Examining the paradoxical relation between number of spikes and gaze amplitude in abducens neurons.

During head-unrestrained gaze shifts, the number of spikes in the burst of abducens neurons increases with gaze amplitude, even when corrected for the component of the discharge related to the change in eye position. We examine this paradoxical dissociation between the number of spikes and eye amplitude, which occurs because eye amplitude in the head saturates for larger gaze shifts. First, we show that the extra spikes are unlikely to be due to antagonist muscle loading because the abducens neurons are completely silent during large gaze shifts when the muscle acts as an antagonist. Next, we divide the firing rate profile of abducens neurons into terms that represent signals related to eye position, velocity, and acceleration; a d.c. offset term specifying the firing associated with straight-ahead gaze; and a slide term, which compensates for the zero of the oculomotor plant. Then we examine the contribution of each term to the number of spikes recorded. A comparison of the number of spikes with the integral of the fitted function, combining all of the terms, for the duration of the burst reveals that the simulation captures much of the actual data. However, even a model with a slide term cannot reproduce the nonlinear relationship of the number of spikes with amplitude that characterizes large gaze shifts.

The infant who is visually unresponsive on a cortical basis.

OBJECTIVE: To further explain cortical abnormalities in infants without visually guided behaviors with anatomically normal eyes by using a battery of objective visual tests and neuroimaging studies. DESIGN: A cohort study. PARTICIPANTS: Thirty-one infants with clear ocular media and normal fundi, who were visually unresponsive by clinical examination, and 31 control subjects. METHODS: Full clinical examinations including Teller Acuity Cards (TAC) and developmental assessment. Infants with reduced acuities and/or developmental delay underwent pattern visual evoked potential (VEP) testing and brain neuroimaging studies. Eye movement recordings were done in individual infants. MAIN OUTCOME MEASURES: Visual acuity, VEPs, eye movement recordings. RESULTS: Infants were separated into two groups on the basis of being developmentally normal (DN) or developmentally delayed (DD). Fourteen DN infants had normal acuities for age and three of three infants had normal VEPs. On the basis of having normal visual function, these infants were considered to have visual inattention (VI). Sixteen DD infants had acuities ranging from normal to no visual orienting to the low vision TAC. All 16 DD infants had abnormal VEPs and abnormal neuroimaging studies (brain computed tomography, magnetic resonance imaging, or both) or microcephaly. On the basis of having structural and functional abnormalities of the brain, these infants were diagnosed as having cortical visual impairment (CVI). One additional infant with DD failed to orient to TACs but had a normal VEP and normal magnetic resonance imaging. In this infant and two infants with CVI the inability to "fix and follow" was attributed completely or partially to an oculomotor apraxia (OMA), which was confirmed by eye movement recordings. CONCLUSIONS: The infant who is visually unresponsive on a cortical basis has either VI or CVI. Infants with OMA can also seem to be visually unresponsive. These disorders can be delineated in infancy on the basis of developmental status and a unique set of responses to visual acuity, VEPs, and oculomotor testing.

A randomized, pharmacokinetic and pharmacodynamic, cross-over study of duodenal or jejunal administration compared to nasogastric administration of omeprazole suspension in patients at risk for stress ulcers.

OBJECTIVES: The aim of this study was to characterize absorption and pH control of simplified omeprazole suspension (SOS), 2 mg/ml in 8.4% sodium bicarbonate, administered via the nasogastric versus jejunal or duodenal route. METHODS: Nine critically ill surgical patients, NPO and mechanically ventilated, were enrolled in this randomized cross-over study. Patients received a single 40 mg dose of SOS by the nasogastric and either the jejunal or duodenal route. Twenty-four-hour continuous intragastric pH monitoring was performed during the study period. Sequential blood samples were collected over 24 h to characterize SOS absorption and pharmacokinetic parameters. RESULTS: Nasogastric administration of SOS resulted in lower maximum mean +/- SD serum concentrations compared to jejunal/duodenal dosing (0.970 +/- 0.436 vs 1.833 +/- 0.416 microg/ml, p = 0.006). SOS absorption was significantly slower when administered via nasogastric tube (108.3 +/- 42.0 vs 12.1 +/- 7.9 min, p < 0.001). However, all routes of administration resulted in similar SOS area under the serum concentration-time curves (AUC(0-infinity)) (415.1 +/- 291.8 vs 396.7 +/- 388.1 microg x min/ml, p = 0.91) [corrected]. Mean intragastric pH values remained >4 at 1 h after SOS administration and remained >4 for the entire 24-h study (6.32 +/- 1.04, 5.57 +/- 1.15, nasogastric vs jejunal/duodenal, p = 0.015), regardless of administration route. CONCLUSIONS: In critically ill surgical patients, pharmacokinetic parameters and subsequent pH control after the administration of SOS are similar by the jejunal, nasogastric, or duodenal route. SOS suspension offers an alternative acid control measure when patients are unable to take oral medications, yet have an enteral tube in place.

