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D A August

Publications and source records attributed to D A August.

At least 19 recordsLinked to original sources

Temporal sequence compression by an integrate-and-fire model of hippocampal area CA3.

Cells in the rat hippocampus fire as a function of the animal's location in space. Thus, a rat moving through the world produces a statistically reproducible sequence of "place cell" firings. With this perspective, spatial navigation can be viewed as a sequence learning problem for the hippocampus. That is, learning entails associating the relationships among a sequence of places that are represented by a sequence of place cell firing. Recent experiments by McNaughton and colleagues suggest the hippocampus can recall a sequence of place cell firings at a faster rate than it was experienced. This speedup, which occurs during slow-wave sleep, is called temporal compression. Here, we show that a simplified model of hippocampal area CA3, based on integrate-and-fire cells and unsupervised Hebbian learning, reproduces this temporal compression. The amount of compression is proportional to the activity level during recall and to the relative timespan of associativity during learning. Compression seems to arise from an alteration of network dynamics between learning and recall. During learning, the dynamics are paced by external input and slowed by a low overall level of activity. During recall, however, external input is absent, and the dynamics are controlled by intrinsic network properties. Raising the activity level by lowering inhibition increases the rate at which the network can transition between previously learned states and thereby produces temporal compression. The tendency for speeding up future activations, however, is limited by the temporal range of associations that were present during learning.

Animals

Augmentation of hepatic doxorubicin extraction with extracorporeal filtration avoids the dose-dependent, nonlinear increase in AUC observed with systemic administration.

PURPOSE: Regional therapy of primary or metastatic liver cancer with low hepatic extraction ratio drugs such as doxorubicin is constrained by development of systemic toxicity. To examine the effect of augmentation of hepatic drug extraction, a swine model of hepatic artery infusion (HAI) with minimally invasive hepatic venous isolation and hepatic venous drug extraction (HVDE) was developed to study the comparative pharmacokinetic profiles of regional and systemically administered doxorubicin. METHODS: Doxorubicin 0.5-9 mg/kg was administered to 31 pigs over 90 min either by HAI with simultaneous HVDE or by standard systemic vein infusion. Systemic artery and hepatic vein plasma samples were collected periodically (0 to 240 min) for determination of doxorubicin concentrations by high-performance liquid chromatography. Pharmacokinetic profiles were modeled with PCNONLIN 4.2. RESULTS: Concentration-time data were best described in all pigs by a two-compartment open model of elimination. Independent of the route of administration, AUC and Cmax values increased with dose. Mean systemic AUC and Cmax values were consistently lower with regional administration, with statistically significant decreases at the 0.5 and 3 mg/kg doses, whereas there was no relationship between hepatic vein parameters and route of administration. There was a linear relationship between mean systemic AUC values and dose in pigs receiving doxorubicin via HAI with HVDE, whereas mean systemic AUC values increased exponentially at doses of 5 mg/kg or above with systemic vein administration. CONCLUSIONS: Administration of doxorubicin by HAI with simultaneous HVDE significantly decreases systemic exposure in comparison with standard systemic vein drug infusion, and may protect against nonlinear increases in exposure at higher doses.

Animals

Parenteral zinc supplementation in adult humans during the acute phase response increases the febrile response.

The acute phase response (APR) that follows injury or infection is characterized by a decrease in serum zinc concentrations, which we hypothesized benefits the host. Additionally, we proposed that preventing this decline by supplementing zinc would result in an exaggerated APR as indicated by elevated temperatures, increased serum cytokine concentrations, interleukin 6 and the acute phase protein (ceruloplasmin). A prospective, randomized, double-blinded, clinical trial was conducted. Patients on home parenteral nutrition with a diagnosis of catheter sepsis and patients with a diagnosis of pancreatitis, also on total parenteral nutrition (TPN), were recruited for the study. Following enrollment, block randomization was used to assign patients to receive 0 mg (n = 23) or 30 mg (n = 21) of zinc per day for the first 3 d of TPN. Blood samples for measurement of serum zinc, copper, ceruloplasmin and interleukin-6 were obtained upon enrollment and on d 1 through 3 of TPN. The highest temperatures reported on these days in the medical record were also recorded. Repeated measures ANOVA was used to determine differences in the primary outcome variables over time. No significant differences between groups were observed in serum interleukin-6 or ceruloplasmin concentrations. A significantly higher (P = 0.035) temperature was observed in the zinc-supplemented group compared with the control group on d 3 of parenteral nutrition. We conclude that parenteral zinc supplementation in patients experiencing a mild APR resulted in an exaggerated APR as evidenced by a significantly higher febrile response.

