Evaluating anti-tumor activity of palbociclib plus radiation in anaplastic and radiation-induced meningiomas: pre-clinical investigations.

PURPOSE: Meningiomas are common brain tumors, the majority of which are considered benign. Despite surgery and/or radiation therapy, recurrence rates are approximately 8-10%. One likely cause is the dysregulation of cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, which controls the cell cycle restriction point. This pathway is commonly dysregulated in anaplastic meningioma cell lines (AM) and radiation-induced meningioma cells (RIM), making it a rational target for anti-meningioma therapy. In this study, we investigate the effect of a CDK4/6 inhibitor, palbociclib, with radiation in relevant pre-clinical models. METHODS: In vitro cell culture, ex vivo slice culture and in vivo cell line-derived orthotopic xenograft animal models of AM/RIM were utilized to assess treatment efficacy with palbociclib plus radiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression. RESULTS: The in vitro and ex vivo studies demonstrate that palbociclib plus radiation treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G (1) arrest in Rb+ AM and RIM cells, but not in Rb- cells. Our results also demonstrated reduced CDK4 and CDK6 expression as well as reduced E2F target gene expression (CCNA2 and CCNE2) with the combination therapy. MRI results in vivo demonstrated reduced tumor size at 5 weeks when treated with 14 days palbociclib (10 mg/kg) plus 6 Gy radiation compared to saline-treated tumors. Finally, no hepatic toxicity was found after treatments. CONCLUSION: A pre-clinical murine model provides preclinical evidence for use of palbociclib plus radiation as a therapeutic agent for Rb+ meningiomas.

Superconductivity and the quantization of energy.

Ideas about quantized energy levels originated in atomic physics, but research in superconductivity has led to unparalleled precision in the measurement of energy levels. A comparison of levels produced by two Josephson junctions shows that they differ by no more than 3 parts in 10(19) at an energy of 0.0003 electron volt. The fact that the myriad of interactions of 10(12) particles in a macroscopic body, a Josephson junction, can produce sharply defined energy levels suggests a dynamical state effectively divorced from the complexities of its environment. The existence of this state, the macroscopic quantum state of superconductors, is well established, but its isolation from intrinsic perturbations has recently been shown to be extraordinary. These new results, with an improved precision of about ten orders of magnitude, are discussed in the context of highly accurate results from quantum electrodynamics, atomic spectroscopy, and the standards of metrology. Further refinements in precision may be achievable at higher energy levels, about 12 electron volts, as they become available from a new series array of 18,992 Josephson junctions.

The relationships among sprint performance, voluntary swimming activity, and social dominance in juvenile rainbow trout.

The specific objectives of this study were to determine whether sprint performance in juvenile rainbow trout is correlated with either voluntary swimming activity or aggressive behaviors and to determine the reciprocal: the effect of swimming activity and aggression on sprint performance. Sprint performance was assessed by rapidly accelerating trout (5-7-cm fork length) to a fixed velocity (40, 42, or 45 cm s(-1)) and then holding them at that velocity until fatigue. There was considerable interindividual variation in sprint performance not explained by variations in body size, but intraindividual performance was highly repeatable over at least 2 mo. Voluntary swimming was measured as the frequency of transits (voluntary transit activity, VTA) between two identical tanks via a connecting channel with two different flow regimes: zero or minimum velocity (0 or 2.5 cm s(-1)) and high velocity (84 cm s(-1)). There was a strong correlation between sprint performance and VTA in minimal current but no correlation in high current. Furthermore, sprint performance did not predict the outcome of dominance encounters. Experience with rapid acceleration, especially when voluntary, led to a pronounced improvement in sprint performance in proportion to the number of acceleration events. Social dominance encounters had a more complex effect: a significant reduction in sprint performance in previously high-performance sprinters and the reverse for low performers. We propose that there are four independent axes of interindividual variation in juvenile rainbow trout: spontaneous and rheotaxis-stimulated locomotor activity, aggressive activity, and the trainability of sprint performance. The independence of these axes has the potential to produce a much larger diversity in behavioral and ultimately physiological phenotypes than would be produced if the axes were linked.

The recovery of locomotory activity following exhaustive exercise in juvenile rainbow trout (Oncorhynchus mykiss).