Self-motion perception: assessment by real-time computer-generated animations.

We report a new procedure for assessing complex self-motion perception. In three experiments, subjects manipulated a 6 degree-of-freedom magnetic-field tracker which controlled the motion of a virtual avatar so that its motion corresponded to the subjects' perceived self-motion. The real-time animation created by this procedure was stored using a virtual video recorder for subsequent analysis. Combined real and illusory self-motion and vestibulo-ocular reflex eye movements were evoked by cross-coupled angular accelerations produced by roll and pitch head movements during passive yaw rotation in a chair. Contrary to previous reports, illusory self-motion did not correspond to expectations based on semicircular canal stimulation. Illusory pitch head-motion directions were as predicted for only 37% of trials; whereas, slow-phase eye movements were in the predicted direction for 98% of the trials. The real-time computer-generated animations procedure permits use of naive, untrained subjects who lack a vocabulary for reporting motion perception and is applicable to basic self-motion perception studies, evaluation of motion simulators, assessment of balance disorders and so on.

Apparent dissociation between saccadic eye movements and the firing patterns of premotor neurons and motoneurons.

Saccadic eye movements result from high-frequency bursts of activity in ocular motoneurons. This phasic activity originates in premotor burst neurons. When the head is restrained, the number of action potentials in the bursts of burst neurons and motoneurons increases linearly with eye movement amplitude. However, when the head is unrestrained, the number of action potentials now increase as a function of the change in the direction of the line of sight during eye movements of relatively similar amplitudes. These data suggest an apparent uncoupling of premotor neuron and motoneuron activity from the resultant eye movement.

Apoptosis and tumorigenesis in human cholangiocarcinoma cells. Involvement of Fas/APO-1 (CD95) and calmodulin.

We have previously demonstrated that tamoxifen inhibits the growth of human cholangiocarcinoma cells in culture and inhibits tumor growth when cells are injected into nude mice. However, the mechanism of action of tamoxifen remains unknown. Here we demonstrate that tamoxifen and trifluoperazine, both potent calmodulin antagonists, induce apoptosis in vitro, probably acting via the Fas system, in human cholangiocarcinoma cells. Human cholangiocarcinoma cell lines heterogeneously express Fas antigen on their surface. Fas-negative and Fas-positive surface-expressing cells were isolated, cloned, and cultured. Fas antibody, tamoxifen, and trifluoperazine induced dose-dependent apoptosis only in Fas-positive cells; Fas-negative cells were unaffected. Furthermore, apoptosis induced by tamoxifen in Fas-positive cells was blocked by an inhibitory Fas antibody. Tamoxifen was not acting through an anti-estrogenic mechanism, because neither Fas-negative nor Fas-positive cells expressed estrogen receptors and the pure anti-estrogen compound, ICI 182780, did not induce apoptosis in either cell line. Fas-negative cells, but not Fas-positive cells, were able to produce tumors when subcutaneously injected into nude mice. These findings suggest Fas may be a candidate oncogene involved in the pathogenesis of cholangiocarcinoma. Furthermore, the similarity between the pro-apoptotic effects of tamoxifen and trifluoperazine support an underlying molecular mechanism for Fas-mediated apoptosis that involves calmodulin.

A population-based treat-to-target pharmacoeconomic analysis of HMG-CoA reductase inhibitors in hypercholesterolemia.

