Mechanisms of Bile Formation and Cholestasis: Clinical Significance of Recent Experimental Work

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72481/1/j.1572-0241.1986.tb01599.x.pd

Cosmic Infrared Background Fluctuations and Zodiacal Light

We have performed a specific observational test to measure the effect that the zodiacal light can have on measurements of the spatial fluctuations of the near-IR background. Previous estimates of possible fluctuations caused by zodiacal light have often been extrapolated from observations of the thermal emission at longer wavelengths and low angular resolution, or from IRAC observations of high latitude fields where zodiacal light is faint and not strongly varying with time. The new observations analyzed here target the COSMOS field, at low ecliptic latitude where the zodiacal light intensity varies by factors of $\sim2$ over the range of solar elongations at which the field can be observed. We find that the white noise component of the spatial power spectrum of the background is correlated with the modeled zodiacal light intensity. Roughly half of the measured white noise is correlated with the zodiacal light, but a more detailed interpretation of the white noise is hampered by systematic uncertainties that are evident in the zodiacal light model. At large angular scales ($\gtrsim100"$) where excess power above the white noise is observed, we find no correlation of the power with the modeled intensity of the zodiacal light. This test clearly indicates that the large scale power in the infrared background is not being caused by the zodiacal light.Comment: 17 pp. Accepted for publication in the Ap

Severe Cholestasis Associated with Methyltestosterone: A Case Report

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75504/1/j.1572-0241.1987.tb01706.x.pd

Bile acid transport: Lessons from the intestine

The transport of bile acid was studied in basolateral membrane vesicles isolated from rat small intestine. Taurocholate transport into an osmotically reactive intravesicular space was Na + independent. The uptake of taurocholate in jejunal and ileal vesicles preloaded with sulfate was stimulated with respect to uptake in unpreloaded vesicles. Glycocholate inhibited the transstimulation of taurocholate uptake by sulfate. Sulfate and taurocholate uptake in ileal vesicles preloaded with bicarbonate was stimulated with respect to uptake in unpreloaded vesicles. Taurocholate inhibited the transstimulation of sulfate uptake by bicarbonate. When ileal vesicles were loaded with p -aminohippurate, an early transstimulation of taurocholate was found that exceeded equilibrium uptake, was insensitive to a K + diffusion potential, and was cis -inhibited by taurocholate, glycocholate, pyruvate, p -aminohippurate, probenecid, chloride, sulfate, and bicarbonate. These data indicate the presence of an anion exchanger in intestinal basolateral membrane vesicles that may be involved in the exit of bile acids from the enterocyte.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38331/1/1840070235_ftp.pd

New insights into canalicular organic anion secretion

The effect of partial and complete dissipation of the membrane potential and partial depletion of cellular ATP content on the efflux of dinitrophenyl-glutathione and oxidized glutathione was examined in hepatocytes isolated from normal and mutant (TR − ) rats exhibiting defective organic anion transport. Whereas alterations in the membrane potential difference had no effect on the initial efflux rate of dinitrophenyl-glutathione and oxidized glutathione, depletion of cellular ATP inhibited dinitrophenyl-glutathione and oxidized glutathione efflux and a linear relationship between the cellular ATP content and the initial efflux rate of dinitrophenyl-glutathione was observed in normal isolated rat hepatocytes. In contrast, depletion of cellular ATP content had no significant effect on the slower rate of dinitrophenyl-glutathione efflux from TR − rat hepatocytes. These findings implicate an ATP-dependent hepatic transport system for oxidized glutathione and glutathione conjugates that is absent in TR − mutants. Fluorescence image analysis reveals normal secretion of a fluorescent bile acid fluorescein isothiocyanate glycocholate into the canalicular lumen of isolated normal and TR − mutant rat hepatocyte couplets, but negligible canalicular accumulation of a non-bileacid organic anion (carboxydichlorofluorescein diacetate) in TR − hepatocyte couplets. Canalicular membrane vesicles derived from normal rats exhibited saturable temperature- and ATP-dependent transport of sulfobromophthalein and sulfobromophthalein-glutathione that was absent in canalicular membrane vesicles from TR − rats. However, ATP-dependent daunomycin transport, reflecting transport mediated by the multidrug resistance gene product, p-glycoprotein, was present in canalicular membrane vesicles from both normal and TR − rats. Canalicular membrane vesicles from normal and TR − rats contained equal amounts of p-glycoprotein on immunoblots. These studies demonstrate that the conjugated hyperbilirubinemia in TR − mutant rats is the result of a functional absence of an ATP-dependent organic anion transport system on the canalicular membrane.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38344/1/1840130130_ftp.pd

Intracellular acidosis: Can it delay the inevitable?