This study investigated the recovery of locomotory activity in exhausted juvenile rainbow trout (Oncorhynchus mykiss, approximately 6-10-cm fork length) in response to two conditions: (1) direct transfer to a range of velocities (0-15 cm s(-1)) in a swim flume (forced swimming) and (2) direct transfer to a pool downstream of a swim channel where a choice of velocities was presented: 2-3 cm s(-1) in the lower half of the pool, a range of velocities from 7 to 40 cm s(-1) in the upper half the pool near the channel entrance, and a velocity of 57 cm s(-1) in a swim channel emptying into the pool (volitional swimming). Exhausted trout showed a pronounced delay in the recovery of normal locomotory activity. With forced swimming, the time required to resume swimming was inversely proportional to water velocity. At 15 cm s(-1), almost all exhausted fish recovered immediately, whereas it took about 1 h for recovery at a current of 5 cm s(-1). In contrast, nonexhausted fish responded to imposed velocity with immediate rheotactic responses (orientation and station holding) at all test velocities. In voluntary swim trials, exhausted trout showed a marked preference for holding station in current in the downstream pool (approximately 11 cm s(-1)) but took, on average, 2 h longer than nonexhausted fish to make transits in the swim channel. Moreover, their ground speed in the swim channel was significantly slower. We conclude that swimming performance is impaired for at least 6 h by exhaustive exercise. Maladaptive behaviors during this time include a preference for current near the surface over cover and a reduced capacity for burst activity, both of which would translate into greater predation risk and reduced ability to forage.

The use of lamotrigine, vigabatrin and gabapentin as add-on therapy in intractable epilepsy of childhood.

PURPOSE: Lamotrigine (LTG), vigabatrin (VGB) and gabapentin (GBP) are three anti-epileptic drugs (AEDs) used in the treatment of children with epilepsy for which long-term retention rates are not currently well known. This study examines the efficacy, long-term survival and adverse event profile of these three agents used as add-on therapy in children with refractory epilepsy over a 10-year period. METHODS: Three separate audits were conducted between February 1996 and September 2000. All children studied had epilepsy refractory to other AEDs. Efficacy was confirmed if a patient became seizure free or achieved >50% reduction in seizure frequency for 6 months or more after starting therapy. Adverse events and patient survival for each drug were recorded at the end of the study period. RESULTS: Between September 1990 and February 1996, 132 children received LTG, 80 VGB and 39 GBP. At the 10-year follow-up audit, 33% of the children on LTG had a sustained beneficial effect on their seizure frequency in contrast to 19% for VGB and 15% for GBP. No significant difference in efficacy was found in children with partial seizures. Children with epileptic encephalopathy (EE) including myoclonic-astatic epilepsy and Lennox-Gastaut Syndrome (LGS) achieved a more favorable response to LTG. The main reasons for drug withdrawal were lack of efficacy for VGB, apparent worsening of seizures for GBP and the development of a rash for LTG. CONCLUSIONS: Lamotrigine is a useful add-on therapy in treating children with epilepsy. It has a low adverse event profile and a sustained beneficial effect in children with intractable epilepsy.

Familial childhood onset neuropathy and cirrhosis with the 4977bp mitochondrial DNA deletion.

The common 4977 base pair mitochondrial deletion has been identified in association with a number of distinct clinical phenotypes. These include the Kearns-Sayre syndrome, the Pearson marrow-pancreas syndrome, and chronic progressive external ophthalmoplegia. We report the clinical and pathological findings in two siblings in whom the 4977 base pair mitochondrial DNA deletion was identified in muscle-derived mitochondrial DNA. One sibling manifested early onset liver and renal failure, and both developed prominent peripheral sensorimotor neuropathy. These clinical findings have not been previously described in association with the 4977bp mtDNA deletion and thus represent a further expansion of the spectrum of mitochondrial disease.

Mitral valve prolapse in rheumatic mitral stenosis.

Four adult women with histories of rheumatic fever and clinical findings of mitral stenosis and regurgitation had echocardiograms demonstrating moderately severe mitral stenosis (EF slope less than 20 mm/sec, mean left atrial size 3.0 cm/m2, mean anterior mitral leaflet excursion 25 mm) as well as typical mitral valve prolapse. Three patients underwent cardiac catheterization which confirmed the presence of mitral stenosis, as well as systolic prolapse and excessive scalloping of the mitral valve with no visible mitral calcium and no coronary artery disease. One patient had associated mild aortic stenosis and regurgitation. Two patients underwent mitral valve surgery which revealed anterior and posterior commissural fusion consistent with rheumatic disease and intact chordal apparatus. Both leaflets were large and the anterior leaflets were redundant. There were no vegetations. Pathology revealed myxomatous degeneration of the valve leaflets. In the absence of heavy calcification and thickening, the presence of mitral stenosis with commisural fusion does not exclude the possibility of a redundant mitral valve. When these entities coexist, systolic clicks may be absent.