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have become the drugs of choice for the treatment of patients with hypercholesterolemia. However, one of the major concerns with these drugs is cost. In an attempt to develop a cost-effective treatment strategy for patients referred to our lipid clinic, we conducted a meta-analysis to estimate the lipid-lowering efficacy of the various HMG-CoA reductase inhibitors alone or in combination with niacin or cholestyramine. Based on cholesterol-lowering efficacy estimates derived from a literature-based meta-analysis, we performed a population-based treat-to-target analysis. Fifty-six trials with 101 monotherapy cohorts and 20 trials with 31 combination-therapy cohorts (573 patients) were included in the meta-analysis. Based on reduction in low-density lipoprotein cholesterol (LDL-C), the most effective monotherapy was atorvastatin and the least effective monotherapy was fluvastatin. Combination therapy was more effective in reducing LDL-C than monotherapy with the respective HMG-CoA reductase inhibitor. However, on the basis of dollars spent per percentage of LDL-C reduction, combination therapy was frequently less cost-effective than monotherapy. In addition, combination therapy was associated with a higher rate of noncompliance and a greater risk of drug-drug interactions. As a result, we based our treat-to-target analysis on the use of monotherapy as first-line treatment, with combination therapy reserved for patients failing to achieve the target LDL-C levels of the US National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP-II) with monotherapy. In the population-based treat-to-target analysis, atorvastatin was the most cost-effective drug for high-risk patients (those with coronary heart disease [CHD]), whereas fluvastatin was the most cost-effective agent for low-risk patients (<2 risk factors for CHD) and moderate-risk patients (> or =2 risk factors for CHD). If 1 drug is chosen to treat all patients (i.e., in cases of formulary restriction), atorvastatin would be the most cost-effective agent. In adapting the findings on cholesterol-lowering efficacy from this analysis to our lipid clinic, we concluded that the most cost-effective treatment approach is to individualize the selection of an HMG-CoA reductase inhibitor based on both coronary risk and the LDL-C reduction required to achieve NCEP ATP-II goals. Based on our results, 2 agents--atorvastatin and fluvastatin--should be available on the formulary.

Short- and long-term consequences of canal plugging on gaze shifts in the rhesus monkey. I. Effects on gaze stabilization.

Short- and long-term consequences of canal plugging on gaze shifts in the rhesus monkey. I. Effects on gaze stabilization. To study the contribution of the vestibular system to the coordinated eye and head movements of a gaze shift, we plugged the lumens of just the horizontal (n = 2) or all six semicircular canals (n = 1) in monkeys trained to make horizontal head-unrestrained gaze shifts to visual targets. After the initial eye saccade of a gaze shift, normal monkeys exhibit a compensatory eye counterrotation that stabilizes gaze as the head movement continues. This counterrotation, which has a gain (eye velocity/head velocity) near one has been attributed to the vestibuloocular reflex (VOR). One day after horizontal canal plugging, the gain of the passive horizontal VOR at frequencies between 0.1 and 1.0 Hz was <0.10 in the horizontal-canal-plugged animals and zero in the all-canal-plugged animal. One day after surgery, counterrotation gain was approximately 0.3 in the animals with horizontal canals plugged and absent in the animal with all canals plugged. As the time after plugging increased, so too did counterrotation gain. In all three animals, counterrotation gain recovered to between 0.56 and 0.75 within 80-100 days. The initial loss of compensatory counterrotation after plugging resulted in a gaze shift that ended long after the eye saccade and just before the end of the head movement. With recovery, the length of time between the end of the eye saccade and the end of the gaze movement decreased. This shortening of the duration of reduced gain counterrotation occurred both because head movements ended sooner and counterrotation gain returned to 1.0 more rapidly relative to the end of the eye saccade. Eye counterrotation was not due to activation of pursuit eye movements as it persisted when gaze shifts were executed to extinguished targets. Also counterrotation was not due simply to activation of neck receptors because counterrotation persisted after head movements were arrested in midflight. We suggest that the neural signal that is used to cause counterrotation in the absence of vestibular input is an internal copy of the intended head movement.

Action of the brain stem saccade generator during horizontal gaze shifts. I. Discharge patterns of omnidirectional pause neurons.

