Nighttime dosing assures postdistribution sampling for therapeutic drug monitoring of digoxin.

To study the appropriateness of phlebotomy for digoxin therapeutic drug monitoring (TDM) in outpatients, we conducted a retrospective chart review, a computer search of all previous TDM testing, and a questionnaire of all outpatients (n = 86) who had serum digoxin determinations between April 10 and April 28, 1992 (585 tests). In patients who took digoxin at the same time daily (40 patients, 300 tests), 52% of tests were performed on inappropriate samples drawn within 6 h of the last dose. No patient who took digoxin after 1700 had inappropriate tests. Phlebotomy for serum digoxin determinations before distribution of digoxin is complete is a common problem in outpatients, leading to clinically uninterpretable test results. Postdistribution sampling can be assured by nighttime dosing, and this recommendation has been implemented at our hospital.

Ischemic changes in fetal myocardium. An autopsy series.

It has been assumed that fetal myocardial necrosis is an uncommon event that occurs only under unusual circumstances. We studied random heart sections on 76 fetal and perinatal autopsies from a 4-year period to determine the types and frequency of histologic abnormalities that occur in fetal myocardium. Vacuolar degeneration was extremely common (43% of stillbirths, 84% of live births) but a nonspecific finding. Ischemic changes, which are typically associated with coagulation necrosis, myofiber waviness, or contraction band necrosis, were seen in 21% of stillbirths and 32% of live births. In the majority of cases with histologic evidence of ischemic change, a combination of either contraction band necrosis, coagulation necrosis, and/or myofiber waviness was identified. Only rarely was any one of the abnormalities seen as an isolated feature. In only two autopsies were the ischemic changes identified in the initial autopsy report. We conclude that the histologic changes associated with ischemia that may represent myocardial necrosis are not uncommon and are frequently overlooked at autopsy.

Value of repeat cervical smears at the time of colposcopic biopsy.

At our institution, gynecologists perform Pap smears not only as an initial screening procedure but also at the time of colposcopy and biopsy. We compared the results of initial Papanicolaou (Pap) smears with those taken at colposcopic biopsy to determine if repeating the Pap smear at the time of colposcopy contributed to patient management. We found that repeat colposcopic smears often agreed with the referral smears and biopsies. When there was disagreement, the colposcopic smear was more often a lower grade than the referral smear and correlated best with the biopsy. Both referral and colposcopic smears underestimated the severity of cervical lesions with the same frequency. We could document only 5/414 (1.2%) colposcopic smears that contributed to patient care.

Intra-blood-brain barrier synthesis of IgG: comparison of IgG synthesis formulas in a computer model and in 1,629 consecutive specimens.

We evaluated four formulas for estimating the intra-blood-brain barrier (IBBB) synthesis of IgG in a computer model of two types of BBB damage and in 1,629 consecutively received pairs of CSF and serum. These four formulas were the IgG synthesis rate (SR), IgG(loc) (ie, local), IgG index, and IgG extended index. Results from the 1,629 specimens and the computer model of type 2 BBB damage (partial or total loss of selective filtration) accurately predicted problems encountered with the IgG SR in clinical practice. In both the model and with the results from the 1,629 specimens, the combination of the IgG(loc) and IgG index formulas minimized the possibility of false-positive and false-negative results and yielded the most reliable results for IBBB synthesis of IgG in the presence or absence of increased permeability of the BBB. Additional studies with detailed clinical correlations will allow an accurate assessment of how effectively this combination of formulas can help to rule in or out the diagnosis of a particular disease or inflammatory condition of the CNS.

Genetically engineered endothelial cells remain adherent and viable after stent deployment and exposure to flow in vitro.