Acute-Phase Reaction

Using simulation to improve the operational efficiency of a multi-disciplinary clinic.

A recent trend in health care is to provide patients with the benefits of multi-disciplinary care during a single clinic visit. The University of Michigan Breast Care Center is a leading example of a multi-disciplinary clinic which has served the Midwest United States since 1985. A hallmark of the Breast Care Center operation is a patient care conference immediately following the clinical evaluation sessions, where each case is discussed by a group of experts for immediate evaluation and generation of recommendations. The Center has experienced significant increases in the number of patient visits over the nine years since its inception. The patient mix, initially all new patients, has matured, and returning patients are now a significant portion of the clinic load. Unfortunately, the success of the Breast Care Center strained its smooth operation. Physicians were unable to attend the patient care conference because the clinical evaluation sessions were too busy, and this undermined the quality of the care recommendations generated. Patients were complaining about long waits in the Breast Care Center and delays in getting their next appointment. To examine these operational problems and to suggest corrective actions, a simulation study was conducted. This paper reports the results of this study. Our findings provide interesting insights into the operation and management of multi-disciplinary clinics.

Appointments and Schedules

Carotenoids, vitamin A, and estrogen receptor status in breast cancer.

Among patients with breast cancer, tumors that contain estrogen receptors (ER) are associated with improved survival and better response to hormone therapy than those not expressing these receptors. The purpose of these case comparison studies was to examine the relationship between carotenoids, vitamin A, and the tumor ER status in women at diagnosis of primary breast cancer. The focus of the first study was the relationship between dietary intake and ER status, and the focus of the second study was the relationship between ER status and the plasma carotenoid, retinol, and tocopherol concentrations. We evaluated tumor ER status and self-reported dietary intake in 142 women and plasma concentrations of carotenoids, retinol, and tocopherols in 149 women, at diagnosis of breast cancer, before any medical or surgical treatment. In the first study the overall odds of ER-positive status were increased in relation to number of mammograms in the past five years, number of breast-fed babies, dietary carotenoid intake, and more frequent intake of yellow and green vegetables. Overall odds of ER-positive status were decreased in relation to years of oral contraceptive use and preformed vitamin A intake. In the second study older women, women with higher plasma lutein concentration, and women not using beta-carotene supplements were more likely to be ER positive, when data were adjusted for body mass index and factors that may influence breast cancer risk or hormonal status. Significant independent relationships between plasma retinol or tocopherol concentrations and ER status were not observed. The strong and independent relationships between carotenoid intake, plasma lutein concentration, and ER status may relate to observations linking a carotenoid-rich diet with improved prognosis after diagnosis of breast cancer.

Adolescent

A simple spike train decoder inspired by the sampling theorem.

Reconstructing a time-varying stimulus estimate from a spike train (Bialek's "decoding" of a spike train) has become an important way to study neural information processing. In this paper, we describe a simple method for reconstructing a time-varying current injection signal from the simulated spike train it produces. This technique extracts most of the information from the spike train, provided that the input signal is appropriately matched to the spike generator. To conceptualize this matching, we consider spikes as instantaneous "samples" of the somatic current. The Sampling Theorem is then applicable, and it suggests that the bandwidth of the injected signal not exceed half the spike generator's average firing rate. The average firing rate, in turn, depends on the amplitude range and DC bias of the injected signal. We hypothesize that nature faces similar problems and constraints when transmitting a time-varying waveform from the soma of one neuron to the dendrite of the postsynaptic cell.

Action Potentials

Theoretic and experimental aspects of regional liver infusion.