Omnidirectional pause neurons (OPNs) pause for the duration of a saccade in all directions because they are part of the neural mechanism that controls saccade duration. In the natural situation, however, large saccades are accompanied by head movements to produce rapid gaze shifts. To determine whether OPNs are part of the mechanism that controls the whole gaze shift rather than the eye saccade alone, we monitored the activity of 44 OPNs that paused for rightward and leftward gaze shifts but otherwise discharged at relatively constant average rates. Pause duration was well correlated with the duration of either eye or gaze movement but poorly correlated with the duration of head movement. The time of pause onset was aligned tightly with the onset of either eye or gaze movement but only loosely aligned with the onset of head movement. These data suggest that the OPN pause does not encode the duration of head movement. Further, the end of the OPN pause was often better aligned with the end of the eye movement than with the end of the gaze movement for individual gaze shifts. For most gaze shifts, the eye component ended with an immediate counterrotation owing to the vestibuloocular reflex (VOR), and gaze ended at variable times thereafter. In those gaze shifts where eye counterrotation was delayed, the end of the pause also was delayed. Taken together, these data suggest that the end of the pause influences the onset of eye counterrotation, not the end of the gaze shift. We suggest that OPN neurons act to control only that portion of the gaze movement that is commanded by the eye burst generator. This command is expressed by driving the saccadic eye movement directly and also by suppressing VOR eye counterrotation. Because gaze end is less well correlated with pause end and often occurs well after counterrotation onset, we conclude that elements of the burst generator typically are not active till gaze end, and that gaze end is determined by another mechanism independent of the OPNs.

Clinical utility of pH paper versus pH meter in the measurement of critical gastric pH in stress ulcer prophylaxis.

OBJECTIVE: To evaluate the clinical utility of measuring gastric pH with a pH meter vs. pH paper in critical care patients. DESIGN: Prospective comparison of gastric pH measurements, using both pH meter and pH paper. SETTING: Surgical intensive care unit (ICU) at a rural Midwestern university medical center. PATIENTS: Fifty-one patients who received therapy for prophylaxis of stress ulcers in the surgical ICU. INTERVENTIONS: Therapy for stress ulcer prophylaxis was monitored. MEASUREMENTS AND MAIN RESULTS: The pH of 985 gastric samples, taken from 51 patients, was measured with both pH meter and pH paper. The pH meter and pH paper measures demonstrated a concordance correlation coefficient of .896. The mean difference between the two measures (pH paper - pH meter) was estimated to be between -0.4 and 1.4, suggesting a positive bias for the paper. The prevalence of events representing clinically relevant differences between the pH meter and pH paper in the measurement of the same gastric sample was calculated. The frequency with which each of the events occurred consecutively (or, in one case, two nearly consecutive events on the same day) was also calculated. Bias in a clinically relevant range was estimated. A set of "probability profiles" was constructed. CONCLUSIONS: A hand-held pH meter and pH paper are not interchangeable measures of gastric pH. The pH paper exhibits an appreciable positive bias compared with a hand-held pH meter in the clinically relevant range of 2 to 6. More research is needed to determine if that bias affects treatment outcomes. We recommend the use of a pH meter for patients who demonstrate pH readings of < or = 4, consecutive with readings of < or = 5.

A prospective study of omeprazole suspension to prevent clinically significant gastrointestinal bleeding from stress ulcers in mechanically ventilated trauma patients.

OBJECTIVE: To prospectively evaluate the incidence of clinically significant bleeding, side effects, and cost of therapy in mechanically ventilated trauma patients at high risk for stress ulcers who received simplified omeprazole suspension (SOS). METHODS: Prospective, evaluative study in a Level I trauma center. Mechanically ventilated trauma patients admitted with at least one additional risk factor for stress ulcer development received SOS for stress ulcer prophylaxis. RESULTS: Sixty trauma patients were enrolled. The mean Injury Severity Score was 27.3. After starting SOS, there were no cases of clinically significant upper gastrointestinal bleeding related to stress ulceration. Baseline pH was 3.3, and mean gastric pH after SOS was increased to 6.7 (p < 0.005). There were no adverse effects thought to be related to omeprazole suspension. Incidence of nosocomial pneumonia after beginning SOS was 28.3%. The cost of acquisition plus administration of SOS was $13.13 per day, whereas the cost of drug acquisition alone was $3.83 per day. CONCLUSION: In a prospective, evaluative study of 60 trauma patients who required mechanical ventilation and had at least one additional risk factor for stress ulcer development, omeprazole suspension prevented clinically significant gastrointestinal bleeding, maintained excellent control of gastric pH, produced no toxicity, and was the least costly medication alternative.

