Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers.

Neural control of bone metabolism and growth has been suggested, although the identity of participating neurons and neurotransmitters effecting this control has not been established. Immunohistochemical studies demonstrated a system of vasoactive intestinal peptide (VIP)-immunoreactive nerve fibers that innervate periosteum and bone in several mammalian species. Thoracic sympathetic chain ganglionectomy resulted in an ipsilateral loss of VIP-immunoreactive fibers in the periosteum of ribs, whereas dorsal root ganglionectomy had no effect. Injection of fast blue into rib periosteum labeled a population of VIP-immunoreactive sympathetic postganglionic neurons. Thus, postganglionic sympathetic neurons may provide an important means by which VIP regulates bone mineralization.

Transcatheter closure of patent ductus arteriosus in piglets.

To better determine the risks of transcatheter closure of a patent ductus arteriosus (PDA), a model of PDA was made in newborn piglets by using 5- to 7-mm angioplasty catheters to dilate the probe PDA. This maneuver resulted in a permanent PDA in most piglets. Four to 6 weeks later PDA closure was attempted using the Rashkind PDA occluder. Twelve such procedures were attempted, using clean but nonsterile technique. Nine of 12 PDAs were successfully closed. Two failures were the result of inability to successfully traverse the PDA. This problem was solved by using a long sheath to position the device properly. Four complications occurred, all related to device release: left pulmonary artery embolization in 1 case, femoral artery embolization in 1, torn pulmonic valve cusp in 1 and lodgment of a prosthesis on a pulmonic valve cusp. Two successfully implanted devices were infected at necropsy. This study demonstrates the value of a piglet model in testing transcatheter PDA occlusion devices, the importance of sterile technique in such procedures, the hazards of device retrieval through the right heart and the feasibility of transcatheter PDA closure.

Considerations in setting up a positron emission tomography center.

Clinically oriented imaging with position emission tomography (PET) has come of age. Given an adequate referral base and physician interest, a compelling argument can be made at all levels of the review process for setting up a PET program in a clinical setting. PET is expensive. It is obvious that the cost of running a PET service depends heavily on an institution's ability to obtain reasonable financing. Educational institutions have the opportunity to acquire special funding through a variety of sources. On the other hand, money can be expensive for private entrepreneurs. It appears that in the near future PET centers will probably remain at educational institutions or large well-financed community hospitals able to raise money at reasonable rates until reimbursement issues are better resolved. Finally, the future of clinical PET may hinge significantly on the ability of commercial radiopharmaceutical suppliers to provide regional fluorodeoxyglucose distribution. As an institutional program development, PET offers opportunities by providing unique clinical data aiding the referral pattern. PET may serve as a magnet for recruitment in many areas and may promote interdisciplinary cooperation. A clinical PET center serves both as a model for future and more widespread use of PET and as a training ground for medical personnel. Finally, the unique capabilities of PET may facilitate grant opportunities.

Iopamidol as a gastrointestinal contrast agent. Lack of peritoneal reactivity.

The ideal contrast agent in patients suspected of having gastrointestinal perforation is an iso-osmolar, or nearly iso-osmolar substance, that causes no peritoneal reaction. Iopamidol is a nonionic water-soluble contrast medium that may be considered in such situations. Intraperitoneal injections of ionic and nonionic contrast agents were compared in rats to study potentially harmful peritoneal inflammation. Only intraperitoneal barium injection produced any significant tissue reaction, such as adhesions and ascites. There was no difference between iopamidol and the other water-soluble contrast agents. Iopamidol may satisfy the need for nonreactive and nearly iso-osmolar contrast agents for evaluating patients with possible bowel perforation. However, the high cost of this agent may make its clinical application impractical.

Synthesis of (+/-)-[18F]BMY 14802, its enantiomers and their anatomical distributions in rodents.

