Edge restenosis after implantation of high activity (32)P radioactive beta-emitting stents.

BACKGROUND: A high restenosis rate has been reported at the edges ("edge restenosis") of (32)P radioactive stents with an initial activity level of 3 to 12 microCi. This edge effect might be due to balloon injury and to a low dose of radiation at the stent margins. The aim of this study was to evaluate whether the implantation of (32)P radioactive stents with a higher activity level (12 to 21 microCi) combined with a nonaggressive stent implantation strategy could solve the problem of edge restenosis. METHODS AND RESULTS: We compared the results of lesions treated with single radioactive BX stents with an activity of 12 to 21 microCi (group 2, n = 54 lesions) with the results of lesions treated by single radioactive BX stents with an initial activity level of 3 to 12 microCi (group 1, n = 42 lesions). There were no procedural events. At the 6-month follow-up, no myocardial infarctions, deaths, or stent thromboses had occurred. Intrastent binary restenosis was 0% in group 1 versus 4% in group 2 (n = 2, both at the ostium of the right coronary artery, P = NS). Intrastent neointimal hyperplasia was significantly lower in group 2 than in group 1. The intralesion (intrastent plus peri-stent) restenosis rate was 38% in group 1 versus 30% in group 2 (P = NS). Conclusions-Single (32)P radioactive stents with an initial activity level of 12 to 21 microCi reduced intrastent neointimal hyperplasia compared with stents of 3 to 12 microCi, but they did not solve the problem of edge restenosis, even if a nonaggressive stent implantation strategy was used.

Cerebral protection with filter devices during carotid artery stenting.

BACKGROUND: Distal embolization of debris during percutaneous carotid artery stenting may result in neurological deficit. Filter devices for cerebral protection potentially reduce the risk of embolization. METHODS AND RESULTS: Elective carotid stent implantation using 3 different types of distal filter protection devices was attempted in 88 consecutive lesions (84 patients) in the internal carotid artery that had >70% diameter stenosis (mean, 78.7+/-10.7%). Procedures were performed in 3 different centers. The mean age of the patients was 69+/-8 years, 75% were men, and 35.7% had neurological symptoms. In 86 lesions, a stent was successfully implanted (97.7%). In 83 of these 86 procedures (96.5%), it was possible to position a filter device. In 53% of filters, there was macroscopic evidence of debris. Collected material consisted of lipid-rich macrophages, fibrin material, and cholesterol clefts. Neurological complications during the procedure, in the hospital, and at 30 days of clinical follow-up occurred in only one patient (1.2%). This patient suffered a minor stroke that resolved within 1 week. Two major adverse cardiac events (2.3%) occurred during the 30 days of follow-up. CONCLUSIONS: Filter protection during carotid artery stenting seems feasible and safe. In the present series, the incidence of neurological complications was low.

Bifurcation lesions: two stents versus one stent--immediate and follow-up results.

OBJECTIVES: The purpose of this study was to evaluate two different techniques of stent placement in bifurcation lesions. BACKGROUND: Although stent placement with dedicated techniques has been suggested to be a useful therapeutic modality for bifurcation lesions, limited information is available if stent placement on the side branch and on the parent branch provides any advantage over a simpler strategy of stenting the parent vessel and balloon angioplasty of the side branch. METHODS: Between March 1993 and April 1999, we treated a total of 92 patients with bifurcation lesions with two strategies: stenting both vessels (group B, n = 53) or stenting the parent vessel and balloon angioplasty of the side branch (group P, n = 39). Paired angiograms were analyzed by quantitative angiography, and clinical follow-up was obtained. RESULTS: Stent placement on both branches resulted in a lower residual stenosis (7.4 +/- 10.9% vs. 23.4% +/- 18.7%, p < 0.001) in the side branch. Acute procedural success was similar in the two groups (group B: 87% vs. Group P: 92%). In-hospital major adverse cardiac events (MACE) occurred only in group B (13% vs. 0%, p < 0.05). At the six-month follow-up, the angiographic restenosis rate (group B: 62% vs. Group P: 48%) and the target lesion revascularization rate (38% vs. 36%, respectively) were similar in the two groups. There was no difference in the incidence of six-month total MACE (51% vs. 38%). CONCLUSIONS: For the treatment of true bifurcation lesions, a complex strategy of stenting both vessels provided no advantage in terms of procedural success and late outcome versus a simpler strategy of stenting only the parent vessel.

Cerebellar output regulation by the climbing and mossy fibers with and without the inferior olive.