Gain adaptation of eye and head movement components of simian gaze shifts.

Gain adaptation of eye and head movement components of simian gaze shifts. J. Neurophysiol. 78: 2817-2821, 1997. To investigate the site of gaze adaptation in primates, we reduced the gain of large head-restrained gaze shifts made to 50 degrees target steps by jumping the target 40% backwards during a targeting saccade and then tested gain transfer to the eye- and head-movement components of head-unrestrained gaze shifts. After several hundred backstep trials, saccadic gain decreased by at least 10% in 8 of 13 experiments, which were then selected for further study. The minimum saccadic gain decrease in these eight experiments was 12.8% (mean = 18.4%). Head-unrestrained gaze shifts to ordinary 50 degrees target steps experienced a gain reduction of at least 9.3% (mean = 14.9%), a mean gain transfer of 81%. Both the eye and head components of the gaze shift also decreased. However, average head movement gain decreased much more (22.1%) than eye movement gain (9.2%). Also, peak head velocity generally decreased significantly (20%), but peak eye velocity either increased or remained constant (average increase of 5.6%). However, the adapted peak eye and head velocities were appropriate for the adapted, smaller gaze amplitudes. Similar dissociations in eye and head metrics occurred when head-unrestrained gaze shifts were adapted directly (n = 2). These results indicated that head-restrained saccadic gain adaptation did not produce adaptation of eye movement alone. Nor did it produce a proportional gain change in both eye and head movement. Rather, normal eye and head amplitude and velocity relations for a given gaze amplitude were preserved. Such a result could be explained most easily if head-restrained adaptation were realized before the eye and head commands had been individualized. Therefore, gaze adaptation is most likely to occur upstream of the creation of separate eye and head movement commands.

Adenoviral vector infection of the human exocrine pancreas.

OBJECTIVE: To determine if a viable cadaveric pancreas might be used to study viral transfection efficacy in a manner precisely mimicking in vivo human studies. DESIGN: Ex vivo gene transfer to an intact human pancreatic duct. SETTING: Molecular biology laboratory and organ procurement center. INTERVENTION: The recombinant adenoviral vector that contains the Escherichia coli beta-galactosidase (LacZ) gene driven by the human cytomegalovirus promoter, ie, AdCMVLacZ, was used to transfect the epithelial cells of the pancreatic ductal system. A human pancreas (150 g wt/wt) procured for transplantation, but subsequently found unsuitable, was used for the study. The splenic, superior mesenteric arteries and portal vein were cannulated and perfused in a heat-controlled organ procurement perfusion system. A segment of vascularized, perfused distal pancreatic duct was isolated with a balloon occlusion catheter. The recombinant adenoviral vector AdCMVLacZ was introduced into the lumen of the distal segment of the pancreatic duct and incubated for 6 hours at 25 degrees C. The proximal segment of the pancreatic duct was not exposed to the vector and served as control tissue. Tissue was harvested and processed for evaluation of beta-galactosidase activity. RESULTS: Adenoviral vector-infected pancreatic ducts exhibited intense blue staining, indicative of reporter gene expression in the epithelial cells of the pancreatic duct. The phenotype of these cells was confirmed by immunohistochemical studies using anti-annexin III polyclonal antibody. Control tissue not exposed to the adenoviral vector was subjected to an identical analysis and did not reveal evidence of expression of the reporter gene. CONCLUSIONS: This study demonstrates the first successful transfection of epithelial cells of the pancreatic duct from normal human pancreas with a recombinant adenovirus. This system will provide not only information on the efficacy of transfection but also a novel gene therapeutic approach to target pancreatic ductal adenocarcinoma.

Tamoxifen-mediated growth inhibition of human cholangiocarcinoma.