A potential antipsychotic drug, BMY 14802 was labeled with 18F and its distribution in rodents was studied. No-carrier-added (NCA) (+/-)-[18F]BMY 14802 (5) was synthesized by two methods in 5-10% radiochemical yield in a synthesis time of 130-140 min from EOB with a specific activity of 0.5-1.5 Ci/microM. (+)- and (-)-[18F]BMY 14802 was synthesized by the chiral reduction of alpha-(4-[18F]fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-b utanone (4) with chiral reducing agent, (+)- and (-)-beta-chlorodiisopinocampheylborane [(+)- and (-)-DIP chloride] in 6-10% radiochemical yield in a synthesis time of 150 min from EOB. Animal studies in mouse and in rat revealed that the distribution of 5 in each tissue was high at 5 min, the radioactivity then declined rapidly in all tissues studied except in the liver and in the small intestine. The radioactivity in the femur did not increase with time indicating in vivo defluorination may not occur. The uptakes of (+/-)-[18F]BMY 14802 and its enantiomers, (+)- and (-)-[18F]BMY 14802 in rat cerebellum, brain stem, hippocampus and spinal cord were similar and were significantly reduced by prior treatment of rat with haldol. This suggests that (+/-)-[18F]BMY 14802 and its enantiomers bind to sigma-receptors in a similar fashion.

Synthesis and biological evaluation of [11C]MK-912 as an alpha2-adrenergic receptor radioligand for PET studies.

In vitro studies showed that MK-912 ((2S, 12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octahydro -2H-benzo[b]furo[2,3-a]quinolizine)-2,4'-pyrimidin-2'-one) is a potent alpha2-adrenergic receptor antagonist with high affinity (Ki = 0.42, 0.26 and 0.03 nM to alpha2A, alpha2B and alpha2C, respectively) and high selectivity (alpha2A/alpha1A = 240; alpha2A/D-1 = 3600; alpha2A/D-2 = 3500; alpha2A/5-HT1 = 700; alpha2A/5-HT2 = 4100). The compound was labeled with 11C and evaluated in rodents and monkey as a specific radioligand for studying alpha2-adrenergic receptors using PET. [11C]MK-912 was synthesized by methylation of its desmethyl precursor, L-668,929, with [11C]CH3I in (Bu3O)P=O at 85 degrees C for 8 min followed by purification with HPLC in 18% yield in a synthesis time of 45 min from end of bombardment (EOB). The specific activity was 0.83-0.93 Ci/micromol and the radiochemical purity was 97%. The initial uptake of [11C]MK-912 in mouse brain, heart, lung, liver and kidney was high (5%, 4%, 5%, 17% and 8% per gram of organ, respectively, at 5 min postinjection) and the activities were then slowly cleared from these organs. The uptake of [11C]MK-912 in rat olfactory tubercle, a brain region with high density of alpha2-adrenergic receptors, was reduced by 30%, and the ratio of radioactivity in olfactory tubercle/cerebellum was reduced from 2:1 to 1:1 by coinjection of [11C]MK-912 with a potent alpha2-adrenergic receptor antagonist, atipamezole (3 mg/kg), indicating that compound 2 binds to alpha2-adrenergic receptors. However, a PET study in a rhesus monkey revealed that the initial influx of [11C]MK-912 into various brain regions (cerebellum, cortex, olfactory tubercle and striatum) was high (0.02%/cc), and the radioactivity was then washed out slowly and without significantly differential retention in these brain regions. This, coupled with the fact that none of the high-density alpha2-adrenergic receptor brain regions exceeds a few millimeters in diameter, suggests that [11C]MK-912 is probably not an ideal radioligand for studying alpha2-adrenergic receptors in humans using commercially available PET.

Fluorine-18 and carbon-11 labeled amphetamine analogs--synthesis, distribution, binding characteristics in mice and rats and a PET study in monkey.

No-carrier-added (NCA) (+-)-p-[18F]fluoroamphetamine (2a) and (+-)-6-[18F]fluoro-3,4-methylene-dioxy-amphetamine (2b) were synthesized through a multistep synthesis by nucleophilic substitution of the appropriate precursors (p-nitrobenzaldehyde, 1a and 6-nitropiperonal 1b, respectively) with [18F]fluoride followed by condensation with nitroethane and reduction with LAH in 20-30% yield (EOB) in a synthesis time of 90-109 min from EOB. NCA (-)-[11C]methamphetamine (4a) and (+-)-3,4-methylene-dioxy-N-[11C]methamphetamine (4b) were synthesized by methylation of the appropriate desmethyl precursors 3a and 3b with [11C]H3I in 40-60% yield (EOB) in a synthesis time of 30 min from EOB. Animal studies in mouse and rat revealed that the relative tissue uptake of these radiotracers was kidneys > lungs > liver > spleen > brain > heart > blood. The uptakes of these radiotracers in mouse brain were high and similar at 5 min post-injection (approx. 5%/g) but radioactivity then declined rapidly (approx. 1%/g at 60 min post-injection). For compounds 2a and 2b, the activity in the femur did not increase with time indicating in vivo defluorination may not be the major route of metabolism. Monoamine uptake inhibitors (nomifensine, fluoxetine and nisoxetine) did not inhibit but enhance the uptake of (-)-[11C]methamphetamine (4a) in the rat brain by greater than 50%. A PET study in a Rhesus monkey revealed that the uptakes of (-)-[11C]methamphetamine in different brain regions were similar and the retention of the radioactivity in these regions remained constant throughout the study. Analysis of arterial plasma by HPLC showed that 50% of radioactivity remained as 4a at 60 min post-injection.

