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Purpose: To determine the light dose required for photodynamic therapy of atherosclerotic lesions in the miniswine., Methods: Aortic atherosclerosis was created in seven Yucatan miniswine by a combination of balloon endothelial injury and 2% cholesterol and 15% lard for 7 weeks. Six animals received the photosensitizer Photofrin 2.5 mg/kg, while an additional swine received no drug. After 24 hours, the abdominal aorta was exposed and the aorta opened longitudinally in each animal. Three 1-cm spots were illuminated with energy densities of 60, 120, and 240 J/cm2 from an argon-pumped dye laser tuned to 630 nm with a laser output of 1 W. Four weeks later, the animals were killed, abdominal aortae removed, and intimal thickness determined by morphometry., Results: The percentage intimal thickness (mean +/- SD) was 36.7 +/- 27.1, 9.1 +/- 5.0, and 6.4 +/- 8.1 for the three energy densities, respectively. Although both 120 and 240 J/cm2 energy densities produced significant (p < 0.05) reduction in atheroma, considerable damage to the underlying media was also observed in the 240 J/cm2 group., Conclusions: A Photofrin dose of 2.5 mg/kg and 120 J/cm2 light are necessary for adequate ablation of atheroma while avoiding extensive medial damage.

Photodynamic therapy has been recommended as a method of preventing intimal hyperplasia. The purpose of this study was to determine the dose and timing of Photofrin porfimer sodium needed to achieve a 3:1 or higher ratio between injured and control arteries after balloon endothelial injury. New Zealand White rabbits were anesthetized and their right femoral artery surgically exposed. A 4Fr Fogarty balloon catheter was passed retrograde into the lower abdominal aorta, inflated and pulled distally into the external iliac artery six times. All rabbits received heparin 100 IU/kg. Arteriotomies were closed and the animals recovered. Rabbits (n = 5 per group) were given intravenous Photofrin at a dose and time according to the following scheme: group I, 5.0 mg/kg immediately after balloon injury; group II, 2.5 mg/kg immediately after injury; group III, 5.0 mg/kg after 1 week; group IV, 5.0 mg/kg after 2 weeks; or group V, 2.5 mg/kg after 2 weeks. Animals were killed 24h after drug administration and the aortoiliac segments removed for spectrophotofluorometric determination of Photofrin levels from injured and control segments. Mean(s.d.) ratios of injured: control arteries for groups I to V were 4.8 (2.6), 2.8 (1.2), 3.0 (1.0), 1.4 (0.3) and 1.0 (0.0) respectively. This ratio was significantly higher for group I rabbits compared with groups IV and V (P < 0.01, ANOVA). Fluorescence and light microscopy showed that Photofrin was localized primarily in the tunica media, and that the drug must be administered before significant intimal hyperplasia occurs.(ABSTRACT TRUNCATED AT 250 WORDS)

The Yucatan miniswine has been recommended as an animal model of advanced atherosclerosis. Atherosclerotic plaques developed in this model demonstrate foam cells, widespread fibrosis, and calcification, features suggestive of human atherosclerosis. We have observed the occurrence of intraluminal projections that appear peculiar to this animal model. Forty-three miniswine, weighing between 20 and 30 kg, were rendered atherosclerotic with a combination of balloon endothelial injury of the aortoiliac segments and dietary supplementation with 2% cholesterol and 15% lard. Endothelial injury was created by retrograde balloon catheter injury of the aorta and both external iliac arteries via cutdowns on the femoral arteries. Serum cholesterol prior to starting the diet and at 1, 2, and 6 weeks following initiation of the diet was 2.0 +/- 0.4, 11.6 +/- 4.0, 15.9 +/- 5.0, and 16.4 +/- 4.2 mM, respectively (p < .0001, ANOVA). Angiographically significant lesions were apparent in 33 of 37 (89%) animals (occlusion 20/37, stenosis 17/37) at 6 weeks postinjury. In three of six (50%) animals followed up to 16 weeks postinjury, trabecular areas were seen in the external iliac arteries on angiography. Light and electron microscopy demonstrated that these areas were covered with normal endothelium and projected into the lumen or bridged with the adjacent arterial wall. Foam cells and calcification were not seen in these lesions. This finding is not typical of human atherosclerosis and appears peculiar to this type of animal model.