Cholangiocarcinoma represents a challenging primary malignancy of the liver with no effective medical therapy and a poor prognosis. We have investigated the role of tamoxifen and estrogen receptors (ERs) in the regulation of growth of human cholangiocarcinoma. Two human cholangiocarcinoma cell lines, OZ and SK-ChA-1, were grown in the presence of graded concentrations of tamoxifen; the effects on cell growth were determined by cell counting or 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium proliferation assay. The presence of ER protein was tested by indirect immunofluorescence and immunoprecipitation. In addition, cells were grown in estrogen-depleted media supplemented with exogenous 17beta-estradiol. ER mRNA was evaluated by reverse transcription-PCR and Northern blotting. Finally, one cholangiocarcinoma cell line was grown as a xenograft in athymic nude mice; tamoxifen effects on in vivo tumor growth were determined with biweekly caliper measurements. Tamoxifen (5-10 microM) caused dose-dependent in vitro growth inhibition of two human cholangiocarcinoma cell lines. In addition, growth inhibition of one cell line (SK-ChA-1) grown as a xenograft in nude mice by tamoxifen was observed. The presence of ER protein was suggested by 17beta-estradiol stimulation of tumor cell growth in vitro and confirmed by immunoprecipitation. Immunofluorescence microscopy was ineffective at detection of ER protein. Reverse transcription-PCR demonstrated the presence of ER mRNA in both cell lines. Northern blot analysis confirmed the presence of full-length 6.5-kb ER mRNA. No ER deletion mutants were detected. Tamoxifen inhibited the growth of human cholangiocarcinoma in vitro and in vivo. ER protein and mRNA were detected in both cell lines. The mechanism(s) of tamoxifen-mediated growth inhibition is unclear but may occur via ER protein or additional pathways. The ability of tamoxifen to inhibit tumor growth may offer an alternative adjunctive treatment for cholangiocarcinoma.

Receptor-dependent growth inhibition of human pancreatic cancer by 9-cis retinoic acid.

Pancreatic cancer continues to be a lethal disease and ranks as the fifth major cause of cancer death with a 2-year survival rate of only 8%. Although significant progress has been made in the surgical management of this malignancy, there have been only minimal advances in adjuvant therapy. Based on the lack of effective adjuvant or primary therapy for these patients, we tested the effects of various retinoids (all-trans, 9-cis, and 13-cis retinoic acids) on the growth of several human pancreatic cancer cell lines. Four human pancreatic cancer cell lines, designated PANC-1, ASPC, BxPc, and HPAF, were studied. Three types of retinoic acid were added to subconfluent monolayers of the different cancer cell lines over a range of concentrations (1 to 20 micromol/L). Effects on cell growth were determined daily over 96 hours by a cell proliferation assay (MTT). Nuclear receptor (RAR/RXR) transcript and protein were determined by reverse transcription polymerase chain reaction and Western blot analyses. Three (PANC-1, ASPC, and BxPc) pancreatic cancer cell lines responded in a dose-dependent fashion with a significant decrease in cell growth at clinically relevant concentrations of 9-cis retinoic acid (7.5 to 10 micromol/L). All-trans and 13-cis retinoic acid did not affect cell growth in the four pancreatic tumors.

Molecular and functional heterogeneity of cholangiocytes from rat liver after bile duct ligation.

Cholangiocytes, the epithelial cells that line intrahepatic bile ducts, participate in bile secretion via basal and agonist-stimulated transport of solutes and water. On the basis of subtle structural differences between cholangiocytes lining small vs. large bile ducts, as well as known phenotypic variations among transporting epithelia in other organs, we demonstrated that cholangiocytes are functionally heterogeneous along the intrahepatic biliary tree of normal rats. In studies reported here, we confirm and extend the concept of functional heterogeneity of cholangiocytes by employing the bile duct-ligated (BDL) rat model of cholestasis associated with selective cholangiocyte proliferation. Using novel isolation and separatory techniques, we prepared subpopulations of pure small, medium, and large cholangiocytes from BDL rats and compared them with regard to gene expression and basal or agonist-responsive transport activities. Although transcripts for gamma-glutamyl transpeptidase and cytokeratin 19, two cholangiocyte-specific proteins, and glyceraldehyde-3-phosphate dehydrogenase, a housekeeping gene, were in all three subpopulations, genes for several proteins involved in solute transport [Cl-/HCO3- exchanger, cystic fibrosis transmembrane conductance regulator (CFTR), and secretin receptor] were expressed only in medium and large cholangiocytes. Consistent with these findings, secretin increased intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) and 36Cl- efflux rates in medium and large cholangiocytes but not in small cholangiocytes. Also, forskolin/8-(4-chlorophenylthio)-cAMP stimulated 36Cl- efflux rates only in medium and large cholangiocytes, consistent with selective functional expression of CFTR in these subpopulations. These results support the molecular and functional heterogeneity of cholangiocytes within the intrahepatic biliary ductal system and are consistent with the notion that hormone-regulated transport of solutes after BDL occurs principally in medium and large cholangiocytes in a fashion similar to that observed in normal rat liver.