The activity of the olivocerebellar complex and the structures related in series with it have been studied using the complementary action of harmaline and 3-acetylpyridine to isolate the two principal inputs to the cerebellar Purkinje cells. The activities of the various nuclei as well as the entire brain have been simultaneously monitored using the [14C]2-deoxy-glucose method under the various combined effects of the pharmacological agents. (1) Tremogenic doses of harmaline increased the frequency of discharge in selected parts of the olivocerebellar system, increasing climbing fiber input and reducing Purkinje cell simple spike discharges in corresponding parts of the cerebellar cortex. The metabolic activity increased in the inferior olive and in the red nucleus. The results are interpreted as a net reduction of Purkinje cell inhibition on their target neurons, leading to a facilitatory cerebellar output. (2) Systemic injection of neurotoxic doses of 3-acetylpyridine selectively produced total degeneration of the neurons in the inferior olive, resulting in the suppression of complex spikes and a net increase in simple spike output from the Purkinje cells. The metabolic consequences were a reduction or absence in the inferior olive, decrease in the red nucleus, and increases in the Purkinje cell target neuron regions, including the intracerebellar and vestibular nuclei. The study of long survival times following the neurotoxic treatment revealed a transient metabolic marking of the inferior olive during the active glial processes accompanying the degeneration. In other parts the radioautographic changes caused by the destruction of the inferior olive persisted for about 1 month after the administration of the drug. (3) Tremogenic doses of harmaline were given to rats at different times following treatment with 3-acetylpyridine. It was demonstrated that: (a) intoxication of the inferior olive started within the second hour after 3-acetylpyridine administration, corresponding to the time at which the metabolic response to harmaline was also abolished; and (b) the increased metabolic activity produced by harmaline in the olivocerebellar complex was a consequence of an increased activity of the neurons of the inferior olive rather than a direct pharmacological effect of the drug. (4) Partial lesions of the inferior olive led to increased metabolic activity of those parts of the intracerebellar nuclei topographically related to the destroyed parts of the inferior olive. (5) In 3-acetylpyridine-treated animals, local ablation as well as local inactivation of the cerebellar cortex produced localized suppression of the intense labeling in the intracerebellar nuclei obtained in these animals. Since these regions receive synapses which are normally inhibitory, suppression of labeling clearly supports the hypothesis that regional marking may very well be produced by the activity of the presynaptic terminals themselves...

Ultrastructure and synaptic targets of the raphe-nigral projection in the rat.

A major input to the substantia nigra is from the 5-hydroxytryptamine-containing neurons in the dorsal raphe nucleus. In order to examine the morphology and distribution of this projection, rats were given injections of the anterograde tracers, Phaseolus vulgaris-leucoagglutinin or biocytin, in the dorsal raphe nucleus and the substantia nigra was examined at both the light and electron microscopic levels. In addition, sections of the substantia nigra were immunostained for 5-hydroxytryptamine and examined in both the light and electron microscopes. Since dopaminergic neurons of the substantia nigra are known to be responsive to stimulation of the raphe and to applied 5-hydroxytryptamine, sections that contained anterogradely labelled terminals were further processed to reveal tyrosine hydroxylase immunoreactivity to determine whether the raphe input makes direct synaptic contact with dopaminergic neurons. Light microscopic analysis revealed that all divisions of the substantia nigra received input from the dorsal raphe which, in agreement with previous observations, showed a topographical organization. In that formed asymmetrical synaptic contact with dendritic shafts and spines. The synaptic boutons were often associated with subjunctional dense bodies. Terminals that displayed immunoreactivity for 5-hydroxytryptamine had a similar morphology, synaptic specialisations and postsynaptic targets to the anterogradely labelled terminals. In those sections that were stained for both anterogradely labelled terminals and tyrosine hydroxylase, the raphe-nigral terminals were seen to form asymmetrical synaptic contact with the dendrites of the dopaminergic neurons. It is concluded that dendrites of dopaminergic neurons in the substantia nigra pars reticulata represent at least one of the synaptic targets of the raphe-nigral projection and that these contacts provide an anatomical substrate for the effects of the dorsal raphe, and presumably 5-hydroxytryptamine, on dopaminergic systems in the substantia nigra.

Intravascular ultrasound criteria for the assessment of the functional significance of intermediate coronary artery stenoses and comparison with fractional flow reserve.