Pharmacokinetic theory of hepatic arterial infusion chemotherapy predicts that parameters, such as hepatic blood flow, hepatic drug extraction, and extrahepatic drug clearance, may potentially be manipulated to enhance the selectivity of hepatic artery drug administration. In practice, diminution of hepatic blood flow through the use of degradable starch microspheres or gelatin sponge embolization has been accomplished and has improved drug selectivity. Likewise, augmentation of hepatic drug extraction improves the pharmacokinetic advantages of regional chemotherapy for liver tumors. Development of optimal hepatic infusion chemotherapy approaches can be undertaken rationally and in an expeditious fashion by applying pharmacokinetic principles to create innovative treatment regimens and by testing them in preclinical and phase I investigations.

Antineoplastic Agents

Pharmacokinetic evaluation of percutaneous hepatic venous isolation for administration of regional chemotherapy.

Hepatic artery infusion (HAI) chemotherapy has been used to treat patients with unresectable liver tumours. We report a preclinical study of the pharmacokinetics of HAI combined with hepatic venous drug extraction (HVDE) for regional administration of doxorubicin. HVDE was aided by a double balloon catheter inserted via femoral vein cutdown into the inferior vena cava to collect all hepatic vein blood. Pigs received doxorubicin 0.5-9.0 mg kg-1 over 90 min via HAI or systemic infusion (SYSI). HVDE was performed for 240 min. SYSI pigs underwent hepatic venous isolation without drug filtration. Doxorubicin levels were assayed using high-pressure liquid chromatography (HPLC). HAI/HVDE reduced systemic exposure to doxorubicin with equivalent hepatic exposure at all doses. Pharmacokinetic enhancement ranged from 7.0 to 22.3 for peak concentration, 8.8-23.2 for the area under the curve and 2.9-4.2 for tissue concentration. HAI/HVDE also prevented the mortality which was observed with SYSI administration of high-dose (5.0 and 9.0 mg kg-1) doxorubicin. We conclude that HAI/HVDE reduces systemic exposure to doxorubicin as compared with SYSI of equivalent doses. Pharmacokinetic enhancement indices suggest that HAI/HVDE may allow equivalent hepatic drug exposure with reduced systemic exposure. This method may be applicable to other drugs and to other anatomic settings in which enhanced regional drug delivery is desirable.

Animals

An evaluation of hepatic extraction and clearance of doxorubicin.

A swine model was developed to study quantitatively the pharmacokinetics of hepatic extraction and clearance of doxorubicin (DOX). Systemic and hepatic artery infusions of DOX (0.5-9 mg kg-1) were administered to 34 pigs. Pharmacokinetic analysis was simplified by use of a double-balloon catheter in the inferior vena cava to collect hepatic venous effluent. During hepatic artery infusion only, DOX in hepatic venous blood was extracted using activated carbon filters to prevent drug recirculation. Hepatic extraction and clearance of DOX were independent of dose and route of administration. Extraction ratios varied from 0.75 to 0.91 during hepatic artery infusion and from 0.50 to 0.72 during systemic infusion. Clearance results were analogous. After cessation of drug infusions, hepatic extraction and clearance of DOX was negative, suggesting that the liver serves as a drug reservoir during DOX infusion and subsequently is a net source of unmetabolised drug. Liver extraction and clearance of DOX in pigs are substantial. During either systemic or hepatic artery infusion of DOX, the liver serves as a drug reservoir. Subsequent mobilisation of this hepatic pool of DOX may cause prolonged systemic exposure to drug.

Animals

Patient evaluation of care within a multidisciplinary breast care center.

To understand patient perceptions of multidisciplinary medical care, a survey instrument was developed to poll 1,023 consecutive visitors to the University of Michigan Breast Care Center (BCC). Factors influencing patient satisfaction included staff concern for patients, one-stop shopping, medical thoroughness, and length of waiting in the reception area (negative correlation). These factors are well addressed by a multidisciplinary approach to medical care. Similar models of multidisciplinary care can probably be implemented at other institutions and in other clinical settings.

Adult

Immediate transverse rectus abdominis musculocutaneous flap reconstruction after mastectomy.