Smooth pursuit in 1- to 4-month-old human infants.

The ability of human infants < or = 4 months of age to pursue objects smoothly with their eyes was assessed by presenting small target spots moving with hold-ramp-hold trajectories at ramp velocities of 4-32 deg/sec. Infants as young as 1 month old followed such target motions with a combination of smooth-pursuit and saccadic eye movements interrupted occasionally by periods when the eyes remained stationary. The slowest targets produced variable performance, but targets moving 8-32 deg/sec produced consistent pursuit behavior, even in the youngest infants. By the fourth month, eye-movement latency decreased and smooth-pursuit gain and the percentage of smooth pursuit per trial increased for all target velocities, though these measures had not yet reached adult levels.

A prospective study of simplified omeprazole suspension for the prophylaxis of stress-related mucosal damage.

OBJECTIVES: To determine the efficacy, safety, and cost of simplified omeprazole suspension in mechanically ventilated critically ill patients who have at least one additional risk factor for stress-related mucosal damage. DESIGN: Prospective, open-label study. SETTING: Surgical intensive care and burn unit at a university tertiary care center. PATIENTS: Seventy-five adult, mechanically ventilated patients with at least one additional risk factor for stress-related mucosal damage. INTERVENTIONS: Patients received 20 mL of simplified omeprazole suspension (containing 40 mg of omeprazole) initially, followed by a second 20-mL dose 6 to 8 hrs later, then 10 mL (20 mg) daily. Simplified omeprazole suspension was administered through a nasogastric tube, followed by 5 to 10 mL of tap water. The nasogastric tube was clamped for 1 to 2 hrs after each administration. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was clinically significant gastrointestinal bleeding determined by endoscopic evaluation, nasogastric aspirate examination, or heme-positive coffee ground material that did not clear with lavage, which was associated with at least a 5% decrease in hematocrit. Secondary efficacy measures were gastric pH measured 4 hrs after omeprazole was first administered, mean gastric pH after omeprazole was started, and the lowest gastric pH during omeprazole therapy. Safety-related outcomes included the occurrence rate of adverse events and pneumonia. No patient experienced clinically significant upper gastrointestinal bleeding after receiving omeprazole suspension. The 4-hr postomeprazole mean gastric pH was 7.1, the mean gastric pH after starting omeprazole was 6.8, and the mean lowest pH after starting omeprazole was 5.6. The occurrence rate of pneumonia was 12%. No patient in this high-risk population experienced an adverse event or a drug interaction that was attributable to omeprazole. CONCLUSIONS: Simplified omeprazole suspension prevented clinically significant upper gastrointestinal bleeding and maintained gastric pH of > 5.5 in mechanically ventilated critical care patients without producing toxicity.

In vivo gene transfer to the human biliary tract.

The human biliary tract offers an excellent model for gene transfer studies for a variety of diseases localized to the liver. The aim of this study was to determine if a viable liver might be employed to study viral transfection of the human biliary system in order to mimic in vivo human experiments. Using a normal human liver initially procured for transplantation, but subsequently found unsuitable, and with an intact biliary tree, the hepatic vascular supply was accessed for continuous perfusion. The common and left hepatic biliary system was isolated by balloon catheterization. A replication defective adenoviral vector containing the Escherichia coli beta-galactosidase (lac Z) reporter gene (AdCMVLacZ) was injected into the catheter-isolated left and common bile duct lumen. Viral exposure to the right duct system was prevented by ligation. The bile duct segments were excised and prepared for enzymatic (X-gal) staining. Intense staining was observed in the biliary epithelium exposed to the adenoviral vector. No evidence of beta-galactosidase staining was noted in the unexposed biliary mucosa. We report direct transfection of biliary epithelial cells from normal human liver with a recombinant adenovirus. Our data suggest potential therapeutic applications for gene therapy of hepatobiliary disorders.