Intravascular stents, currently in experimental human use for recurrent arterial stenosis, are plagued by subacute thrombosis. As a therapeutic approach to stent-related thrombosis, we and others have suggested coating stents with endothelial cells before implantation. In a previous study we demonstrated the feasibility of coating stents with endothelial cells that were genetically modified to secrete large amounts of human tissue plasminogen activator. In the present study we attempted both to develop a clinically applicable protocol for stent seeding and to test whether seeded cells would remain adherent to stents after exposure to pulsatile flow. Endothelial cells were harvested from the saphenous veins of sheep with survival of the donor animals. Harvested cells were transduced with a retroviral vector containing a marker gene and seeded onto catheter-mounted stents under sterile conditions. Scanning electron microscopy revealed complete coverage of the stent surfaces by seeded cells. Stents were expanded and exposed to pulsatile flow in vitro. Substantial cell retention was observed on the lateral stent surfaces by light microscopy and scanning electron microscopy; fewer cells were seen on the luminal and abluminal surfaces. Removal of seeded cells from flow-exposed stents by trypsin digestion resulted in the recovery of approximately 70% of the seeded cells. These cells were viable and healthy as judged by their ability to proliferate to confluence with the same kinetics as control (non-flow-exposed) cells. Autologous genetically modified endothelial cells can be seeded onto catheter-mounted stents in a sterile manner, and stent deployment under flow conditions results in substantial retention of viable cells.

Multicentric papillary-cystic neoplasm of the pancreas.

Two distinct papillary-cystic neoplasms were found in the pancreas of a young black woman. She presented to the hospital in her first trimester of pregnancy with the chief complaint of sharp right upper quadrant abdominal pain that radiated to the right shoulder. This was associated with jaundice, vomiting, and pruritus. On examination, a large, nontender, midepigastric abdominal mass was palpated. Serum liver enzyme levels were moderately to markedly elevated. An abdominal computed tomographic scan revealed a 9-cm solid and cystic mass located within the head of the pancreas with associated marked bile duct dilatation. A total pancreatectomy was performed. Gross examination of the specimen revealed two separate well-circumscribed tumors of unequal size. The larger one was found within the head of the pancreas and contained multiple hemorrhagic, cystic cavities. The smaller one, located within the tail, consisted primarily of solid tissue. Microscopic examination of both lesions revealed papillary-cystic neoplasms. To our knowledge, this is the first report of two synchronous papillary-cystic tumors of the pancreas and the first reported demonstration of the potential of this tumor for multicentricity.

Electrical thermal angioplasty: catheter design features, in vitro tissue ablation studies and in vivo experimental findings.

A prototype electrical thermal tip catheter has been developed for ablation of atherosclerotic plaques. The operating principle is based on establishing an electric arc between a central electrode and the inside of an enclosing metallic tip to convert electrical energy to thermal energy. The metal tip catheter can be heated rapidly and boils water in a saline bath with less than 1 W of power. In vitro studies, using human atherosclerotic aortic segments, demonstrated that effective tissue ablation required more power in saline than in air (more than 9 W vs less than 1 W). The rate of tissue ablation varied with the amount of power delivered and the catheter tip pressure against tissue. In a saline field, 2-mm thickness aortic wall segments were consistently perforated in 3 seconds when 15 W of power and 20 g/mm2 of pressure were applied. Using an atherosclerotic rabbit, in vivo electrical thermal angioplasty (3 W of power for 10-second treatment sequences) was performed in obstructed iliofemoral vessels after mechanical recanalization was attempted. Of the 7 vessels that were more than 50% narrowed (compared with contiguous normal vessel diameter), mechanical recanalization was effective in only 1, but thermal angioplasty resulting in an increased lumen diameter was successful in 6 others. The recanalized segments were 8 to 10 cm; gross morphologic and histologic examination of recanalized vessels demonstrated little or no thermal injury. In addition, significant cholesterol-laden plaques remained in the vessel lumen, which appeared to have been compressed and displaced laterally.(ABSTRACT TRUNCATED AT 250 WORDS)

Glioblastoma: catheter techniques for isolated chemotherapy perfusion.

Techniques have been developed for isolated perfusion of chemotherapeutic agents in patients with glioblastoma. Three catheters that facilitate crossing the carotid siphon have been developed; two are based on an everting or toposcopic principle, and one uses microjets for deflectability and improved mixing. Blood from the ipsilateral jugular vein is aspirated at high volumes (300 ml/min) for extracorporeal circulation through an adsorption column (for recovery of carmustine) or dialysers (for recovery of cisplatin). Preliminary experience in 10 patients suggests that high doses of chemotherapeutic agent can be administered using these catheters, with reduced retinal and systemic toxicity.