Ultrasound in diagnosis and evaluation of lymphoceles after renal transplantation.

Three cases of lymphoceles after renal transplantation are described. The value of ultrasound is stressed in making the diagnosis, totally delineating the size, following the progression, evaluating the transplanted kidney for secondary hydronephrosis, and localizing the lymphocele for aspiration. Ultrasound is, therefore, believed to be a valuable diagnostic study in the evaluation of patients with a transplanted kidney with an unexplained reduction in renal function, leg edema, or a suspicion of a pelvic mass.

Focal upper limb neuropathy in a child.

A 9-year-old girl presented with a 4-week history of right upper limb weakness. Clinical assessment and neurophysiological studies suggested an atypical brachial plexitis. She re-presented 3 1/2 years later with progressive muscle weakness involving both legs and left arm and hand. There had been no interval improvement in her right upper limb. Clinical, neurophysiological and pathological findings were consistent with chronic inflammatory demyelinating polyneuropathy. She responded to a single course of intravenous immunoglobulin--and review more than 6 years after treatment confirms that she remains functionally normal. Focal upper limb neuropathy preceding a diffuse demyelinating process by several years has not been previously described in a child. Long-term follow-up of this patient allows us to comment on the natural history of her condition and the apparent long-term efficacy of intravenous immunoglobulin in this case.

Endoscopic retrograde cholangiopancreatography and gray-scale abdominal ultrasound in the diagnosis of jaundice.

Fifty-five patients with suspected obstructive jaundice were studied with both ERCP and abdominal ultrasound. Biliary tract obstruction was documented in 49 patients and parenchymal liver disease in 7. A definite cause of jaundice was demonstrated by ERCP in 45 of 49 patients with biliary tract obstruction but in only 28 of 49 patients by ultrasound. Bile duct dilatation, where present, was detected by ERCP in only 33 of 42 patients. ERCP was particularly effective in patients with common duct stones; common duct calculi and a dilated common duct were detected in 15 of 16 such patients. Dilated bile ducts where present were detected by ultrasound in 22 of 42 patients. Ultrasound was particularly helpful in patients with pancreatic cancer in whom a dilated common duct could not be opacified during ERCP. ERCP and abdominal ultrasound together provide a rapid and safe method of diagnosis in the jaundiced patient with suspected bile duct obstruction.

Classical conditioning of autonomic responses in alert and drowsy subjects.

The primary purpose of this experiment was to study classically conditioned autonomic responses of alert versus drowsy subjects. Sixty-nine subjects in conditioning and pseudo-conditioning groups were subdivided into alert and drowsy groups on the basis of EEG recordings during conditioning trials, giving a total of four groups: conditioning-alert, conditioning-drowsy, pseudoconditioning-alert and pseudoconditioning-drowsy. Using the latency criterion to define responses, significant conditioning occurred only in the conditioning-alert group for the following measures: skin resistance anticipatory and UCS-omission responses, and finger plethysmograph anticipatory response. Both conditioning groups showed evidence of conditioned UCS-omission plethysmograph responses. Discussion centered primarily on (1) the implications of the results on the question of the feasibility of learning during sleep; and (2) the importance of including EEG recordings in studies of classically conditioned autonomic responses. The relationship between the various responses was also evaluated.

Effects of long term sublethal Cd exposure in rainbow trout during soft water exposure: implications for biotic ligand modelling.