The effects of fructose loading on the integrated cardiovascular function in vivo, glycemic control, glucose tolerance, and plasma lipid levels in nondiabetic and streptozotocin (STZ) diabetic rats were investigated. Endothelial morphology of the thoracic aorta was also assessed with scanning electron microscopy. Fructose-loaded nondiabetic rats exhibited elevated blood pressure and pulse rate, and signs of arterial atherogenesis, such as focal adherence of leukocytes and fibrin to the endothelium. Intraperitoneal glucose tolerance tests revealed a greater increase in plasma insulin in response to glucose challenge in these animals than in the control. Compared with the untreated STZ-diabetic animals, fructose-loaded diabetic rats had significantly greater hyperglycemia, glucose intolerance, and hyperlipidemia and higher blood pressure, but had a similar degree of hypoinsulinemia, cardiac dysfunction, and cardiac enlargement. They also showed signs of early atherogenesis. The central venous pressure and the susceptibilities of the rats to the induction of ventricular arrhythmias by intravenous infusion of aconitine were not significantly affected by either STZ injection or fructose loading. It is concluded that prolonged intake of an excessive amount of fructose has detrimental effects on the cardiovascular system, glucose metabolism, and plasma lipid levels in both nondiabetic and STZ-diabetic rats.

Objective: To determine the feasibility of treating atherosclerotic stenoses with photodynamic therapy (PDT)., Design: A prospective study with a 4-week follow-up., Subjects: Twelve Yucatan miniswine, weighing between 25 and 35 kg., Interventions: Aortoiliac atherosclerosis was created by a combination of balloon endothelial injury and dietary supplementation with 2% cholesterol and 15% lard for 7 weeks. Then the miniswine were given a porphyrin-type photosensitizer (Photofrin), 2.5 mg/kg intravenously, and treated with 630 nm light through an intravascular, cylindrical, diffusing fibreoptic probe, which was coupled to an argon-pumped dye laser to supply 120 J of laser energy., Main Outcome Measures: Differences in luminal narrowing before and after PDT., Results: Seven miniswine had an increase in luminal diameter, but five had no increase. Microscopy demonstrated a broad range of features in treated vessels, including areas with re-endothelialization and regions of platelet and blood cell adherence with absent or abnormal endothelium., Conclusion: Although this study demonstrated resolution in stenoses for some miniswine, questions concerning light dosimetry, mechanism of action and long-term effects remain to be determined.

The lingual foramen in the midline of the mandible causes confusion in terminology, incidence of occurrence and contents. A survey of 314 dried mandibles showed the foramen to be present in 311 specimens (99.04%). Sectioning of cadaver specimens illustrated a canal traversing the bone to approximately 50% of the buccolingual dimension of the mandible. The contents of the foramen were found to be an artery, which was an anastomosis of the sublingual branches of the right and left lingual arteries. Wire markers were placed in the foramen and the genial tubercles were covered with lead foil to illustrate the radiographic relationship between them. The radio-opacity peripheral to the foramen as seen on a radiograph is produced by the wall of the canal and not the genial tubercles as previously reported. While the foramen is not seen on many radiographs of the lower incisor region, this can be accounted for by a change in orientation of the x-ray beam. A pilot study revealed an incidence of 49% of the lingual foramen on periapical radiographs of the mandibular incisor region in an adult population, the previous reported incidence being 28%.

The present study employed a computerized forced-choice recognition memory task, the Multi-Digit Memory Test (MDMT), to examine the effects of instructional set (i.e., dissimulation information provided subjects) and motivation (i.e., monetary incentive) on simulated malingering behavior in a group of 119 university undergraduate students and 33 patients sustaining varying severity of closed-head injury. For the nonpatient groups, a significant effect of instructional set was revealed. Motivational incentive, however, did not affect forced-choice performance. Overall, significant performance differences emerged between all groups with nonmalingering students performing nearly perfectly, the brain-injured patients performing well above chance levels, sophisticated student malingers performing at chance, and naive student malingers performing well below chance levels. These results suggest the MDMT may offer a clinically useful and convenient addition to a neuropsychological assessment when there is suspicion of feigned memory problems. These data also support the use of naive and sophisticated malingering subjects in further analog studies addressing this topic.

This review assesses the efficacy and specificity of psychotropic medications used to control aberrant behavior in persons with mental retardation. It is concluded that neuroleptics, the most widely used psychotropic agents in this population, suppress aberrant behavior, but do so by suppressing behavior generally. An exception to this conclusion is that it may be possible to selectively suppress stereotyped behavior with neuroleptics. In addition, the empirical evidence indicates that, in some persons with mental retardation, opioid antagonists and methylphenidate are useful therapies for self-injurious behavior and hyperactivity, respectively. Lithium and beta-blockers are potentially useful for treating aggression.