Improved safety of splenoportography by plugging of the needle tract.

Splenoportography, a useful preoperative diagnostic procedure in patients with portal hypertension, has been largely discontinued because of the risk of hemorrhage. We have used both Ivalon and Gelfoam in particle and plug form to plug the needle tract after splenoportography. Initial studies were conducted on six dogs. Plugging of the needle tract by injection of suspensions of small Gelfoam or Ivalon particles resulted in intravasation of these particles into the splenic vein. This was demonstrated by radioactive tagging of particles and the direct collection of splenic blood during the intrasplenic injection. Plugging of the splenic needle tract with compressed Gelfoam caused immediate, complete cessation of bleeding in fully heparinized animals. Because of these experimental results, five humans with decreased platelet counts and severe portal hypertension underwent successful splenoportography without significant hemorrhage. At surgery, successful plugging of the needle tract by Gelfoam was confirmed.

Intrarenal Doppler: characteristics of aging kidneys.

The normal range of Doppler findings in native kidneys has not been studied extensively. This study correlates changes in Doppler resistive index (RI) with age in patients without renal risk factors or renal disease. Young and old patients demonstrated the highest RI values (age < 1, mean RI = 0.73; age > 59, RI = 0.68), and patients in the 20-39 year age group showed the lowest values (RI = 0.59). The mean RI for all ages was 0.63. The cause of this variability is unknown. We suggest that age-related changes in Doppler values should be considered in the interpretation of renal Doppler measurements.

Complications of wedge hepatic venography.

During wedge hepatic venography, mechanical injection should be accomplished at the lowest possible rate in order to avoid hemorrhagic infarction. Small amounts of contrast material should be administered. Hepatic angiography may result in an area of tumor blush at the site of a previous wedge injection.

The vasa vasorum and angioplasty.

Interruption of flow in the vasa vasorum may lead to medial necrosis and aneurysm formation. The purpose of this study was to determine whether angioplasty produces significant alterations in the morphology or blood flow of the vasa vasorum of the dilated artery. The morphology of the canine vasa vasorum was studied before and after angioplasty; in a separate experiment vessel wall blood flow (VWBF) in canine carotid arteries was measured after angioplasty to determine whether physiologic regulation of the blood flow was disrupted by arterial dilation. No morphologic changes could be demonstrated in the vasa vasorum of the dilated artery; however, VWBF was increased by 1194 +/- 215% (mean +/- standard error, p less than 0.01) between 90 and 120 minutes after angioplasty. VWBF in the adjacent nondilated arterial segment was also increased (720 +/- 177% between 10-30 minutes, p less than 0.01) but returned toward normal after 60 minutes. Adenosine caused a "paradoxical" decrease in VWBF (p less than 0.05) of the dilated arterial segment while causing increased VWBF (p less than 0.05) in the thoracic aorta. Angioplasty appears to produce persistent hyperemia in the dilated arterial wall. A paradoxical response to adenosine suggests that vasa vasorum in the dilated arterial segment are maximally vasodilated. This may be due to mechanical disruption of vasomotor tone or to release of vasoactive substances.

Spermatic vein obliteration using hot contrast medium in dogs.

Obliteration of varicoceles in men with infertility has been shown to improve semen quality and increase fertility rates. Many current techniques involve complex procedures and specialized equipment and may be associated with adverse effects. Transcatheter thermal vessel occlusion was utilized for spermatic vein obliteration in dogs. Diatrizoate (76%) contrast medium at a temperature of 100 degrees C was injected into canine spermatic veins. Follow-up venography and histologic examination revealed thrombosis of the injected veins without damage to the surrounding tissues in all cases. Clinical and laboratory examination of the animals revealed no adverse systemic effects. It is concluded that transcatheter thermal venous occlusion is an effective technique for spermatic vein occlusion in a canine model.