The objectives of the study were to determine the physiological and toxicological effects of chronic cadmium exposure on juvenile rainbow trout in soft water. Particular attention focused on acclimation, on comparison to an earlier hard water study, and on whether a gill surface binding model, originally developed in dilute soft water, could be applied in this water quality to fish chronically exposed to Cd. Juvenile rainbow trout, on 3% of body weight daily ration, were exposed to 0 (control), 0.07, and 0.11 microg l(-1) Cd [as Cd(NO(3))(2).4H(2)O] in synthetic soft water (hardness=20 mg l(-1) as CaCO(3), alkalinity=15 mg l(-1) as CaCO(3), pH 7.2) for 30 days. Mortality was minimal for all treatments (up to 14% for 0.11 microg l(-1) Cd). No significant effects of chronic Cd exposure were seen in growth rate, swimming performance (stamina), routine O(2) consumption, or whole body/plasma ion levels. In contrast to the hard water study, no acclimation occurred in either exposure group in soft water, with no significant increases in 96-h LC(50) values. Cadmium accumulated in a time-dependent fashion to twice the control levels in the gills and only marginally in the liver by 30 days. No significant Cd accumulation occurred in the gall bladder or whole body. Cadmium uptake/turnover tests were run using radioactive 109Cd for acute (3 h) exposures. Saturation of the gills occurred for control fish but not for Cd-exposed fish when exposed to up to 36 microg l(-1) Cd for 3 h. Cd-exposed trout accumulated less 'new' Cd in their gills compared to controls and they internalized less 109Cd than control fish. This effect of lowered Cd uptake by the gills of acclimated trout was earlier seen for the fish acclimated to 10 microg l(-1) Cd in hard water. The affinity of the gill for Cd was greater in hard water (logK(Cd-gill)=7.6) than in soft water (logK(Cd-gill)=7.3) but the number of binding sites (B(max)=0.20 microg g(-1) gill) was similar in both media. In addition, there was a shift in affinity of the gill for Cd (i.e. lowered logK(Cd-gill)) and increased B(max) with chronic Cd exposure in both soft water and hard water. We conclude that the present gill modelling approach (i.e. acute gill surface binding model or Biotic Ligand Model) does work for soft and hard water exposures but there are complications when applying the model to fish chronically exposed to cadmium.

Plasma clearance of cadmium and zinc in non-acclimated and metal-acclimated trout.

Adult rainbow trout were pre-exposed to a sublethal concentration of waterborne cadmium (Cd, 26.7 nmol/l) or waterborne zinc (Zn, 2294 nmol/l) for 30 days to induce acclimation. A single dose of radiolabeled Cd (64.4 nmol/kg) or Zn (183.8 nmol/kg) was injected into the vascular system of non-acclimated and Cd- or Zn-acclimated trout through indwelling arterial catheters. Subsequently, repetitive blood samples over 10 h and terminal tissue samples (liver, heart, bile, stomach, intestine, kidney, gills, muscle, and spleen) were taken to characterize the effect of metal acclimation on clearance kinetics in vivo. Plasma clearance of Cd in Cd-acclimated fish (0.726+/-0.015 and 0.477+/-0.012 ml/min per kg for total and newly accumulated Cd, respectively), was faster than that in non-acclimated trout (0.493+/-0.013 and 0.394+/-0.009 ml/min per kg). Unlike plasma Cd, the levels of Cd in red blood cells (RBCs) were 1.2-2.2 times higher in Cd-acclimated fish than in non-acclimated fish. At 10 h post-injection, the liver accumulated the highest proportion ( approximately 22%) of the injected Cd dose in both non-acclimated and Cd-acclimated fish but did not account for the difference in plasma levels of Cd between two groups. Plasma clearance of Zn ( approximately 0.23 ml/min per kg for new Zn) was substantially lower than Cd clearance. Pre-acclimation to waterborne Zn reduced the new Zn levels in RBCs, but did not affect the clearance of Zn from blood plasma or tissue burdens of Zn in fish. Bile concentrations of both Cd and Zn were elevated in acclimated fish, but total bile burden accounted for <1% of the injected metal dose. The results suggest that the detoxification process of injected plasma Cd is stimulated by pre-acclimation to waterborne Cd, and that Zn levels are homeostatically controlled in both non-acclimated and acclimated trout.

Gastrointestinal uptake and fate of cadmium in rainbow trout acclimated to sublethal dietary cadmium.