A technique to produce teaching models of the maxillary sinus is described. Dental impression material is injected into the maxillary sinus of a cadaver and subsequently dissected out. Using an impression and mould technique in a series of steps, a stone model of the maxillary sinus is produced. The shape, size and configuration of the model can be seen and the dimensions measured. A radiopaque impression material can be used so that the radiographic outline of the maxillary sinus on standard radiographic projections can be shown. Models of both dentate and edentulous patients can be used to show anatomical variation and the relationship to teeth and are useful in teaching both gross and radiographic anatomy. Since 10 out of 11 specimens had 3 walls leading to the apex from a 4-sided base, it would appear that the classical description of a 4-sided pyramidal shape to the maxillary sinus is relatively uncommon.

In recent decades, the complexity of the endothelium and its major role in maintaining or altering blood vessel architecture are being revealed. In contrast, the vascular smooth muscle cell previously received the most attention. I suggest support of the hypothesis that the endothelium is the key to vascular disease. An altered endothelium in diabetes mellitus likewise is likely to be pivotal in vascular complications that develop. We have demonstrated that adherent monocytes, indicators of altered endothelium, occur in deoxycorticosterone acetate induced hypertension in male Wistar rats. The coronary artery and thoracic aorta were investigated using transmission electron microscopy. Details of hypertensive changes were revealed as well as early atherogenic pathology in the absence of dietary modifications. Scanning electron microscopy of thoracic aorta showed details of the luminal endothelial surface and adherent monocyte-macrophages in hypertensive animals. There were two cell types: numerous typical monocytes with upstream tails, and larger cells that may have been free grazing macrophages or macrophages that had returned to the circulation. Debris and amorphous material were particularly evident in vessels from hypertensive animals. Monocytes squeezed between intact endothelial plasma membranes (as seen in section), and were found as subendothelial foam cells and phagocytosing macrophages. The endothelial adherence of monocytes to the aortas from diabetic animals was significantly (p less than 0.05) elevated over that found in controls (but not different from control-hypertensive or diabetic-hypertensive animals) supporting the concept of altered endothelium in diabetes.

The portal vein was investigated in male spontaneously hypertensive rats (SHR), from Wistar-Kyoto (WKY) and Wistar strains, in animal 16-20 weeks old. In SHR, the inner circular smooth muscle was unchanged, but the outer longitudinal layer showed marked alterations in shape and size, readily observed in three-dimensional micrographs using scanning electron microscopy. The cells in both Wistar and WKY were elongate and tubular with little variation along their lengths and with a relatively smooth sarcolemma. This applied to both the inner and outer layers of smooth muscle. In contrast, the smooth muscle cells from SHR in the outer layer varied considerably in thickness along their lengths, and had very irregular outlines with numerous pits or depressions of varying sizes. In addition, the cells frequently had major forks or branches. The vasa vasorum running through the muscle layer, fibroblasts and nerve bundles were also identified. Sectioned material (transmission electron microscopy) showed a change in shape and hypertrophy of the smooth muscle cells from the portal vein of SHR, and also demonstrated a significant increase in paracellular connective tissue in the outer layer of smooth muscle. Such major morphological alterations in the outer layer of smooth muscle in the portal vein from SHR could have profound effects on functional studies.

Thigh vessels of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were unilaterally surgically denervated at 10 days of age by femoral nerve section. Denervated and contralateral control segments of saphenous arteries from 3- and 6-week-old rats were mounted in a small vessel myograph for study. Both strains showed growth changes in blood pressure, but there was no significant difference between WKY and SHR. Both strains also had significant growth changes in vessel dimensions and the in vitro measurements suggested that SHR vessels had a thicker wall. Denervation did not affect vessel size. Transmural nerve stimulation indicated loss of innervation due to the surgical procedure. In the denervated vessels, both norepinephrine (NE) and 5-hydroxytryptamine (5-HT) dose response curves were shifted to the left, indicating a postjunctional increase in sensitivity. Maximum tension developed was in the order K+ greater than 5-HT greater than NE. In comparing the two strains, vessels from 6-week-old SHR were less sensitive to 5-HT. Relaxation to acetylcholine was significantly decreased in denervated arteries from WKY, whereas in SHR the significant decrease occurred only at 3 weeks. Denervated vessels from both rat strains at 3 weeks showed greater relaxation to beta-receptor activation, but not at 6 weeks of age. Therefore, the absence of functional innervation resulted in altered function of the saphenous artery wall.