The functional significance of coronary artery stenoses of intermediate severity is important in determining strategy in patient care. Intravascular ultrasound (IVUS) is often used to evaluate coronary stenosis severity. However, at present, few data are available about the role IVUS in the assessment of functional significance of intermediate lesions. Myocardial fractional flow reserve (FFR) <0.75 is a reliable index of a functionally severe coronary stenosis. In 53 lesions we assessed (1) by pressure wire: FFR (index of functional significance), and (2) by IVUS: minimal lumen cross-sectional area (MLA, square millimeters), minimal lumen diameter (MLD, millimeters), lesion length (millimeters), and percent area stenosis at the lesion site. By regression analysis, percent area stenosis and lesion length had a significant inverse correlation with FFR (r = -0.58, p <0.001, r = -0.41, p <0.004, respectively). MLD and MLA showed a significant positive relation with FFR (r = 0.51, p <0.001, r = 0.41, p <0.004, respectively). By using a receiver operating characteristic (ROC) curve, we identified a percent area stenosis > 70% (sensitivity 100%, specificity 68%), a MLD < or = 1.8 mm (sensitivity 100%, specificity 66%), a MLA < or =4.0 mm2 (sensitivity 92%, specificity 56%), and a lesion length of >10 mm (sensitivity 41%, specificity 80%) to be the best cut-off values to fit with a FFR <0.75. The combined evaluation of both percent area stenosis and MLD made the IVUS examination more specific (sensitivity 100%, specificity 76%). In 53 intermediate coronary lesions found by angiography, IVUS area stenosis >70%, MLD < or =1.8 mm, MLA < or =4.0 mm2, and lesion length > 10 mm reliably identified functionally critical intermediate coronary stenoses.

Ultrastructure of supraspinal dorsal root projections in the toads. I. The obex region.

The ultrastructure of the dorsal column nucleus (DCN) has been investigated at the level of the obex region in normal and experimental toads. Large 'isolated' neurons (greater than 20 micrometer) and clusters of small neurons (less than 20 micrometer) have been identified in this region. Synaptic profiles have been classified into three types: large 'en passant' LR boutons, containing round synaptic vesicles and neurofilaments, small R boutons with round vesicles and F boutons with pleomorphic vesicles. The axon terminals exhibited synaptic contacts with cell somata, with dendrites of varying calibers and with other axons. The terminals involved in the axo-axonic contact were the F boutons which were presynaptic to the LR boutons, thus representing the morphological basis for presynaptic inhibition. Transection of the second dorsal root was performed in order to identify the terminals of the primary afferents to the DCN, after different survival periods (16 h--50 days). Only the LR boutons underwent degeneration, thus representing the central endings of the primary dorsal root afferents. The functional significance of these findings was discussed.

Vestibular projections to the nucleus intercalatus of Staderini mapped by retrograde transport of horseradish peroxidase.

Medullary afferent projections to the nucleus intercalatus of Staderini have been studied by retrograde transport of horseradish peroxidase (HRP) from highly localized injections. This nucleus receives afferent projections particularly from the medial and descending vestibular nuclei as well as from the nucleus praepositus hypoglossi of both sides. The nucleus intercalatus of Staderini represents therefore an area of integration for the vestibular systems of both sides.

Immunocytological localization by monoclonal antibodies of alpha-latrotoxin in the venom gland of the spider Latrodectus tredecimguttatus.

Monoclonal antibodies, raised against alpha-latrotoxin, have been used on serial sections of the venom glands with localization by indirect immunofluorescence. Colloidal gold immunovisualization and electron microscopy were used in order to localize the structure of the cells that synthesize and store the toxin. The antibodies were able to recognize the native toxin revealing its presence mainly in the 'replacement cell' layer, a layer of cells close to the muscular sheath of the gland. These cells apparently replace the disintegrated epithelial cells at the end of the holocrine cycle. Gold grains were predominantly observed around the free ribosomes and the secretion droplets of the 'replacement cells'.

Effectiveness and complications of vascular access closure devices after interventional procedures.

BACKGROUND: Vascular closure devices are designed to obtain a fast hemostasis of the vascular access site after diagnostic and interventional procedures. This result should be obtained with a low incidence of complications. METHODS: A retrospective, non-randomized study was performed to evaluate the success rate and vascular complications associated with the use of two different vascular sealing devices [Angio-Seal (Daig Corporation, Minnetonka, Minnesota) and Prostar (Perclose, Inc., Redwood City, California)] after interventional procedures. RESULTS: Eight-hundred and twenty-seven devices were used (245 Angio-Seal and 582 Prostar). Angio-Seal success rate was 92% with a 2.5% rate of vascular complications; Prostar success rate was 89% with a 3.4% rate of vascular complications. Multivariate logistic regression analysis identified advanced age (p < 0.05) and lower weight (p < 0.05) as independent predictors of vascular complications associated with Angio-Seal use, while diabetes (p < 0.05) was found to be a predictor of vascular complications in the Prostar group. Abciximab use and larger sheath size were not associated with an increased probability of vascular complications. CONCLUSION: Angio-Seal and Prostar obtain a fast vascular access hemostasis after interventional procedures, with a low incidence of major vascular complications.