Adult rainbow trout were pre-exposed to a sublethal concentration of dietary Cd (500 mg/kg dry wt.) for 30 days to induce acclimation. A gastrointestinal dose of radiolabeled Cd (276 microg/kg wet wt.) was infused into the stomach of non-acclimated and Cd-acclimated trout through a stomach catheter. Repetitive blood samples over 24 h and terminal tissue samples were taken to investigate the gastrointestinal uptake, plasma clearance kinetics, and tissue distribution of Cd. Only a small fraction of the infused dose (non-acclimated: 2.4%; Cd-acclimated: 6.6%) was internalized across the gut wall, while most was bound in the gut tissues (10-24%) or remained in the lumen (16-33%) or lost from the fish (approximately 50%) over 24 h. Cadmium loading during pre-exposure produced a profound increase of total Cd in the blood plasma (approximately 28-fold) and red blood cells (RBC; approximately 20-fold). The plasma Cd-time profiles consisted of an apparent rising (uptake) phase and a declining (clearance) phase with a maximum value of uptake in 4 h, suggesting that uptake of gastrointestinally infused Cd was very rapid. Acclimation to dietary Cd did not affect plasma Cd clearance (approximately 0.5 ml/min), but enhanced new Cd levels in the plasma (but not in the RBC), and resulted in a longer half-life for plasma Cd. Tissue total and new Cd levels varied in different regions of the gastrointestinal tract, and overall levels in gut tissues were much greater than in non-gut tissues, reflecting the Cd exposure route. Dietary Cd, but not the infused Cd, greatly increased total Cd levels of all gut tissues in the order posterior-intestine (640-fold) > cecae (180-fold) > mid-intestine (94-fold) > stomach (53-fold) in Cd-acclimated fish relative to naïve fish. Among non-gut tissues in the Cd-acclimated fish, the great increases of total Cd levels were observed in the liver (73-fold), kidney (39-fold), carcass (35-fold), and gills (30-fold). The results provide some clear conclusions that may be useful for environmental risk assessment of dietary Cd exposure in fish.

The effects of trace metal exposure on agonistic encounters in juvenile rainbow trout, Oncorhynchus mykiss.

The effects of five trace metals, copper, cadmium, nickel, zinc and lead (presented as soluble salts) on the ability of juvenile rainbow trout to form social relationships were investigated. Comparable concentrations of the five metals in relation to their acute 96 h LC50s (concentration at which population mortality=50% at 96 h) were used (i.e. 15% of the 96 h LC50) and water quality parameters (hardness=120 mg l(-1) as CaCO(3), pH 8; DOC=3 mg l(-1)) were kept constant throughout. In the first experiment, trout exposed to sublethal concentrations of cadmium for 24 h displayed significantly lower numbers of aggressive attacks during pair-wise agonistic encounters than fish paired in the copper, nickel, zinc, lead and control water. In a second experiment, fish were exposed to the same concentration of metal for 24 h, and then returned to normal water for 24 h. When these metal pre-exposed fish were paired with non-exposed fish only cadmium pre-exposure had a significant effect on social interaction. All of the cadmium pre-exposed fish became subordinate when paired with non-exposed fish, whereas the probability of a fish pre-exposed to copper, nickel, zinc or lead becoming subordinate did not significantly differ from random. Therefore, at around 15% of the 96 h LC50, different metals exert different effects on the social behaviour of fish, suggesting potential implications for social structure and population stability.

Relating intramuscular fuel use to endurance in juvenile rainbow trout.

This study examined fuel depletion in white muscle of juvenile rainbow trout sprinted to fatigue to determine whether the onset of fatigue is associated with a measurable metabolic change within the muscle and whether muscle glycogen levels influence endurance. In this study, "fuels" refer to any energy-supplying compounds and include glycogen, phosphocreatine (PCr), and ATP. Fuel depletion in white muscle was estimated by the calculation of the anaerobic energy expenditure (AEE; in micromol ATP equivalents g(-1)) from the reduction of PCr and ATP and the accumulation of lactate. Progression of fuel use during sprinting was examined by sampling fish before they showed signs of fatigue and following fatigue. Most of the AEE before fatigue was due to PCr depletion. However, at the first signs of fatigue, there was a 32% drop in ATP. Similarly, when fish were slowly accelerated to a fatiguing velocity, the only significant change at fatigue was a 30% drop in ATP levels. Muscle glycogen levels were manipulated by altering ration (1% vs. 4% body weight ration per day) combined with either daily or no exercise. Higher ration alone led to significantly greater muscle glycogen but had no effect on sprint performance, whereas sprint training led to higher glycogen and an average threefold improvement in sprint performance. In contrast, periodic chasing produced a similar increase in glycogen but had no effect on sprint performance. Taken together, these observations suggest that (i) a reduction in ATP in white muscle could act as a proximate signal for fatigue during prolonged exercise in fish and (ii) availability of muscle glycogen does not limit endurance.

Effect of air breathing on acid-base and ion regulation after exhaustive exercise and during low pH exposure in the bowfin, Amia calva.