The relationships between extracellular pH (pH o ), intracellular pH (pH i ), and loss of cell viability were evaluated in cultured rat hepatocytes after ATP depletion by metabolic inhibition with KCN and iodoacetate (chemical hypoxia). pH i was measured in single cells by ratio imaging of 2′, 7′ -biscarboxy-ethyl-5, 6-carboxyfluorescein (BCECF) fluorescence using multiparameter digitized video microscopy. During chemical hypoxia at pH o of 7.4, pH i decreased from 7.36 to 6.33 within 10 min. pH i remained at 6.1–6.5 for 30–40 min. (plateau phase). Thereafter, pH i began to rise and cell death ensued within minutes, as evidenced by nuclear staining with propidium iodide and coincident leakage of BCECF from the cytoplasm. An acidic pH o produced a slightly greater drop in pH f , prolonged the plateau phase of intracellular acidosis, and delayed the onset of cell death. Inhibition of Na + /H + exchange also prolonged the plateau phase and delayed cell death. In contrast, monensin or substitution of gluconate for Cl − in buffer containing HCO 3 − abolished the pH gradient across the plasma membrane and shortened cell survival. The results indicate that intracellular acidosis after ATP depletion delays the onset of cell death, whereas reduction of the degree of acidosis accelerates cell killing. We conclude that intracellular acidosis protects against hepatocellular death from ATP depletion, a phenomenon that may represent a protective adaptation against hypoxic and ischemic stress.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38339/1/1840110430_ftp.pd

The Educational Impact of the Specialty Care Access Network–Extension of Community Healthcare Outcomes Program

Background: With the aging hepatitis C cohort and increasing prevalence of fatty liver disease, the burden on primary care providers (PCPs) to care for patients with liver disease is growing. In response, the Veterans Administration implemented initiatives for primary care-specialty referral to increase PCP competency in complex disease management. The Specialty Care Access Network?Extension of Community Healthcare Outcomes (SCAN-ECHO) program initiative was designed to transfer subspecialty knowledge to PCPs through case-based distance learning combined with real-time consultation. There is limited information regarding the initiative's ability to engage PCPs to learn and influence their practice. Materials and Methods: We surveyed PCPs to determine the factors that led to their participation in this program and the educational impact of participation. Results: Of 51 potential participants, 24 responded to an anonymous survey. More than 75% of respondents participated more than one time in a SCAN-ECHO clinic. Providers were motivated to participate by a desire to learn more about liver disease, to apply the knowledge gained to future patients, and to save their patients time traveling to another center for specialty consultation. Seventy-one percent responded that the didactic component and case-based discussion were equally important. It is important that participation changed clinical practice: 75% of providers indicated they had personally discussed the information they learned from the case presentations with their colleague(s), and 42% indicated they helped a colleague care for their patient with the knowledge learned during discussions of other participants' cases. Conclusions: This study shows that the SCAN-ECHO videoconferencing program between PCPs and specialists can educate providers in the delivery of specialty care from a distance and potentially improve healthcare delivery.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140279/1/tmj.2013.0302.pd

Reducing the Read Noise of the James Webb Space Telescope Near Infrared Spectrograph Detector Subsystem

We describe a Wiener optimal approach to using the reference output and reference pixels that are built into Teledyne's HAWAII-2RG detector arrays. In this way, we are reducing the total noise per approximately 1000 second 88 frame up-the-ramp dark integration from about 6.5 e- rms to roughly 5 e- rms. Using a principal components analysis formalism, we achieved these noise improvements without altering the hardware in any way. In addition to being lower, the noise is also cleaner with much less visible correlation. For example, the faint horizontal banding that is often seen in HAWAII-2RG images is almost completely removed. Preliminary testing suggests that the relative gains are even higher when using non flight grade components. We believe that these techniques are applicable to most HAWAII-2RG based instruments