Assessment of the functional significance of coronary lesions using a monorail catheter.

Myocardial fractional flow reserve (FFR) < 0.75 is a reliable index of a functionally severe coronary stenosis. FFR is best assessed by a sensor-tipped pressure monitoring guidewire (PW). The purpose of this study was to assess whether a multifunctional probing catheter (MFP), a 3 French dual-lumen monorail catheter, can be used to accurately measure intracoronary pressure and FFR. In 35 lesions (35 patients; learning group), we calculated FFR by both PW (FFRPW) and MFP (FFRMFP). Using ROC analysis, the FFRMFP value of 0.65 had the highest sensitivity with the FFRPW < 0.75. FFRMFP cut-off (0.65) was tested in 40 patients (testing group). In all cases, lumen diameter was documented by an intracoronary ultrasound examination. In the learning group, the FFRPW was 0.82 +/- 0.17 and FFRMFP was 0.70 +/- 0.23 (r = 0.88; p < 0.001). The FFRMFP cut-off value (0.65) correctly predicted the FFRPW in 37/40 cases in the testing group. In the 3 discordant cases, FFR was critical (< 0.65) by MFP and normal (> 0.75) by PW. In all these cases, minimal lumen cross-sectional area was < 2.8 mm2. When FFRMFP is > 0.65, FFRPW is always > 0.75. These data demonstrate that even with larger cross-sectional area than a pressure wire, the MFP catheter can easily and reliably be used to assess the functional severity of coronary stenosis.

Coronary stenting beyond standard indications. Immediate and follow-up results.

BACKGROUND: Coronary stent has become an accepted treatment modality for selected indications. However, the literature shows diverse results when indications for coronary stenting are different from those tested in large randomized trials. The purpose of this study was to determine immediate and follow-up clinical and angiographic results in patients treated with coronary stenting for indications not specifically tested in large randomized trials. METHODS: Coronary stents were implanted in a total of 2060 lesions (1757 patients) in seven groups with expanded indications: left main coronary lesions, calcified lesions, small vessels (< 3 mm in size), small vessels with diffuse disease, large vessels with diffuse disease, and bifurcation lesions treated with stents in both branches or with one stent implanted only in the major branch. Stents were implanted using high balloon pressure for final inflation and in most cases with intravascular ultrasound. Clinical follow-up was achieved in 96% of patients at a mean time of 12+/-7 months. RESULTS: Primary success (range 89-96%) and acute complications (range 5.7-13%) were comparable in all groups. At follow-up, the mortality rate was highest in the group of left main stenting (12.5%) but 20% of these patients had coronary stenting on non-elective basis. The restenosis rates ranged between 16-43%. The restenosis rate was highest in the group of bifurcation lesions with stent implantation in both vessels leading to a major adverse cardiac event (MACE) rate of 62% in this group. However, the survival rate at 1 and 2 years in the overall study group was 97 and 96%, and the event free survival was 76 and 74%, respectively. The procedure-related predictors of MACE were: final intravascular ultrasound result, use of stents with non-slotted tube morphology, final stent percent stenosis, and vessel size. CONCLUSIONS: Coronary stenting beyond standard indications is feasible, with acceptable primary success and complication rates. However, the overall MACE rates were relatively high (34-62%), in particular for the indication of bifurcation lesions with stents implanted in both vessels.

Intracellular localization of nerve growth factor in PC12 cells. An immuno-gold electron microscopic approach.

Nerve growth factor (NGF) localization in the clonal cell line PC12 has been assessed with the immunocytochemical colloidal gold staining (IGS) method. Three distinct fixation and staining procedures have been adopted to avoid possible artifactual localizations and to better assess NGF intracellular targets. Colloidal gold particles are observed in the cytoplasm and also within the nuclear compartment, close to the nuclear envelope. Gold particles are also detectable, in aggregates or patches, in proximity of or in association with, cytoskeletal elements tentatively identified with microfilaments (MF) present in the growth cone and microtubules (MT) running in parallel within the neurites or present in the perikaryon. Neurofilaments (NF), on the contrary, were devoid of any NGF-antibody cross-reacting material detectable with colloidal gold staining. It is postulated that the association of NGF or NGF-receptor complexes with cytoskeletal elements is instrumental for the mechanism of action of NGF.