To explore a potential conflict between air breathing and acid-base regulation in the bowfin (Amia calva), we examined how individuals with access to air differed from fish without air access in their response to acidosis. After exhaustive exercise, bowfin with access to air recovered significantly more slowly from the acidosis than fish without air access. While arterial blood pH (pH(a)) of fish without air access recovered to resting levels by 8 h, pH(a) was still significantly depressed in fish having access to air. In addition, Pco(2) was slightly more elevated in fish having air access than those without it. Fish with access to air still had a significant metabolic acid load after 8-h recovery, while those without air access completely cleared the load within 4 h. These results suggest that bowfin with access to air were breathing air and, consequently, were less able to excrete CO(2) and H(+) and experienced a delayed recovery. In contrast, during exposure to low pH, air breathing seemed to have a protective effect on acid-base status in bowfin. During exposure to low pH water, bowfin with access to air developed a much milder acidosis than bowfin without air access. The more severe acidosis in fish without air access was caused by an increased rate of lactic acid production. It appears that enhanced O(2) delivery allowed air-breathing bowfin to avoid acidosis-induced anaerobic metabolism and lactic acid production. In addition, during low pH exposure, plasma Na(+) and Cl(-) concentrations of fish without air access fell slightly more rapidly than those in fish with air access, indicating that the branchial ventilatory changes associated with air breathing limited, to some degree, ion losses associated with low pH exposure.

The further development of ionoregulatory measures as biomarkers of sensitivity and effect in fish species.

Extensive season-by-season sampling was used to establish the normal range of whole-body Na+ and Cl- and Na+ uptake in healthy populations of two fish species, rainbow trout, Oncorhynchus mykiss, and fathead minnow, Pimephales promelas, of known differences in sensitivity to ionoregulatory toxicants (low pH, trace metals). These data together with responses of both species to six different ionoregulatory challenge tests of increasing severity (mild handling, exposure to low Ca2+ water, epinephrine injection, net-confinement stress, exposure to copper, and osmotic shock) were evaluated for their potential as biomarkers of sensitivity and of effect of ionoregulatory toxicants. There were no obvious biomarkers of sensitivity in the ion measures themselves, but four of the six challenges (exposure to low Ca2+ water, epinephrine injection, exposure to copper, and osmotic shock) produced a significantly greater effect in the more sensitive of the two species, fathead minnow. Based on the responses of both species, this article makes a number of recommendations for the application of ion measures alone and in combination with challenge tests to the assessment of chronic effects in populations experiencing sublethal ionoregulatory stress.

Effects of chronic Cd exposure via the diet or water on internal organ-specific distribution and subsequent gill Cd uptake kinetics in juvenile rainbow trout (Oncorhynchus mykiss).

New regulatory approaches to metal toxicity (e.g., biotic ligand model [BLM]) focus on gill metal binding and tissue-specific accumulation of waterborne metals; the dietary route of exposure and dietary/waterborne interactions are not considered, nor are the consequences of chronic exposure by either route. Therefore, we studied the effect of the same gill Cd load (approximately 2.5 microg/g), achieved by a chronic, 30-d exposure to Cd either via the diet (1,500 mg/kg) or the water (2 microg/L), on tissue-specific Cd distribution and subsequent uptake of waterborne Cd in juvenile rainbow trout (Oncorhynchus mykiss). These two exposure regimes resulted in a branchial Cd load that had been taken up across either apical gill membranes (waterborne Cd) or basolateral gill membranes (through the bloodstream for dietary Cd). The BLM characteristics of the gills (i.e., short-term Cd uptake kinetics) were altered: affinity (log K(Cd Gill) [95% confidence level]) decreased from 7.05 (6.75-8.76) for control to 6.54 (6.32-7.03) for waterborne Cd and 5.92 (5.83-6.51) for dietary Cd, whereas binding capacity (Bmax) increased from 3.12 (2.14-4.09) to 4.80 (3.16-6.43) and 5.50 (2.86-8.17) nmol x g(-1) for control, waterborne, and dietary Cd, respectively. Fish exposed to dietary Cd accumulated a much greater overall chronic Cd body burden relative to fish exposed to waterborne Cd or control fish. The carcass accumulated the greatest percentage of total body Cd in control and waterborne-exposed fish, whereas the intestinal tissue accumulated the greatest percentage in dietary-exposed fish. Tissue-specific Cd burdens were highest in the kidney in both dietary and waterborne treatments. We conclude that chronic Cd exposure alters Cd uptake dynamics, and that the route of Cd exposure, whether waterborne or dietary, results in differences of internal Cd accumulation and branchial Cd uptake characteristics. These factors should be considered in future BLM development.