BACKGROUND: This study examines the early and long-term outcomes of immediate transverse rectus abdominis musculocutaneous (TRAM) reconstruction of the breast after mastectomy. STUDY DESIGN: The records of all patients undergoing mastectomy and immediate TRAM breast reconstruction between December 1989 and October 1993 were reviewed retrospectively using hospital and breast care center databases. RESULTS: Fifty-three patients underwent a total of 73 immediate TRAM breast reconstructions. Reconstruction was successfully completed in all patients, using 46 pedicle flaps and 27 free tissue transfers. There were no flap losses or cardiopulmonary complications. Overall, the complication rate was 26 percent (29 percent for pedicle TRAM and 22 percent for free TRAM flaps). The median follow-up period among the 53 patients was 22.6 months (range of three to 48 months). All patients employed preoperatively resumed their occupations postoperatively. CONCLUSIONS: Our experience indicates that immediate TRAM breast reconstruction is a safe and viable option for patients seeking reconstruction at the time of mastectomy.

Adult

Effect of sublethal liver injury on doxorubicin metabolism.

Centrilobular hepatocyte contribution to doxorubicin (DOX) metabolism and myelotoxicity was probed with bromobenzene (BRB), a known centrilobular hepatotoxin. New Zealand White rabbits were given DOX, 3 mg/kg i.v. After 4 weeks, the rabbits were pretreated i. p. with 2.6 ml/kg 40% solution of BRB in corn oil followed 72 h later with a 3-mg/kg dose of DOX. Pharmacokinetics of DOX after BRB pretreatment was mildly changed from control. Significantly increased plasma concentrations of doxorubicinol and its aglycone product, 7-deoxydoxorubicinol aglycone, were detected. Treatment with BRB alone was not lethal; however, in three of seven rabbits, the combination of DOX and BRB was. The mortality appeared to be related to myelosuppression. We conclude that toxin-induced hepato-cellular necrosis causes increased DOX-induced myelotoxicity. Following BRB pretreatment, the relatively small pharmacokinetic changes of parent compound concentrations as compared with greater changes in plasma pharmacokinetics of its alcohol metabolites suggest systemic changes in drug metabolism and distribution in the setting of hepatic disease may be the cause of increased toxicity.

Animals

Hepatic artery infusion of doxorubicin with hepatic venous drug extraction.

Hepatic artery infusion (HAI) has been used to take advantage of the steep dose-response relationship characteristic of chemotherapeutic agents. Systemic toxicity, however, remains the dose limiting factor for HAI of low hepatic extraction drugs. This investigation compared the pharmacokinetics of doxorubicin administered using a system that combines HAI and hepatic venous drug extraction (HVDE) versus systemic administration without HVDE. HAI was accomplished by transfemoral cannulation of the hepatic artery. HVDE was aided by use of a double-balloon catheter inserted fluoroscopically via femoral vein cutdown into the inferior vena cava. Inflation of the balloons above and below the hepatic veins allowed collection of hepatic venous effluent. Hepatic venous blood was pumped through the double-balloon catheter into an extracorporeal circuit with activated carbon filters to extract drug prior to return to the systemic circulation. Domestic female swine (25-35 kg) received 3 mg/kg doxorubicin over 90 min via HAI. HVDE was performed for 240 min following initiation of HAI (Time 0-240 min). Control swine underwent hepatic venous isolation using the double-balloon catheter without drug filtration and received 3 mg/kg doxorubicin over 90 min via systemic vein (SYSI). Serum and myocardial doxorubicin and doxorubicinol levels were assayed using HPLC. Blood was serially sampled from hepatic vein blood, from the extracorporeal circuit after filtration, and from a systemic artery. Area under the curve (AUC) was integrated from time-concentration plots over Time 0-180 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

Hepatoma registry of the Western world. Repeat Hepatic Resection Registry.

The western HCC registry comprised data from 322 patients who underwent hepatic resection for HCC over a 50-year period. The majority of patients had lesions > 4 cm and were symptomatic at presentation. Lesions were mostly unicentric. Cirrhosis was not a prevalent problem, unlike the East. In the most recent decade, 1980-1989, we noted a significant decrease in operative mortality from 19% to 10% overall, and 15% to 4% in the noncirrhotic group. We identified four variables that resulted in poorer postresectional outcome: cirrhosis, regional nodal disease, multicentric disease, and tumor-free resectional margin < 1 cm. Although these factors are associated with a poorer outcome after resection, whether they should serve as contraindications to surgery should be determined by individual surgeons, taking into account the patient's overall status, concomitant risk factors, and treatment objectives.

Adolescent