Brain cyclosporin A levels are determined by ontogenic regulation of mdr1a expression.

Cyclosporin A (CyA) toxicity is a common occurrence in pediatric organ transplant patients. We hypothesized that reduced mdr1a expression in newborn and developing mice would affect CyA accumulation within organs and/or toxicity. For functional studies, CyA was administered (5 mg kg(-1) i.p.) to 1-, 12-, and 19-day, and adult male and female mdr1a+/+ and mdr1a-/- mice. Peak blood CyA was lower in 1-, 12-, and 19-day-old (1000 ng ml(-1)) versus adult (1500 ng ml(-1)) mice but was similar in mdr1a+/+ and mdr1a-/- mice. Kidney mdr1a expression (measured by quantitative polymerase chain reaction) increased 2.5-fold in 19-day-old male and female mice and increased another 4-fold in adult females compared with adult males. Liver mdr1a expression increased 6-fold by day 12 compared with neonatal mice. Thereafter, maintenance of hepatic mdr1a expression in females and a reduction to neonatal levels in males was observed. Kidney/blood (8- to 9-fold) and liver/blood (12- to 15-fold) CyA levels were highest on days 12 and 19 and were not dependent on maturational changes in mdr1a mRNA levels. Adults had higher brain expression of mdr1a mRNA (3-fold), a corresponding 5-fold increase in immunodetectable P-glycoprotein, and 80% lower brain accumulation of CyA compared with 1-day-old mice. Conversely, in mdr1a-null mice, brain/blood CyA was similar in newborn and adult mice. A similar pattern was observed for the brain accumulation of the mdr1a substrate 3H-digoxin. We conclude that the risk for central nervous system drug toxicity could be higher in neonates or young children as a consequence of underdeveloped P-glycoprotein.     

The ED50 and ED95 of Intrathecal Isobaric Bupivacaine with Opioids for Cesarean Delivery

Background: The ideal intrathecal isobaric bupivacaine dose for cesarean delivery anesthesia is uncertain. While small doses (5-9 mg) of bupivacaine may reduce side effects such as hypotension, they potentially increase spinal anesthetic failures. This study determined the ED50 and ED95 of intrathecal isobaric bupivacaine (with adjuvant opioids) for cesarean delivery.

Methods: After institutional review board approval and written informed consent were obtained, 48 parturients undergoing elective cesarean delivery under combined spinal-epidural anesthesia were enrolled in this double-blind, randomized, dose-ranging study. Patients received a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-mg intrathecal isobaric bupivacaine dose with 10 [mu]g fentanyl and 200 [mu]g morphine. Overall anesthetic success was recorded when no intraoperative epidural supplement was required during the cesarean delivery. ED50 and ED95 values for overall anesthetic success were determined using a logistic regression model.

Results: ED50 and ED95 values for overall anesthetic success were 7.25 and 13.0 mg, respectively. No advantages for low doses could be demonstrated with regard to hypotension, nausea, vomiting, pruritus, or maternal satisfaction, although this study was underpowered to detect significant differences in secondary outcome variables.     

Virtual real-time digital processing of hemodynamic data

At present, the majority of cardiac catheterization laboratories acquire and store hemo-dynamic data in analog form. To examine the possibility of performing complex analysis of digital data during the catheterization procedure, we examined whether virtual realtime digital (fast Fourier) analysis improves the accuracy of clinical data. We compared digital filtering of fluid manometry during right heart catheterization with 10-Hz and 250-Hz analog filters. Using the simultaneously acquired micromanometry as the “gold standard,” we found that analog filtering is associated with a greater error and time delay than digital filtering. This study demonstrates that digital hemodynamic data analysis performed during cardiac catheterization can improve the quality of data obtained during right heart catheterization, with the results available within seconds. More extensive use of computers in the cardiac catheterization laboratory may be useful for both clinical and research purposes. © 1992 Wiley-Liss, Inc.     

Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: A phase I study

Background: We performed a phase I study of a novel system of complete hepatic venous isolation and extracorporeal chemofiltration in patients with unresectable hepatocellular carcinoma (HCC) to determine (a) whether systemic exposure to doxorubicin could be limited after high-dose hepatic arterial infusion (HAI), and (b) the hepatic maximum tolerated dose (MTD) of doxorubicin. Methods: Ten patients with biopsy-proven HCC were treated with 20-min HAI of doxorubicin (17 total treatments). Two patients were treated with doxorubicin 60 mg/m², three patients were treated at 90 mg/m², and five patients received 120 mg/m². A newly developed dual-balloon vena cava catheter was advanced from the femoral vein, and the balloons were inflated to isolate and capture total hepatic venous outflow. The hepatic venous blood was pumped through extracorporeal carbon chemofilters before return of the blood to the systemic circulation. Results: Peak systemic doxorubicin levels were an average 85.6% lower than were peak prefilter levels (p<0.01). Because all catheters were placed percutaneously and because the chemofiltration markedly limited systemic chemotherapy exposure, patients were discharged 1 day after 16 of the 17 treatments. The hepatic and systemic MTD of doxorubicin in this treatment protocol was 120 mg/m². Conclusions: This novel system of complete hepatic venous isolation and chemofiltration limits systemic chemotherapy toxicity and will allow use of higher doses of chemotherapeutic agents to treat HCC. The results of this study were presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.     

Malignant oncocytoma of the maxillary sinus— An ultrastructural study

A unique case of a malignant oncocytoma of the maxillary sinus is reviewed in detail. The ultrastructural findings are presented. The histologic and ultrastructural criteria that characterize onco-cytes and the clinicopathologic features of benign and malignant oncocytomas are discussed. This case represents the eleventh reported case that would truly qualify as a malignant oncocytoma of the paranasal sinuses.     

In vivo mapping of drug-induced seizures with voltage-sensitive dye

The voltage-sensitive dye diO-C2-5 was used to produce an in vivo map of the membrane potential in two types of seizures. Mild limbic seizures were induced in rats with kainic acid; clonic convulsive seizures were induced with bicuculline. Kainic acid animals showed various levels of neural depolarization during their seizures in limbic, thalamic, cortical, and brainstem sites. The bicuculline animals showed uniformly greater levels of neural depolarization during their seizures. The magnitude of these changes relative to controls varied across seizure models and reflected the different underlying neural mechanisms for each model. The ability of the technique to capture local electrical events provides a new tool in which to explore brain activity.     

Subclavian vein repair in patients with an ipsilateral arteriovenous fistula

Management of subclavian vein occlusive disease in persons with an ipsilateral arteriovenous fistula can be challenging. From July 1991 to May 1993, nine patients underwent direct exploration and repair of an obstructed subclavian vein following medial claviculectomy. Eight patients had polytetrafluoroethylene (PTFE) grafts; one patient had a Brescia-Cimino fistula. Intractable arm edema was the major symptom in five of eight. The site of the occlusive disease ranged from the midsubclavian vein to the proximal innominate vein. Pathology varied from a focal occluding web to a long segment of intimai fibroplasia. Five veins were occluded; four were stenotic. Surgical procedures consisted of endovenectomy and vein patch (four), endovenectomy and PTFE patch (one), resection of a focal stricture with end-to-end anastomosis (two), resection with PTFE interposition (one), and end-to-end internal jugular to subclavian vein transposition (one). Postoperative contrast venograms revealed a patent subclavian vein in eight of eight patients. One patient died postoperatively from unrelated causes; two patients died with a functioning fistula 8 and 12 months, respectively, after surgery. Two grafts were removed for infection and one deteriorated graft was abandoned because of repeated thrombosis. Only three of nine original grafts are currently in use, including one in which the ipsilateral subclavian vein rethrombosed. Although stent placement may now be the preferred treatment for subclavian vein stenosis, vein repair may still have a role in the treatment of subclavian vein occlusion, particularly in patients with a Brescia-Cimino fistula.Presented at the Twelfth Annual Meeting of the Southern California Vascular Surgical Society, Coronado, Calif., September 17–19, 1993.