitopénica idiopática.

We report a case of a 35 year-old woman with idiopathic thrombocytopenic purpura (ITP) who, under treatment with immunosuppressive drugs, developed bilateral interstitial pulmonary disease. Previously she had been splenectomized and treated with corticosteroids and cyclosporin. During the clinical course, the patient developed alterations of the hepatogram and presented a positive serology for Epstein-Barr virus. The lung biopsy showed the histologic pattern of obliterative bronchiolitis, interstitial inflammatory infiltration and intraalveolar pneumonia (BOOP). We could not find in the literature a previous report in which ITP was associated with BOOP. Of interest was the spontaneous remission of the pulmonary disease after suppression of cyclosporin and positive serology for Epstein-Barr virus.

Direct comparison of arbutamine and dobutamine stress testing with myocardial perfusion imaging and echocardiography in patients with coronary artery disease.

Arbutamine, a new sympathomimetic compound, appears to elicit a more balanced inotropic and chronotropic response than dobutamine, currently used as a pharmacologic stress agent. The present study was performed to compare standard dobutamine stress testing with arbutamine for the detection of myocardial ischemia with technetium (Tc)-99m sestamibi tomographic imaging and 2-dimensional echocardiography in patients with coronary artery disease. Twenty-six patients with evidence of coronary artery disease underwent dobutamine infusion of 5 to 40 microg/kg/min in 3-minute stages. On a separate day, arbutamine was administered by an automated, computerized, closed-loop device monitoring both heart rate and blood pressure. Both infusions were terminated upon achievement of target heart rate, completion of maximal infusion dose (dobutamine), heart rate saturation (arbutamine), or standard clinical end points. Tc-99m sestamibi was injected before termination of both infusions followed by tomographic myocardial perfusion imaging, whereas echocardiography was performed at baseline and throughout the infusions. There were no significant differences in maximal heart rate, blood pressure, and rate-pressure product as well as in the development of anginal symptoms or electrocardiographic changes during both infusions. The location and severity of myocardial perfusion defects and echocardiographic wall motion abnormalities were similar between both agents. It is concluded that arbutamine produces similar imaging results compared with standard dobutamine stress with both Tc-99m sestamibi single-photon emission computed tomographic myocardial perfusion imaging and 2-dimensional echocardiography.