Ultrastructure of dorsal root projections in the toad spinal cord. An experimental neuroanatomical study following transection of dorsal root.

The distribution and the modalities of termination of the dorsal root afferents in the toad spinal cord have been investigated. The morphological changes of degenerating fibres and boutons at different survival times after root transection have been followed. Degenerating boutons were clearly identified due to the occurrence of both the dark and the filamentous types of degeneration similar to that described in cats. Most of the central endings of the primary afferents terminated in the dorsal horn of the spinal cord; however, degenerating boutons were also observed in the ventral horn region of the gray matter. The density of the degenerating elements located in the ventral gray was always lower than that observed in the dorsal horn. Dark and filamentous boutons which were present in the motoneuronal region, did not appear to be in synaptic contact with the soma of the motoneurons.

Effects of sleep deprivation on the postnatal development of visual-deprived cells in the cat's lateral geniculate nucleus.

1. Observations made by Wiesel and Hubel in kittens during the critical period have shown that monocular visual deprivation (MD) produces hypotrophic changes in the deprived layers of the LGN. Since, in addition to retinal inputs, the LGN also receives extraretinal inputs which are particularly active during REM sleep (a phase which is highly represented at birth), we performed experiments to find out whether total sleep deprivation (SD) interferes with the neuronal maturation in the LGN, thus modifying the susceptibility of LGN neurons to MD. 2. Ten groups of twin kittens were submitted to eyelid suture of one side at the age of 12 to 42 days after birth, and maintained into MD for periods of time which produced only slight or negligible changes in the deprived LGN layers. However, one of the twins in each group was allowed to sleep, while the other was submitted to 2 to 6 days of SD obtained by gentle handling during the last period of MD. At the end of the experiments cross-sectional areas of cell bodies were measured in the binocular segment of different layers of the LGN of both sides, at comparable levels. 3. MD, started 25 to 42 days after birth and continued for 11 to 23 days produced a slight but significant reduction of the mean cell area in the visual-deprived magnocellular ventral (C) and/or dorsal (A) layers of the contralateral LGN, but not in the middle (A1) layer of the ipsilateral LGN. This shrinkage, however, was most severe and involved also the layer A1 if kittens were also submitted to 5-6 days of SD during the last period of MD. There was also a tendency towards increased size in the nondeprived geniculate layers, probably due to an increased monocular visual experience resulting from an increased wake time in the light. However, the slight increase in cell size seen in these layers contrasted with the prominent increase in shrinkage of the visual-deprived layers after SD, indicating that this finding might have resulted from removing an influence of sleep. The effects of SD appeared to depend on the age of kittens (critical period) and the duration of MD. 4. In conclusion, shortly after birth, SD enhanced the structural abnormalities produced by monocular eyelid closure in the visual-deprived LGN layers. Since rhythmic discharges of pontine structures impinge on the LGN neurons during REM sleep, it is postulated that they could represent an endogenous source of stimulation leading to periodic read out of the synaptic connections between primary optic fibers and LGN neurons. This extraretinal input may thus collaborate with the retinal input to facilitate neuronal maturation of the LGN. The possibility that specific noradrenergic and cholinergic neurons, normally acting on the visual system during the sleep-waking cycle, intervene in the postnatal development of the LGN neurons has been discussed.

Spinal projections from the rhombencephalon in the toad.

Rhombencephalic cell groups projecting to the spinal cord are demonstrated following single pressure injections and/or iontophoretic ejections of HRP solution in either cervical or lumbar enlargements of the toad spinal cord. A group uptake and transport of HRP were obtained with both application techniques, when sufficiently long survival times (8-11 days) were used. Following injections in the cervical cord labeled cells are located mostly in the ventral nucleus of the VIIIth nerve and in the medial zone of the rhombencephalic reticular formation, i.e. the nucleus reticularis inferior, medius and superior. Following injections in the lumbar enlargement the majority of labeled cells are situated in the caudalmost portion of the ventral nucleus of the VIIIth nerve and in the nucleus reticularis inferior. These observations indicate that in the toad the main supraspinal descending pathways from the rhombencephalon originate in the ventral nucleus of the VIIIth nerve and the medial zone of the reticular formation, and that both these pathways are somatotopically organized.