Long-term survival of normal adult human tissues as xenografts in congenitally athymic nude mice.

Bronchi, pancreatic ducts, and colons from adult human were maintained as xenografts in congenitally athymic nude N:NIH(S) mice for 715, 145, and 89 days, respectively. After an ischemic crisis and revascularization of the human tissue, the epithelium regenerated to a normal differentiated morphology. The long-term survival of normal adult human epithelial tissues as xenografts provides model systems for the study of the interactions of chemical and/or physical carcinogens with human tissues.

Mapping of cerebral cortical strokes in Rhesus monkeys by laser Doppler spectroscopy.

We have demonstrated the feasibility of using laser doppler spectroscopy to map regional blood flow distribution on the surface of the cerebral cortex. Rhesus monkeys underwent craniotomy, with replacement of part of the calvarium by a transparent plastic dome. A stroke was produced on one side by ligation of the middle cerebral artery. A flow index was computed from a weighted bandwidth of the doppler spectrum of helium-neon laser light scattered from the surface of the cortex, the doppler shift being due to scattering from moving blood cells in the microcirculation. By measuring the doppler flow index at a grid of points over the surface, the region of the stroke was easily delineated, and its progression with time observed. The method provides a rapid measurement with a spatial resolution of about 1 mm.

Renal tubular transport of gentamicin in the rat.

The renal handling of gentamicin in the rat was examined by clearance, microinjection, and renal cortical-slice techniques. The steady-state renal clearance of 14C-gentamicin, when corrected for the 7.5% binding to plasma protein, was not significantly different from that of 3H-inulin. At the end of the renal clearance experiments, the cortical concentration of gentamicin was 93 +/- 7 microgram/g of tissue (N = 7), a concentration threefold greater than that of the medulla and 20-fold greater than that of serum. Absorption of 3H-gentamicin along the proximal convoluted tubule and loop of Henle was demonstrated by the tubular microinjection technique. No reabsorption of 3H-gentamicin was detected beyond the early distal convoluted tubule. The tubular absorption of 3H-gentamicin was load dependent. Fractional absorption of 3H-gentamicin averaged 30.1 +/- 2.7% when the dose of 3H-gentamicin injected into early proximal tubular convolutions averaged 132 +/- 17 pg. It was decreased to 13.6 +/- 2.6% when the microinjected dose of gentamicin was increased to 1996 +/- 388 pg. No evidence of transtubular absorption of 3H-gentamicin was detected during the microinjection experiments. Microperfusion of pertubular capillaries failed to demonstrate urinary precession of 3H-gentamicin over 14C-inulin, a finding which argues against a rapid transtubular secretory flux of gentamicin. Significant uptake of gentamicin was demonstrated by renal cortical slices incubated in medium containing 14C-gentamicin. The accumulation of 14C-gentamicin by renal cortical slices was not inhibited by probenecid or N1-methylnicotinamide but was inhibited by netilmicin and tobramycin. These data support the conclusion that the renal accumulation of gentamicin reflects transport of gentamicin across both the apical and basolateral membranes of proximal tubular epithelium.

The microscopic characterization of multinucleated giant cells formed on polymeric surfaces perfused with blood.

Multinucleated, foreign body giant cells were formed by the fusion of blood monocytes on polymeric membranes perfused with blood during extended extracorporeal circulation. In the current study, heparinized blood, flowing in an arteriovenous shunt in a sheep, perfused polycarbonate, polypropylene and silicone rubber membranes of a recently developed bioartificial tissue culture system. The multinucleated giant cells were studied by light, scanning electron, and transmission electron microscopy, after membrane perfusion for periods of one to two weeks. The giant cells, which were the predominant cellular components of the blood-polymer interface layer, contained from a few to more that one hundred nuclei and varied in diameter up to 400 microns. The cellular interaction with the three membrane types was similar, although fewer mononuclear cells were observed adhering to the silicone rubber membrane. The presence or absence of micropores in the membranes had no effect on the formation of giant cells, nor did the presence of foreign tissue in culture behind the microporous membranes. High blood flow rates and chronic anticoagulation with heparin permitted observation of this foreign body reaction of blood independent of thrombosis.