The postnatal development of adrenergic innervation was followed in peripheral blood vessels of Wistar rats. The femoral vessels and their branches, the superficial epigastric and saphenous vessels, and the tail artery, were investigated from birth to maturity. The proximal ends of the vessels were studied with fluorescence microscopy after the catecholamine was converted to a fluorophore by hot formaldehyde vapour, and ultrastructural morphology confirmed that the nerve varicosities mainly contained small vesicles with dense cores, typical of adrenergic innervation. Further confirmation was obtained with reserpine pre-pretreatment, the sodium borohydride specificity test, and experiments to alter the non-specific fluorescence of elastin. The nerves in the arteries were immediately adjacent to the external elastic lamina, and they retained this position throughout postnatal development. Of the three muscular arteries, the development of innervation was earlier and more intense in the saphenous and superficial epigastric arteries than in the tail artery. However, the tail artery surpassed the other two both in the total number of nerves and in the density of innervation per unit area beyond 12 days of age, and maintained this lead to maturity. The superficial epigastric artery had the smallest total number of nerves but had a greater density of innervation than the saphenous. The femoral artery did not develop any appreciable innervation. The femoral vein demonstrated the greatest amount of fluorescence of any of the veins, the others having considerably less innervation than their companion arteries.

The rat-tail artery was maintained in vitro for 2 weeks to investigate its suitability as an experimental model. The criteria were that (a) it should retain the overall histological organization with normal ultrastructural appearance of the smooth-muscle cells; (b) stored neurotransmitter which could be activated by experimental treatment should be absent; and (c) smooth-muscle ion transport mechanisms should fall within normal range. Vessels were maintained in Falcon tissue-culture dishes in Dulbecco's modified Eagle's medium. Either 2% or no serum supplement was found to be more suitable than 10% serum due to the high rate of cell proliferation induced by the latter. Light and electron microscopy of cross sections of the vessels indicated that the overall normal vessel architecture was retained, and the ultrastructural features predicted normal function. There were no discernible differences dependent on the length (up to 8- to 10-cm lengths) of the cultured vessel. Preliminary experiments with fluorescent microscopy showed that stored neurotransmitter in the nerves of the vessel wall was no longer present after 48 hr. Ultrastructural examination revealed that storage vesicles in vitro lost their dense cores, representing noradrenalin, between 41 and 48 hr in culture. Normal ion transport mechanisms were retained in the smooth-muscle cells of the arteries in vitro for up to 2 weeks when tested with ion-specific electrodes. Morphological and physiological evidence support the suitability of the rat-tail artery as a model for experimental testing of vascular tissues.

An improved method has been developed for fixation with potassium permanganate. Although this is one of the methods widely used to preserve the dense cores of adrenergic storage vesicles, fixation of other tissue components is usually poor. The main differences from previously reported methods using potassium permanganate are the use of a physiological saline as the vehicle for all solutions, and, following this, very rapid dehydration before infiltration with plastic. Cellular and intercellular details of tissue ultrastructure may, in general, be evaluated as satisfactorily as with conventional fixatives, with the exception of certain protein elements associated with ribosome, microtubule, and myofilament organization. Nerve endings with agranular or clear vesicles may be distinguished from adrenergic endings since the dense cores of the vesicles of the latter are preserved by this method.

The effects of micromolar concentrations of the ionophore X-537A (RO 2-2985) were studied using isolated preparations of the rat tail artery. The ionophore causes complete release of catecholamines from adrenergic nerves, which is the sole cause of the transient contractile response. The amines are released by a nonexocytotic process which seems to be related to the ability of X-537A to act as an efficient transmembrane carrier of Na+, k+, and H+. The ionophore also causes an almost complete and irreversible loss of the cocaine-sensitive component of metaraminol uptake by the tissue. X-537A dissipates the transmembrane concentration gradients of Na and K in the smooth muscle component of the preparation. This effect is unrelated to the release of endogenous catecholamines, and it can also be observed after the Na pump has been inhibited with ouabain. It is fully reversible, though not readily, and it can be induced repeatedly. In catecholamine-depleted strips, X-537A dissipates the transmembrane Na+ and K+ gradients without causing any change in tension. Stimulation of the rate of O2 consumption by X-537A in catecholamine-depleted tissue is reversible, and it is unaffected by ouabain and (or) removal of external Ca2+.

Laboratory and clinical experience in the monitoring of circulating heparin concentration of bioassay shows that the whole blood clotting time and the activated partial thromboplastin time differ in their reflection of the state of anticoagulation. The decay of biologic activity may be as short as 30 minutes in one patient or as long as 360 minutes in another. This fact may drastically affect patient response to the drug. Safe and rational clinical heparinization is dependent upon periodic monitoring of the circulating heparin concentration. The success of this method was illustrated in two representative patients.