Work in progress. Transcatheter thermal venous occlusion: a new technique.

Diatrizoate (76%) contrast agent heated to 100 degrees C was injected into the veins of dogs and one human volunteer for the nonsurgical occlusion of the vessels. Follow-up venograms and histologic examinations, at intervals varying from one day to four weeks later, revealed thrombosis of the injected veins in all animals. Thrombosis occurred one to five days after injection of contrast agent. The authors conclude that hot contrast medium is a safe and convenient agent for inducing thrombosis. It is much easier to use than mechanical devices, tissue glues, and plastics, which involve complex procedures and specialized equipment. In contrast to other sclerosing agents, hot contrast agent is rapidly converted into a nonsclerosing agent by cooling. The new technique allows a more controlled thermal injury to the vascular wall and is under fluoroscopic control.

A combination of stainless steel coil and compressed Ivalon: a new technique for embolization of large arteries and arteriovenous fistulas.

The abdominal aortas in eight dogs were successfully occluded with a combination of stainless steel coils and compressed Ivalon (polyvinyl alcohol). There was no evidence of recanalization up to six months later. This combination is useful for the embolization of large arteries and arteriovenous fistulas.

Therapeutic blockade of arteries using compressed Ivalon.

A new technique for embolization with compressed Ivalon plugs is described. Fourteen arteries--six renal, three splenic, two pulmonary, one left gastric, and two abdominal aortas--were occluded in six dogs. In one case of renal artery embolization, three plugs were used, and in one case of abdominal aorta embolization, two were needed for total occlusion. In all other cases only one plug was used. Total occlusion was angiographically demonstrated up to five months following embolization in all but one case. In this case, recanalization was thought to have occurred because of overcompression of the Ivalon plug.

The use of the bristle brush for transcatheter embolization.

Small nylon brushes with a stainless steel core have been found safe and effective for transcatheter arterial occlusion. Studies performed in 14 dogs demonstrate the brushes result in rapid occlusion of the renal artery. Follow-up studies for periods up to ten months document the safety and permanence of the occlusion. The animal studies reported herein suggest that these devices can be safely used in humans in cases where large artery occlusion is desired.

Detachable stainless-steel spider. A new device for vessel occlusion.

A new device for transcatheter vessel occlusion consists of a stainless-steel spider which can be screwed onto a threaded guide wire. Since the spider can be retrieved after it is extruded from the catheter, accurate placement is possible. The device was tested in the aorta and pulmonary artery of dogs. The spider blocked the movement of steel coils and wool streamers and occluded the vessel. This device is particularly useful for occlusion of large arteriovenous fistulas in the lungs.

Endovascular diathermic vessel occlusion.

The feasibility of endovascular diathermic vessel occlusion (EDVO) is demonstrated in canines. The technique was standardized by measuring current flow through a monopolar intravascular electrode. Between 150 and 350 mA were applied to a spider-shaped intravascular electrode producing venous occlusion without perivascular damage. With further refinements in instrumentation, EDVO holds promise as a quick, safe method of therapeutic vascular occlusion that may eventually be applied clinically for spermatic vein occlusion.

Percutaneous arterial grafting.

A new technique for percutaneous arterial grafting was developed using a unique metal alloy (nitinol) with a heat dependent memory. Ten tightly wound nitinol coils (5-15 mm in diameter and 2-5 cm in length) were straightened in ice water and passed via catheter into the iliac artery or abdominal aorta of nine animals. Long term patency (15 weeks) was demonstrated in all but one graft. In one animal, an experimentally created abdominal aortic aneurysm was successfully treated by interposition of a nitinol graft. This new technique may be a valuable adjunct to conventional treatment of both obstructive and aneurysmal arterial disease in man.

Percutaneous removal of ureteral calculi: clinical and experimental results.

Between May 1983 and October 1984, 51 patients who had 68 ureteral stones underwent treatment at the University of Minnesota. All 68 stones were removed successfully using percutaneous techniques. The 100% success rate is a great improvement over previous results at our institution. The primary factors appear to be the development of the retrograde-flush technique, familiarity with and access to a wider range of methods, and the increasing use of the retrograde ureterorenoscope to see stones in the lower ureter. The average patient was a 45-year-old man who had no other medical problems. The average hospital stay was 6.8 days. Experimental studies with dogs indicate that injection rates of up to 30 ml/sec of contrast material through a retrograde catheter in the ureter are safe if a vent is present in the upper collecting system.